Download 2013 ADA Posters 1339-2294.indd

EPIDEMIOLOGY—AGING
CATEGORY
EPIDEMIOLOGY—AGING
1397-P
Age of Diagnosis of Type 2 Diabetes Is More Than 9 years Younger in
Asian-British Compared With the Rest of the UK Population
1395-P
ANDREW J. HARTLAND, JANE DEVILLE-ALMOND, MATTHEW T. ORTON, VICKIE
HARTLAND, Walsall, United Kingdom, Liverpool, United Kingdom
Does Functional Decline in Older Adults Hasten the Onset of Diabetes? The Health and Retirement Study 1998-2010
Walsall, UK (population approx 175 000) has the second highest
prevalence of type 2 diabetes in England and Wales. Observational evidence
suggests the age of diagnosis is reducing. This study’s aim was to establish
the age distribution at time of diagnosis and quantify the effect of increased
pre-disposition for the development of type 2 diabetes amongst AsianBritish. In Walsall, the oral glucose tolerance test (OGTT) remains the main
diagnostic test for diabetes. All samples are analyzed at a single Hospital
Blood Sciences laboratory. An audit of OGTT requests (excluding ante-natal
requests) against the laboratory identification code for OGGT identified 22
735 OGTTs (the majority requested within a 12 month period up to April 2012)
of which 3702 were positive, using WHO diagnostic criteria (1929 males,
1773 females) For the total population, mean age at diagnosis = 59.8 years
(male), 61.5 years (female). For males: 14.5% were < 45 years and 21.4% < 50
years. Females 14.6% < 45 years and 20.3% < 50 years.
Asian-British were identified by demographic information provided. When
compared with the rest of the population:
BARBARA H. BARDENHEIER, EDWARD GREGG, XIAOHUI ZHUO, YILING J.
CHENG, LINDA GEISS, Atlanta, GA
Prospective studies have associated diabetes with a high risk of incident
disability among older adults. However, the converse association could also
occur, with functional decline hastening the onset of diabetes, particularly
in those at high risk. 13,134 adults aged over 50 years who entered the
longitudinal Health and Retirement Study between 1992 and 2006 with
no disability or diabetes were followed to 2010 to determine if those who
became disabled would subsequently develop diabetes. Mobility disability
was assessed by self-reported difficulty walking one block; walking several
blocks; climbing one flight of stairs; stooping, crouching, or kneeling; and
pushing or pulling a large object. Participants were classified by disability:
none, mild (difficulty with stooping and walking several blocks or difficulty
with > 2 mobility measures other than climbing), moderate (difficulty with
climbing or difficulty with > 3 mobility measures), and severe (difficulty
with > 4 mobility measures). 1,955 (14.9%) participants developed diabetes,
8,228 (62.6%) reported incident disability, and 2,482 (18.9%) died by 2010.
Among those who did not develop disability, diabetes incidence was 8.67
per 1,000; among those who developed disability and remained disabled at
least 50% of the reporting period, diabetes incidence was 13.5 per 1,000.
In a generalized estimating equation controlling for body mass index, age,
sex, race/ethnicity, net wealth, and year of report, we found a statistically
significant dose-response relationship between incident disability and later
incident diabetes: severe vs. none (OR: 2.18, 95%CI: 1.82, 2.61); moderate
vs. none (OR: 1.50, 95%CI: 1.25, 1.80); mild vs. none (OR: 1.40, 95%CI: 1.26,
1.56). We found those who become mildly disabled are at increased risk of
developing diabetes within a few years. These findings raise the question
of whether approaches to delay functional decline, an almost ubiquitous
aspect of aging, may reduce the risk of diabetes.
1396-P
Genome-Wide Association Study and Linkage Scan Identify Novel
Loci Influencing Circulating Glycated Hemoglobin (HbA1c) Levels in
Nondiabetics: The Long Life Family Study (LLFS)
1398-P
Mother’s Age in Relation to the Haptoglobin Genotype of the Offspring With Type 1 Diabetes
PING AN, IVA MILJKOVIC, BHARAT THYAGARAJAN, ALDI KRAJA, WARWICK
DAW, JAMES S. PANKOW, ELIZABETH SELVIN, LINDA KAO, NISA M. MARUTHUR, MICHAEL A. NALLS, YONGMEI LIU, TAMARA HARRIS, JOSEPH LEE,
INGRID B. BORECKI, KAARE CHRISTENSEN, JOHN H. ECKFELDT, RICHARD MAYEUX, THOMAS T. PERLS, ANNE NEWMAN, MICHAEL A. PROVINCE, St. Louis, MO,
Pittsburgh, PA, Minneapolis, MN, Baltimore, MD, Bethesda, MD, Winston-Salem,
NC, New York, NY, Odense, Denmark, Boston, MA
JESSICA NAN, TREVOR J. ORCHARD, TINA COSTACOU, Pittsburgh, PA
Maternal age may influence intrauterine selection and favor specific
genotypes compared to others. Recent studies suggested that mother’s age
may relate to the haptoglobin (Hp) genotype (Hp 1-1, Hp 1-2, or Hp 2-2) of
the offspring with type 1 diabetes (T1D), such that the likelihood of the T1D
offspring carrying at least one Hp 2 allele increases with mother’s age. As
the Hp 2-2 genotype has further been shown to increase the risk of both
cardiovascular disease and kidney function decline in diabetes, evaluating
the presence of an association between mother’s age and Hp in T1D is
important. We evaluated the hypothesis that maternal age at birth was
greater among individuals with T1D and the Hp 2 compared to Hp 1 allele
among participants of the Epidemiology of Diabetes Complications study, a
prospective study of childhood onset T1D (baseline mean age 28 and duration
19 years). Data on mother’s age and Hp genotype were available for 350
participants. The distribution of the Hp genotype was 12.9% Hp 1-1, 44.9%
Hp 2-1, and 42.3% Hp 2-2. Mother’s age was grouped according to previously
published categories (≤22 years, 23-36 years, and >36 years). Results are
presented in Table 1. Despite a slight suggestion of a trend toward a greater
proportion of individuals with Hp 1-1 in the youngest and a lower proportion
in the oldest group of mothers, these data do not provide strong evidence for
an association between mother’s age and the Hp genotype of the offspring
with T1D.
Glycated hemoglobin (HbA1c) is a stable index of chronic glycemic status
and hyperglycemia associated with progressive development of insulin
resistance and frank diabetes. HbA1c is also a glycemic marker that is
associated with premature aging and increased mortality. To uncover
additional loci influential on circulating HbA1c levels, we conducted a
GWAS and linkage scan in 4,088 nondiabetic participants with European
ancestry from the Long Life Family Study (LLFS). A total of 11618 nondiabetic
participants from 3 other independent cohorts (ARIC Study, Health ABC
Study, FamHS) were used to verify the discoveries. HbA1c was adjusted for
age, field centers, 20 PCs, w/o BMI, within sex, prior to genetic assessment in
the LLFS. Linear mixed effects model assuming additive genetic fixed effects
was used for association testing with a kinship model to correct for random
effects of familial relationship. Linkage scan was built on haplotypes-based
IBD estimation with 0.5 cM average spacing. From GWAS, two known loci
at GCK-YKT6 and HK1 were confirmed; two best novel loci were found near
OR10R3P and GMPR that were only suggestive. From the linkage scan, two
significant linkages (2p22.2 and 2q31.3 with highest LOD of 3.9) and two
promising linkages (1q42.2, LOD = 2.30; 7q11.23, LOD = 1.85) were found;
all four linkage regions were novel for HbA1c. Our best prioritized common
variants under the two significant linkage peaks were identified at/near
LOC100130842, QPCT, NEUROD1 and NAB1 (p = 3.6×10-5 to 9.4×10-4) but
they were in general nonreplicable in this analysis. Together, our integrative
association and linkage approach allowed reconfirmation of two loci at GCKYKT6 and HK1 and identification of two novel linkage regions on 2p22.2 and
2q31.3 that influence circulating HbA1c levels. Future linkage-guided surveys
of sequence variants including rare functional and regulatory variants may
yield additional findings.
Supported by: NIA
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A365
POSTERS
In conclusion, more than 1 in 4 diagnoses of type 2 diabetes in AsianBritish is made at age < 45 years and more than 1 in 3 < 50 years The mean
age of diagnosis is more than 9 years younger in Asian-British compared to
the rest of the population. The UK National Institute for Health and Clinical
Excellence in July 2012 published guidelines for the prevention of type 2
diabetes. This study identifies the need for these strategies to be effectively
targeted and clinically effective amongst the Asian-British community.
Epidemiology/
Genetics
Asian-British v Non-Asian-British
• Males: mean age of diagnosis 52.9 years v 62.3 years (p<0.01)
• % diagnosed< 45 years: 25.6% v 9.2 5% (p<0.001)
• % diagnosed < 50 years: 38.4 % v 15.2% (p<0.001)
• Females: mean age of diagnosis: 54.5 years v 63.9 years (p<0.01)
• % diagnosed < 45 years:: 25.7% v 8.7% (p<0.001)
• % diagnosed < 50 years: 35.3% v 15.4% (p<0.001)
EPIDEMIOLOGY—CARDIOVASCULAR DISEASE
all-cause death) or end of study. The risk of the composite outcome was
compared between the 2 treatment regimens using marginal structural
Cox proportional hazard models adjusting for baseline and time-varying
demographics, medications, cholesterol, HbA1c, creatinine, blood pressure,
BMI, and co-morbidities.
Among 199,933 metformin monotherapy users, most patients (N=117,466
[59%]) never added a second drug (mean 43 months of follow-up). There were
1316 and 28274 patients who added insulin or sulfonylureas, respectively.
Patients were 95% male and insulin initiators were younger (59 versus 61 years),
added treatment earlier (time to add-on therapy 17 versus 22 months) and had
higher average baseline HbA1c, (8.5% versus 7.7%) compared with patients
who added a sulfonylurea. The CVD or death composite outcome rate was 37.0
versus 19.3 events per 1000 person-years, among insulin versus sulfonylureas
initiators respectively (adjusted hazard ratio [aHR] 1.29, 95% CI 0.85, 1.96).
CVD event rates were 6.3 and 7.1 per 1000 person-years, respectively (aHR
0.40, 95% CI 0.15, 1.06), while all-cause death rates were 30.6 and 12.2 per
1000 person-years, respectively (aHR 1.77, 95% CI 1.12, 2.79).
In preliminary analyses the risk of the composite outcome: CVD or death
was similar among those who added insulin or sulfonylurea to metformin.
These findings do not explain the observed increased risk of death associated
with insulin.
Table 1. Distribution of the Hp genotype among offspring with T1D by mother’s age at the time of birth
Mother’s age
Offspring’s Hp genotype
<22
23-36
>36
p-value
(n=62)
(n=253)
(n=35)
1-1
24.4 (11) 71.1 (32)
4.4 (2)
2-1
14.7 (23) 74.5 (117) 10.8 (17) Fisher’s
exact
2-2
18.9 (28) 70.3 (104) 10.8 (16) 0.43
Combining those with the 2 allele
1-1
24.4 (11) 71.1 (32)
4.4 (2) p-trend
2-1 / 2-2
16.7 (51) 72.5 (221) 10.8 (33) 0.09
p-trend
Proportion of Hp 1 allele
35.8 (181) 36.3 (45) 30.0 (21) 0.46
Supported by: NIH (DK34818)
1399-P
2-Hour Plasma Glucose Increases Much Faster With Age in Abnormal Glucose Tolerant Subjects Than Glucose Tolerant Subjects,
While No Difference in Fasting Plasma Glucose
Supported by: AHRQ, U.S. Dept. of Veteran Affairs
&
POSTERS
Epidemiology/
Genetics
RUDRUIDEE KARNCHANASORN, JEAN HUANG, HORNG-YIH OU, WEI FENG,
RAYNALD SAMOA, LEE-MING CHUANG, KEN C. CHIU, Kansas City, KS, Sylmar,
CA, Tainan, Taiwan, Duarte, CA, Taipei, Taiwan
The prevalence of type 2 diabetes increases with age. Both fasting plasma
glucose (FPG) and 2-hour plasma glucose (2hPG) increase with age. However,
there is little information whether the status of glucose tolerance affects
the rates of change with age in FPG and 2hPG or not.
The subjects with overt diabetes were excluded from the study. Only adult
(age ≥ 18 year olds) subjects with normal glucose tolerance (NGT, FPG < 100
mg/dL, 2hPG < 140 mg/dL, and A1c < 5.7%) and abnormal glucose tolerant
(AGT, any of FPG 100-199 mg/dL, 2hPG 140-199 mg/dL or A1c 5.7-6.4%) were
included in this study with a total of 5,224 participants of the NHANES 20052010. Regression analysis was used to examine the relation of age with FPG
and 2hPG. We also considered gender and BMI as covariates.
Age was significantly correlated with FPG (r=0.2989, P<0.000001) and
2hPG (r=0.3708, P<0.000001) in non-diabetic subjects. For FPG, significant
correlations with age were noted in both NGT (r=0.1235, P<0.000001) and
AGT (r=0.0961, P<0.000001) subjects. After adjustment for gender and BMI,
the annual rates of change in FPG were similar (P=0.06) between NGT (0.041
mg/dL/year, 95% CI: 0.028-0.054) and AGT (0.062 mg/dL/year, 95% CI: 0.0450.078) subjects. For 2hPG, signification correlations with age were also noted
in both NGT (r=0.1884, P<0.000001) and AGT (r=0.2902, P<0.000001) subjects.
After adjustment for covariates, the annual rates of change in 2hPG differed
significantly (P<0.000001) between NGT (0.229 mg/dL/year, 95% CI: 0.1790.278) and AGT (0.553 mg/dL/year, 95% CI: 0.488-0.619) subjects.
After 20 years of aging, FPG increases by 0.82 mg/dL in NGT and 1.24
mg/dL in AGT, while 2hPG increases by 4.58 mg/dL in NGT and 11.06 mg/
dL in AGT. An age specific diagnostic criteria for 2hPG would be required to
avoid the unnecessary treatment in the elderly population, in which the ADA
recommends a different approach in the management of diabetes.
YALI AN, PING ZHANG, JINPING WANG, EDWARD GREGG, BO ZHANG, HUI LI,
QIUHONG GONG, YANYAN CHEN, XIAOYAN XING, MICHEAL ENGELGAU, GOJKA
ROGLIC, YINGHUA HU, PETER H. BENNETT, GUANGWEI LI, Beijing, China, Atlanta,
GA, Daqing, China, Geneva, Switzerland, Phoenix, AZ
While stroke is a leading cause of death in China and the numbers of
persons with diabetes and impaired glucose tolerance (IGT) are large and
growing, the incidence and risk of death attributable to stroke among
Chinese adults with these conditions have not previously been quantified.
We examined incidence of stroke and related mortality over a 23 year
period in a cohort of 630 persons with newly diagnosed diabetes (NDM), 576
with IGT, and 519 with normal glucose tolerance (NGT), who were identified
initially in 1986 by screening 50% of the community aged 25 years and over
in Da Qing, China. Stroke incidence and related mortality were ascertained
up to December 31st, 2009 in some 95% of the cohort.
Stroke, fatal or non-fatal, occurred in 218 (36.8%) persons with NDM, 177
(32.7%) with IGT and 121 (24.6%) with NGT. Stroke incidence was higher
in men than in women with NDM (29.0 vs. 18.5/1000 person-years) and
IGT (22.1 vs. 13.7/1000 person-years), but not with NGT (12.9 vs. 11.4/1000
person-years). The age-adjusted hazard ratios for NDM vs. NGT were 2.15
(95% CI 1.59-2.92) in men and 1.47(95% CI 1.05-2.08) in women.
Among those who developed a stroke, death occurred in 145 (66.5%) with
NDM, 82 (46.3%) with IGT, and 36 (29.8%) with NGT. Case-fatality rates
from stroke (per 1000 person-years) were 130.6 in men and 153.9 in women
with NDM, 95.5 and 56.7 in men and women with IGT, and 56.4 and 46.6 in
men and women with NGT. Age- and sex- adjusted case-fatality rate ratios
were 2.42 (95% CI 1.67-3.69) for NDM vs. NGT and 1.54 (95% CI 1.04-2.29)
for IGT vs. NGT.
In China, diabetes and IGT lead to considerable excess risk for stroke and
excess mortality due to stroke. Persons with diabetes or IGT face double
jeopardy by having both a higher stroke incidence and a higher case-fatality
rate after a stroke.
EPIDEMIOLOGY—CARDIOVASCULAR DISEASE
Guided Audio Tour: Cardiovascular Epidemiology (Posters: 1400-P to 1405-P),
see page 15.
&
1401-P
Stroke Incidence and its Long-Term Impact on Mortality in a Population-Based Cohort With Newly Diagnosed Diabetes and Impaired
Glucose Tolerance in China: The Da Qing Diabetes Study
&
1402-P
Metabolic Syndrome in Type 1 Diabetes Patients over 16 years of
Follow-Up: The DCCT/EDIC Study
1400-P
PATRICIA A. CLEARY, EVRIM B. TURKBEY, JYE-YU C. BACKLUND, JOHN M. LACHIN, JOAO A. LIMA, DAVID A. BLUEMKE, DCCT/EDIC RESEARCH GROUP, Rockville, MD, Bethesda, MD, Baltimore, MD
Cardiovascular Outcomes Associated With Insulin versus Sulfonylureas for Diabetes Treatment Intensification
CHRISTIANNE ROUMIE, ROBERT GREEVY, CARLOS GRIJALVA, ADRIANA HUNG,
XULEI LIU, HARVEY MURFF, TOM ELASY, MARIE GRIFFIN, Nashville, TN
Metabolic syndrome (MetS) represents a cluster of cardiovascular risk
factors with associated increased cardiovascular risk. We describe the
prevalence of MetS in the well-characterized DCCT/EDIC cohort.
The Epidemiology of Diabetes Interventions and Complications (EDIC)
is the observational study of the Diabetes Control and Complications
Trial (DCCT) cohort that received intensive or conventional therapy for 6.5
years. MetS was defined as diabetes plus 2 other abnormalities (elevated
waist circumference or triglyceride or blood pressure levels or reduced
high density lipoprotein). At EDIC year 1, the prevalence of MetS was 16.5
The optimal medication for add-on diabetes therapy after metformin
failure remains uncertain. We compared time to cardiovascular disease
(CVD) events or all-cause death among patients who initiated insulin or a
sulfonylurea as add-on therapy to metformin.
We assembled a national retrospective cohort of veterans who initiated
diabetes treatment with metformin between 10/2001 and 9/2008 and
then added either insulin or sulfonylurea through 12/2010. Follow-up
continued until an outcome (CVD events: AMI or stroke hospitalization; or
&
For author disclosure information, see page 829.
A366
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—CARDIOVASCULAR DISEASE
% in 1271 subjects (mean age 36 years, 45 % female). The prevalence of
MetS increased linearly to 36.8% at year 12 and then stabilized with a
prevalence of 36.3% at year 16 (FIGURE). Hypertension and elevated waist
circumference increased linearly over 16 years (25.7% and 12.3% at year 1,
65.4% and 36.4% at year 16, respectively). Elevated triglyceride was stable
over 10 years (10.5% and 11.5% at year 1 and 10) and then decreased to 8.6 %
at year 16 . Older age at year 1, and higher mean HbA1c were associated with
MetS (Odds Ratio: 1.28 per 10 years, p<0.0001 and 1.22 per 1%, p< 0.0001,
respectively), but not gender or DCCT intensive vs conventional therapy. The
prevalence of MetS in T1DM increased during16 years of follow-up without
any significant difference by gender or treatment group. Older age and poor
glycemic control were predictors of MetS.
&
1404-P
Intensive Glucose-Lowering Therapy May Reduce Cardiovascular
Disease Events in Hispanics in the Veterans Affairs Diabetes Trial
(VADT)
ARAMESH SAREMI, GIDEON BAHN, LING GE, TOM MORITZ, DAWN C. SCHWENKE, WILLIAM C. DUCKWORTH, NICHOLAS EMANUELE, DOMENIC REDA,
RODNEY HAYWARD, PETER D. REAVEN, FOR VADT INVESTIGATORS, Phoenix, AZ,
Hines, IL, Ann Arbor, MI
As veterans have equal access to comprehensive healthcare, potential
health disparities between ethnic groups are less likely related to differences
in medical access. This post-hoc analysis investigated the effect of intensive
glycemic control (INT) on CVD events in the VADT among major race/ ethnic
groups. The VADT (n=1791), included 1111 non-Hispanic Whites (62%), 307
Hispanics (17%) and 306 non-Hispanic Blacks (17%). Other race/ ethnic
combinations (n=67, 3%) were excluded. Hispanics were on average younger,
leaner, and had a lower CVD prevalence, but a higher baseline HbA1c (P <
0.01, for overall comparisons between groups). At study-end, the average
HbA1c decline with INT was greatest in Hispanics (P = 0.03 for overall
comparisons between groups). After adjustment for age, prior CVD, duration
of diabetes, history of hypertension, baseline HbA1c, and on treatment BMI
and total cholesterol-to-HDL ratio, INT was associated with a ~40% lower
rate of CVD events in Hispanics but not in other groups (Figure). However,
after adjustment for on trial HbA1c, the effect of INT in Hispanics was no
longer significant [HR: 0.92, 0.51-1.70, P=0.80)]. These results suggest that
intensive glycemic control may effectively reduce CVD events in Hispanics
with advanced type 2 diabetes.
1403-P
Handgrip Strength Predicts Cardiovascular Mortality: A Subanalysis of the ORIGIN Trial
PATRICIO LOPEZ-JARAMILLO, DANIEL COHEN, DIEGO GOMEZ-ARBELAEZ, HERTZEL GERSTEIN, JACKIE BOSCH, SALIM YUSUF, ORIGIN INVESTIGATORS, Bucaramanga, Colombia, Hamilton, ON, Canada
Low muscular strength is a risk factor for cardiovascular disease (CVD) and
all-cause mortality in initially healthy individuals. The association between
strength and CVD or all-cause mortality in diabetes type 2 (DM2) patients at
elevated risk of CV mortality, has not been evaluated.
As part of the ORIGIN trial of CVD outcomes and mortality, grip strength (GS)
was assessed at baseline in 12516 patients from 40 countries (35% female),
mean age 63.6 years (±7.8) with either impaired glucose tolerance/impaired
fasting glucose (12%), or DM2 (88%) and followed up for a median of 6.2 years.
Raw GS was adjusted for age (GSa) and hazard ratios and 95% CIs for
CVD outcomes and mortality per unit increase of GSa were estimated for
males and females separately. In males, there were significant negative
associations between GSa and stroke, CV death, hospitalised chronic
heart failure and total mortality (Table 1). In females, similar patterns were
observed and additionally, associations between GSa and total myocardial
infarction and revascularisation. In both males and females, associations not
weakened by adjusting for BMI, waist or hip circumference.
We report in a multi-region cohort of pre DM2 and DM2 patients that
higher GS is associated with lower risk of CV and all-cause mortality, with
stronger associations observed in females. These findings support the ADA
recommendation that DM2 patients participate in strength training.
Supported by: U.S. Dept. of Veterans Affairs; NIH (R01-067690), (R01-HL-094775)
&
PETER BOYLE, MATHIEU BONIOL, ALICE KOECHLIN, MARIA BOTA, CHRIS ROBERTSON, CECILE PIZOT, JAY SKYLER, GEREMIA B. BOLLI, JULIO ROSENSTOCK,
PHILIPPE AUTIER, Lyon, France, Glasgow, United Kingdom, Miami, FL, Perugia, Italy,
Dallas, TX
Effectiveness of glucose-lowering agents depends on a number of factors
including the safety profile. A systematic evaluation of the published
literature has been undertaken (DIABAMON project) to evaluate the effect
of diabetes medications on serious adverse events.
Our meta-analysis showed that among diabetes patients recruited to
clinical trials, the death rate from all causes fell from SRR=2.16 (95% CI (1.87,
2.48)) in the 1970s, through 1.82 (1.69, 1.96) in the 1980s and 1.69 (1.57, 1.79)
in the 1990’s to reach SRR=1.89 (1.33, 1.87) in the 2000’s.
There is a two-fold increased risk of cardiovascular disease in diabetes but
in high-resource countries the risk of dying from most forms of cardiovascular
disease (CVD) is decreasing. Comparing Coronary Heart Disease (CHD) risk
in diabetes vs non-diabetes patients through time, the risk in studies which
recruited in the 1970’s (SRR=2.27, (1.64, 3.16)) fell among patients recruited
the 1980s (SRR=2.02, (1.78, 2.29)) and 1990s (SRR = 1.98, (1.78, 2.29)) to
reach SRR=1.58 (1.66, 2.37) among patients recruited to trials in the 2000’s.
Whereas rosiglitazone has been associated with an increased risk of CVD,
pioglitazone has been shown to reduce risk of death, myocardial infarction
and stroke (SRR=0.82, (0.72, 0.94)). Glargine has been shown in randomized
Supported by: Sanofi (NCT00069784)
ADA-Funded Research
&
1405-P
Safety of Glucose-Lowering Medications: The Diabetes Adverse
Event Monitor (DIABAMON) Project: II Cardiovascular Disease
For author disclosure information, see page 829.
Guided Audio Tour poster
A367
POSTERS
&
Epidemiology/
Genetics
Supported by: NIH
EPIDEMIOLOGY—CARDIOVASCULAR DISEASE
0.709 for stroke, 0.681 for MI) and CDS (0.691 for cancer, 0.725 for stroke,
0.699 for MI) alone. The NRI and IDI values were positive and significant
for CCI+CDS combinations compared to individual scores. This indicates
that the combined scores (CCI+CDS) classified patients into correct strata
compared to individual scores.
In conclusion, combining CCI and CDS improved prediction of non-skin
cancer, stroke and MI in T2DM patients.
trials to have no associated increased risk of CVD. A meta-analysis of studies
of metformin yields a reduced risk of CVD (SRR=0.85(0.77, 0.95)).
Progress has been made in reducing the risk of major CVD and death
in diabetes during the past 40 years. There have been improvements in
prevention prospects of CVD during the previous decades with the use of
statins, better control of blood pressure and the trend to reduce tobacco
smoking as well as better management of diabetes. The DIABAMON project
is committed to the systematic monitoring of CVD and glucose lowering
drugs with rigourous meta-analyses and continuous updates using data from
a variety of sources.
1408-P
Real-World Cardiovascular Event Rates among High-Risk Adults
With Type 2 Diabetes Mellitus
KATHLEEN M. FOX, YING WU, JENNIFER KIM, SUSAN GRANDY, Monkton, MD,
Wilmington, DE
1406-P
This investigation ascertained the incidence and time to first non-fatal
myocardial infarction (MI) or stroke among adults with type 2 diabetes
mellitus (T2DM) at high risk for cardiovascular disease (CVD) over 3 and 5
years.
A retrospective cohort study used data from the US population-based
Study to Help Improve Early evaluation and management of risk factors
Leading to Diabetes (SHIELD). High-risk respondents with T2DM were
stratified into 2 cohorts: 1) established CVD with age ≥40 years, prior MI,
prior stroke, atherosclerosis, or peripheral vascular disease, and 2) multiple
risk factors (men ≥55 years and women ≥60 years and ≥1 risk factors of
hyperlipidemia, hypertension, or current smoking, without prior history of
CVD). Proportion of respondents self-reporting a new MI or stroke was
calculated and multivariate discrete logistic hazards models for 3 and 5
years of follow-up were developed.
Among 2122 T2DM respondents, 56.5% had established CVD (mean age =
65 years, 45% men); 43.5% had no established CVD but multiple risk factors
(mean age = 68 years, 49% men). The established CVD cohort had a new MI
or stroke event rate of 16.7% during a 3-year follow up period and 20.5%
during the 5-year follow-up. For the multiple risk cohort, 17.6% within 3
years and 24.5% within 5 years had an incident MI or stroke. Hazard ratio
(HR) of incident MI was 2.1 times higher (95% CI: 1.6-2.8) within 3 years and
1.9 higher (1.5-2.4) within 5 years of follow-up, after adjusting for gender,
age, obesity, duration of diabetes, and comorbidities among the established
CVD cohort than multiple risk cohort (p <0.001). HR of incident stroke was
2.2 (1.4-3.5) and 1.8 (1.2-2.7) times higher within 3 and 5 years, respectively,
after adjustment among the established CVD cohort than multiple risk
cohort (p <0.01).In this large US population-based study, T2DM individuals at
risk for CVD had significant incidence of MI and stroke. T2DM respondents
with established CVD are at higher risk than those with no CVD but have
multiple risk factors.
POSTERS
Epidemiology/
Genetics
WITHDRAWN
1409-P
Blood Pressure and Stroke Risk among Louisiana Diabetic Patients
WENHUI ZHAO, PETER KATZMARZYK, RONALD HORSWELL, YUJIE WANG,
JOLENE JOHNSON, WILLIAM T. CEFALU, DONNA H. RYAN, GANG HU, Baton
Rouge, LA
1407-P
Comparison of Risk Adjustment Methods to Predict Non-Skin Cancer, Stroke and Myocardial Infarction (MI) in Patients With Type 2
Diabetes Mellitus (T2DM)
Blood pressure control can reduce the risk of stroke among diabetic
patents, however, it is not known if the lowest risk of stroke is among
diabetic patients with the lowest blood pressure level. We investigated the
prospective race-specific association of different levels of blood pressure at
baseline and during follow-up with stroke risk among 17,536 African American
and 12,618 White diabetic patients within the Louisiana State University
(LSU) Hospital System. During a mean follow up of 6.7 years, 2,949 incident
stroke cases were identified. The multivariable-adjusted (age, sex, smoking,
income, type of insurance, body mass index, glycosylated hemoglobin, lowdensity lipoprotein cholesterol, estimated glomerular filtration rate, use of
antihypertensive drugs, use of diabetes medications, and use of cholesterollowering agents) hazard ratios (HRs) of stroke associated with different levels
of systolic/diastolic blood pressure at baseline (<110/65, 110-119/65-69, 120129/70-80 [reference group], 130-139/80-90, 140-159/90-100, and ≥160/100
mmHg) were 1.88 (95% confidence interval [CI] 1.38-2.56), 1.05 (0.80-1.42),
1.00, 1.05 (0.86-1.27), 1.12 (0.94-1.34), and 1.47 (1.24-1.75) for African
American diabetic patients, and 1.42 (1.06-1.91), 1.22 (0.95-1.57), 1.00, 0.88
(0.72-1.06), 1.02 (0.86-1.21), and 1.28 (1.07-1.54) for White diabetic patients,
respectively. A U-shaped association of isolated systolic or diastolic blood
pressure at baseline and during follow-up as well as blood pressure during
follow-up with stroke risk was observed among both African American and
White diabetic patients. The U-shaped association was confirmed in both
patients who were and were not taking antihypertensive drugs. The current
study suggests a U-shaped association between blood pressure and the risk
of stroke. Aggressive BP control (<110/65 mmHg) and high blood pressure
HEMALKUMAR MEHTA, VINAY MEHTA, KIMBERLY G. BRODOVICZ, CYNTHIA J.
GIRMAN, Houston, TX, North Wales, PA
Risk adjustment tools such as Charlson’s Comorbidity Index (CCI) and
Chronic Disease Score (CDS) are used to control for confounding or to
predict outcomes in patients with T2DM. The objective was to compare the
performance of CCI, CDS and CCI+CDS in predicting non-skin cancers, stroke
and MI in patients with T2DM.
The Clinical Practice Research Database, electronic medical record data
from primary care in UK, was used for this retrospective longitudinal cohort
study. Patients diagnosed with T2DM from Jan 1, 2003-Dec 31, 2006 and
without prior non-skin cancer (N=74,296), stroke (N=72,872) or MI (N=73,200)
were included; separate cohorts were developed for each outcome. The
index date was defined as the date of the first T2DM diagnosis. Diagnosis
and prescription information up to 1 year prior to index date was used to
create CCI and CDS, respectively. Patients were followed for 3 years from
the index date to observe outcomes. In addition to traditional concordance
(c) statistics from logistics regression, novel reclassification measures (net
reclassification index (NRI) and integrated discrimination index (IDI)) were
used to compare different risk adjustment models.
Non-skin cancers were observed in 6%, stroke in 4.2%, and MI in 2.2%
of the respective cohorts. In logistic regression models controlling for age
and gender, CCI+CDS performed better at predicting non-skin cancer (c=
0.693), stroke (c=0.726) and MI (c=0.700) compared to CCI (0.690 for cancer,
&
For author disclosure information, see page 829.
A368
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—CARDIOVASCULAR DISEASE
hypothesis that T2D itself, i.e. hyperglycemia and its underlying metabolic
derangement, is the primary cause of increased CVD burden in the T2D.
(≥160/110 mmHg) are both associated with an increased risk of stroke among
both African American and white patients with type 2 diabetes.
Supported by: Louisiana State University
Supported by: NIH (R01HL92301)
1412-P
1410-P
Reduced Longevity in Parents Linked to Atherogenic Dyslipidemia
in T2DM Offspring
Various Components of Blood Pressure as Stroke Risk in Japanese
Patients With Type 2 Diabetes: Analysis from the Japan Diabetes
Complications Study (JDCS)
The aim of this study was to determine the best blood pressure index
and its cutoff to predict stroke in Japanese patients with type 2 diabetes
who have different features regarding the incidence of and risk factors for
cardiovascular complications as compared with Western diabetic subjects.
Eligible Japanese men and women (n=1771) aged 40-70 years with type 2
diabetes attending 59 institutes nationwide were followed for a planned
8-year period. Performance of systolic, diastolic, pulse and mean arterial
blood pressure (SBP, DBP, PP and MAP, respectively) and their various
combinations were evaluated as predictors of incident stroke. Hazard
ratios (HRs) per 1-SD change in SBP and PP determined by multivariate Cox
analysis both significantly predicted stroke (HR 1.31 (95%CI, 1.04-1.65), HR
1.28 (1.03-1.59), respectively), and that for MAP was borderline significant
(HR 1.21 (0.97-1.52)), while that for DBP was not predictive. In the tertile
analysis, MAP was the only significant index, and this and spline analyses
clarified an apparent threshold of 90 mmHg for this index. Comparison with
various criteria of hypertension also revealed that MAP≥90 mmHg was more
predictive than any other criteria, including the currently used criterion (i.e.,
SBP≥130 or DBP≥80 mmHg), which was non-significant. This result was also
confirmed by Kaplan-Meyer analysis, in which the p value for log rank testing
was significant for MAP>90 mmHg but not for the currently used criterion.
Reclassification analysis indicated that the new MAP criterion showed an
improvement of nearly 10% over the currently used analysis. In conclusions,
for Japanese patients with type 2 diabetes, MAP≥90 mmHg was a better
criterion than the currently used one for risk evaluation or prediction of
stroke; measurement of this parameter should be considered among the
clinical approaches to risk reduction among type 2 diabetic patients of an
East Asian origin.
1413-P
Effect of Regression or Progression in Glucose Tolerance Status on
Aortic Stiffness: The ADDITION-PRO Study
NANNA B. JOHANSEN, DORTE VISTISEN, KRISTINE FÆRCH, ANNE-LOUISE S.
HANSEN, SIGNE S. RASMUSSEN, NIELS WIINBERG, TORSTEN LAURITZEN,
ANNELLI SANDBÆK, MARIT E. JØRGENSEN, DANIEL R. WITTE, ADDITIONDENMARK STEERING COMMITTEE, Gentofte, Denmark, Copenhagen, Denmark,
Frederiksberg, Denmark, Aarhus, Denmark, Strassen, Luxembourg
1411-P
Analysis of the Origins of CVD in the Diabetes Heart Study
DONALD W. BOWDEN, JIANZHAO XU, JEFFREY CARR, BARRY I. FREEDMAN,
CARL D. LANGEFELD, DAVID HERRINGTON, MAGGIE C.Y. NG, AMANDA J. COX,
FANG-CHI HSU, Winston-Salem, NC
Compared to individuals with normal glucose tolerance (NGT), individuals
with impaired glucose regulation have a higher level of aortic stiffness, a key
indicator of cardiovascular disease. However, it is unclear whether changes
in glycemic status result in concomitant changes in aortic stiffness. Given
different pathophysiological mechanisms underlying isolated impaired
fasting glucose (iIFG), isolated impaired glucose tolerance (iIGT) and
combined IFG+IGT, we examined the effect of progression to diabetes or
regression to NGT on aortic stiffness.
Through a stepwise diabetes screening program, 342 individuals were
identified with iIFG, 241 with iIGT, and 177 with IFG+IGT (54% men, mean
age 59.5 years (SD 2.2)). After a mean follow-up of 6.4 years (SD 1.2), a
health examination including an oral glucose tolerance test and assessment
of aortic stiffness by carotid-femoral pulse wave velocity (aPWV) was
performed. Differences in aPWV between individuals who regressed to
NGT, who had unchanged impaired glucose regulation, or who progressed
to diabetes during follow-up were analyzed using linear regression adjusting
for relevant confounders.
At follow-up, mean aPWV was 8.8 m/s (SD 2.2). Compared with individuals
with stable iIGT, individuals with screen-detected iIGT who progressed
to diabetes had a 1.06 m/s (95% CI: 0.25;1.88) higher aPWV at follow-up,
whereas individuals who regressed to NGT from iIGT had similar levels of
aPWV (difference from stable iIGT: 0.14 m/s (-0.71;1.01)). Among individuals
with screen-detected iIFG or IFG+IGT, changes in glycemic status were not
significantly associated with aPWV.
These results indicate that levels of aortic stiffness are lower among
individuals with stable iIGT compared with individuals who progress to
diabetes from iIGT, whereas regression from iIGT to NGT during 6 years do
People with type 2 diabetes (T2D) have 2-4 fold higher risk of cardiovascular
disease (CVD). Multiple hypotheses have been proposed to explain the
increased CVD risk, but pathways to this CVD risk remain poorly understood.
We evaluated CVD risk in T2D in the Diabetes Heart Study using measures
of coronary artery calcification (CAC), clinical risk factors, and genetic data
(GWAS). CAC is an established powerful independent predictor of CVD
events and mortality and was the measure of CVD burden in this study. Age,
gender, and BMI adjusted residuals of (log) CAC were calculated for 1155
European American subjects (967 T2D, 188 non-T2D). When stratified by
presence of T2D the distribution of CAC in participants was highly different
(Kolmogorov-Smirnov p= 1.6x10-14). Comparable analyses were performed
for BP, CRP, lipids, renal function, smoking. The most significant difference
was with triglycerides (p=0.003). For many traits there was no difference
between T2D and non-T2D, e.g. cholesterol (p=0.10). The cumulative burden
of known genetic risk variants for T2D (36 SNPs), lipids (78 SNPs), and
CVD (30 SNPs) was calculated. T2D participants had a greater genetic risk
burden for T2D (p=0.04) and CVD (p=0.03). Variables that differed between
T2D and non-T2D were added as additional covariates in the CAC residual
model to assess if they reduced the difference in CAC between T2D and nonT2D. Individual variables had little impact. Addition of all risk variables as
covariates reduced the T2D/non-T2D difference in CAC but remained highly
significant (p=2.86x10-9). We estimate these genetic and clinical factors
account for 32% change in the regression coefficient of T2D effect for CAC.
Glucose alone, as a surrogate of T2D, accounts for 43% of the change in
CAC. Thus while CVD burden in T2D is associated in part with conventional
clinical risk factors and known genetic variants, these findings support the
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A369
POSTERS
Background: It is not known whether the fact of having one (or both)
parent(s) have not reached an advanced age, alters the phenotype of
descendants with type 2 diabetes (T2DM).
Aims: To define the cardiometabolic features of T2DM offspring according
to parental longevity or brevity.
Methods: 405 T2DM patients (mean age 69 (10), M:F 68:32) assessed on
parental longevity (paternal and/or maternal lifespan >80 years), divided
into 2 groups: a long-lived father and long-lived mother [LLF & LLM] (n=82);
and a short-lived father and/or short-lived mother [SLF &/or SLM] (n=323).
Atherogenic dyslipidemia (AD) defined as low HDL-C + high TG; AD severity
quantified using log[TG]/HDL-C ratio. Homeostatic model assessment (HOMA)
of insulin sensitivity [S]; β-cell function [B]; and hyperbolic product [B×S].
Results: Age; DM familial history; education and smoking were similar in
both groups. CV familial history and DM duration were increased in [SLF &/
or SLM]: 12% vs. 4% (p 0.0250) and 16 (9) vs. 13 (9) years (p 0.0073) in [LLF
& LLM]. Use of glucose-lowering; CV and lipid-lowering drugs was similar in
both groups, as were body composition; liver steatosis, hypertension; and
BP values. Metabolic syndrome scored higher in [SLF &/or SLM]: 3.79 (1.12)
vs. 3.48 (1.12) in [LLF & LLM] (p 0.0257). Fasting insulinemia was higher in
[SLF &/or SLM], who were also more insulin resistant than [LLF & LLM], the
mean loss in [S] being 10% (p 0.0440). HbA1c was higher, by 0.36 % (3 mmol/
mol) in [SLF &/or SLM] (p 0.0138). LDL-C; non-HDL-C; apoB100; and TG were
similar in both groups; whereas HDL-C and apoA1 were higher in [LLF & LLM]:
+4 mg/dL and +8 mg/dL (p 0.0233 and 0.0179). Prevalence and severity of AD
were both raised in [SLF &/or SLM]: +53% (prevalence) and +13% (log[TG]/
HDL-C) (p 0.0172 and p 0.0067).
Conclusion: Uni- or bilateral reduction(s) in parental longevity is linked
to insulin resistance; hyperinsulinemia; poorer metabolic control and elevated prevalence, with higher severity, of AD among 1st-degree T2DM
descendants.
HIROHITO SONE, SHIRO TANAKA, SACHIKO TANAKA, SATORU KODAMA, TATSUMI MORIYA, OSAMU HANYU, KOTARO YOKOTE, SHUN ISHIBASHI, SHINICHI
OIKAWA, SHIGEHIRO KATAYAMA, YASUO OHASHI, YASUO AKANUMA, NOBUHIRO YAMADA, JAPAN DIABETES COMPLICATIONS STUDY GROUP, Niigata,
Japan, Kyoto, Japan, Kanagawa, Japan, Chiba, Japan, Tochigi, Japan, Tokyo, Japan,
Saitama, Japan, Tsukuba, Japan
Epidemiology/
Genetics
MICHEL P. HERMANS, SYLVIE A. AHN, MICHEL F. ROUSSEAU, Brussels, Belgium
EPIDEMIOLOGY—CARDIOVASCULAR DISEASE
with previous ACS. Future studies on strategies to prevent CV events in this
population are warranted.
not affect aortic stiffness. Changes in glycemic status from iIFG/IFG+IGT
were not associated with differences in aortic stiffness at follow-up.
Supported by: EFSD/Pfizer, Inc. (74550801); Danish Council for Strategic Research
Supported by: Takeda Pharmaceuticals International, Inc.
1416-P
1414-P
Vitamin E Improves HDL Function in Type 1 Diabetes With the Hp 2-2
Genotype: The HapE Study
Cardiovascular Event Rates in a Type 2 Diabetes Population in a
Real-World UK Setting: A Large Database Study Using the Clinical
Practice Research Datalink (CPRD) and Hospital Episode Statistics
(HES)
TINA COSTACOU, ANDREW LEVY, RABEA ASLEH, RACHEL MILLER, DAN FARBSTEIN, CATHERINE E. FICKLEY, GEORGIA PAMBIANCO, RHOBERT EVANS, TREVOR ORCHARD, Pittsburgh, PA, Haifa, Israel
POSTERS
Epidemiology/
Genetics
AMANDA MCDONELL, STEPHANIE DEVORE, ANUSHINI MUTHUTANTRI, DIRK
DEMUTH, CATRINA RICHARDS, YING WU, JENNIFER KIM, London, United Kingdom, Wilmington, NC
An increased cardiovascular (CVD) risk has been reported in those with
diabetes and the Haptoglobin (Hp) 2-2 vs. the 1-1 genotype. Three clinical
trials showed that vitamin E lowers CVD risk by 14-53% in type 2 diabetes
and Hp 2-2, potentially through improvements in HDL function, which is
thought to be impaired in Hp 2-2; no vitamin E benefit on CVD risk was seen
in Hp 1-1 / 2-1 individuals. We thus conducted a randomized, double-blinded,
placebo controlled, cross-over trial of vitamin E therapy on HDL function
in type 1 diabetes (T1D). Members of two Allegheny County, PA Type 1
Diabetes registries were contacted to assess their willingness and eligibility
to participate in a clinical trial of vitamin E supplementation. Willing and
eligible individuals were invited to a clinic visit for Hp genotyping. Thirty
individuals within each Hp 2-1 and Hp 2-2 were then randomly selected and
allocated to receive 400 IU of α-tocopherol acetate daily or placebo in a
cross-over manner with an 8 week exposure to each treatment and a 4 week
wash-out period between treatments. HDL-associated lipid peroxides (LP)
and HDL-mediated cholesterol efflux from macrophages (CE) were assessed
prior to and after each treatment. At baseline, LP increased (p-trend=0.08)
and CE decreased (p-trend=0.04) linearly with the number of Hp 2 alleles.
During the cross-over study, plasma α-tocopherol increased by 60.3% with
vitamin E therapy and decreased by 3.8% with placebo (p-difference<0.0001)
in Hp 2-1 and 2-2 individuals. Vitamin E therapy also significantly increased CE
by 3.3% (vs. 0.92% decrease with placebo) in the Hp 2-2 group (p=0.01) but
did not affect CE in the Hp 2-1 group. No effect of treatment was observed
for LP in either group. In type 1 diabetes, HDL function worsens with the
number of Hp 2 alleles. Vitamin E therapy improves HDL function in the Hp
2-2, but not Hp 2-1, group suggesting a pharmacogenomic effect. These data
provide further support for a trial of vitamin E therapy to reduce CVD risk in
type 1 diabetes and Hp 2-2.
Type 2 diabetes mellitus (T2DM) is associated with increased risk of
cardiovascular (CV) disease. The primary aim of the epidemiologic study was
to assess time to first major CV event in T2DM patients in a large real-world
UK population at high risk for CV events.
Retrospective analyses were conducted in the UK CPRD, an anonymised,
longitudinal primary care database, linked to secondary care and mortality
data. Patients with a T2DM diagnosis and at least 1 physician visit recorded
1 January 2005 - 31 October 2011 were screened at first recorded physician
visit (index) for study inclusion. Criteria for inclusion were T2DM patients
aged ≥40 years, HbA1c ≥6.5% and either established CV disease and/or
presence of multiple CV risk factors. Eligible patients were followed up to
31 October 2011 for outcome evaluations. Study outcomes were calculated
using the Kaplan-Meier estimator.
21,560 eligible patients were identified (57% male; mean age: 70.1 years;
total follow up period for patient population: 121,523 years). The probability
of experiencing a CV event (defined as fatal/non-fatal myocardial infarction
or stroke) by 1, 3, 5 and 6 years post-index was 4.4%, 9.4%, 13.4% and
15.3%, respectively.
Patients with prior CV events (n=10,154; mean age: 71.1 years) had a
probability of experiencing a subsequent CV event of 7.2%, 14.6%, 19.9%
and 22.3% by 1, 3, 5 and 6 years post-index, respectively. Patients with
multiple risk factors without prior CV events (n=11,406; mean age: 69.2
years) had a probability of experiencing a CV event of 1.9%, 4.7%, 7.7% and
9.0% by 1, 3, 5 and 6 years, respectively.
In this real-world study, T2DM patients with history of CV events or
multiple risk factors were observed to have high rates of CV events. Patients
with a history of prior CV events have a higher probability of experiencing
future CV events compared to patients with no prior CV events, but
presenting with risk factors.
1417-P
Plasma Fibrinogen Level as a Predictor of Cardiovascular Diseases,
Independent of Diabetes, in a Population-Based 16-Year Prospective Study in Hong Kong
1415-P
Incidence, Costs of Cardiovascular Rehospitalization among Diabetes Patients With Pre-Existing Acute Coronary Syndrome: A Retrospective Database Study
ELAINE HUI, TAI HING LAM, WING SUN CHOW, CHUN YIP YEUNG, YU CHO WOO,
CAROL FONG, AIMIN XU, HUNG FAT TSE, BERNARD MY CHEUNG, KAREN SIU
LING LAM, Hong Kong, China
MORGAN BRON, HUAN HUANG, JAY LIU, PENNY FLECK, DUYGU BOZKAYA, MICHAEL MUNSELL, JOE MENZIN, Deerfield, IL, Waltham, MA
Recent evidence from prospective studies in the United States and Europe
suggest plasma fibrinogen level is useful for prediction of cardiovascular risk
in addition to conventional risk factors. As one of the acute-phase reactant
proteins, fibrinogen increases in response to the inflammatory process
of atherosclerosis. Baseline data of the population-based Hong Kong
Cardiovascular Risk Factor Prevalence Study (CRISPS), commenced in 19956, showed close positive relationship between circulating fibrinogen levels
and diabetes, a major cardiovascular risk factor. In this study, we examined
whether plasma fibrinogen was predictive of incident cardiovascular
diseases (CVD) over 15.9 years (IQR 15.5 – 16.5) in the CRISPS cohort, and
whether the prediction was dependent on its association with diabetes.
Of a total of 2774 subjects, 374 had confirmed incident CVD. In addition
to male sex and age, baseline body mass index (BMI), waist circumference
(WC), fasting glucose, 2-hour glucose after oral glucose tolerance test,
insulin resistance index HOMA-IR, systolic and diastolic BP, triglycerides
(TGs), high-density lipoprotein, the presence of diabetes, hypertension,
dyslipidaemia, and fibrinogen level were all predictive of incident CVD over
15.9 years (all p<0.001). Fibrinogen level correlated positively with fasting
glucose, HOMA-IR, BMI, WC, systolic and diastolic BP, and TGs after sex
and age adjustment (all p<0.001).On multivariate analysis, baseline age, WC,
diabetes, hypertension, and fibrinogen level were independent risk factors
(p≤0.001) for incident CVD. In conclusion, the findings from this 16-year
prospective study confirmed plasma fibrinogen level as a strong predictor of
CVD, independent of diabetes, in community-based Chinese adults.
Patients with diabetes mellitus (DM) and pre-existing acute coronary
syndrome (ACS) are at high risk for subsequent cardiovascular (CV) events.
Our objective was to understand the incidence, costs and factors associated
with CV rehospitalization among DM patients following ACS admission.
Using the Truven Health Analytics MarketScan® database, patients with
DM and receiving an antidiabetic treatment other than insulin between
2006-2010 were identified. Patients must have had an ACS hospitalization
(acute myocardial infarction [MI] or coronary revascularization) following the
earliest DM diagnosis and were required to be enrolled for ≥1 month. The
proportion of patients with a subsequent CV event (defined as having ≥1
inpatient claim for acute MI, stroke, or coronary revascularization) and the
rate of CV events (per 100 person-years [PYs]) were evaluated, along with
CV-related and all-cause costs. Logistic regression was conducted to identify
factors associated with the likelihood of having a CV rehospitalization.
55,095 DM patients with an ACS admission were identified (mean age
66 years, 38% female), with a mean (median) follow-up of 19 (16) months.
21% of patients had ≥1 CV event during follow-up, with a rate of 21.4 CV
events per 100 PYs. Adjusting for follow-up time, the likelihood of having
a CV event increased with greater Charlson comorbidity score, longer
stay of the index hospitalization, and having an MI diagnosis for the index
hospitalization. Bypass surgery during the index hospitalization and taking
more than one antidiabetic drug were significantly associated with lower CV
risk. Mean monthly CV-related (all-cause) follow-up cost among all patients
(regardless of whether they had a subsequent event) was $1,092 ($2,965).
CV-related rehospitalization is fairly common and costly among DM patients
Supported by: Hong Kong Research Grant Council (T12-705/11)
&
For author disclosure information, see page 829.
A370
Guided Audio Tour poster
ADA-Funded Research
1420-P
Long-Term Cardiovascular Outcomes With Exenatide Twice Daily
Compared to Insulin: A Retrospective Observational Study
MARCO DAURIZ, ALESSANDRO MANTOVANI, ISABELLA PICHIRI, RICCARDO
RIGOLON, GIACOMO ZOPPINI, ENZO BONORA, GIOVANNI TARGHER, Verona,
Italy
SANJOY K. PAUL, STEVEN P. MARSO, DAVID MAGGS, KERENAFTALI KLEIN, JENNIE H. BEST, Brisbane, Australia, Kansas City, MO, San Diego, CA
Treatment with exenatide has shown beneficial effects on cardiovascular
(CV) risk factors in patients (pts) with T2DM. Long-term effects of treating
T2DM patients (pts) with GLP-1 receptor agonists on CV outcomes remain
limited. Using the GE Healthcare database, we evaluated the risk of heart
failure (HF), myocardial infarction (MI) and stroke in pts initiating exenatide
twice daily (EBID; n=2795) or any insulin (INS; n=51,547) in routine clinical
practice.
A cohort of 54,342 pts who received a first prescription of EBID or INS
between June 2005 and May 2009, combined with oral antidiabetes agents
(OADs), was selected and followed for a minimum of 3 y with minimum 6
mo under the same drug regimen. The possible effects of EBID vs INS on
CV events in this age-matched cohort were evaluated using a stratified Cox
regression model, adjusted for age, sex, race, history of CV disease, OADs,
and cardio-protective medications. EBID/INS pts were 39%/47% men, 56/59
y of age, 54%/48% white, 11%/12% history of CV disease, 89%/61% MET,
55%/46% SFU, 47%/33% TZDs, 74%/82% ACE-ARB, 43%/56% β blocker,
and 85%/84% statins. During median 4.3 y follow-up for EBID and 4.2 for
INS, 2.1%/5.8%, 0.5%/0.9% and 0.9%/2.1% had HF, MI and stroke events
respectively.
CV event rates per 1000 person-years were significantly lower among
patients treated with EBID vs INS (HF: 4.8 vs 13.6, MI: 1.1 vs 2.1, stroke: 2.0
vs 4.9). Compared to INS, pts treated with EBID had significantly lower risk
of HF by 53% (HR CI: 0.36, 0.61) and MI/stroke by 48% (HR CI: 0.38, 0.72).
Patients with a history of CV disease had a 47% (HR CI: 1.35, 1.60) increased
risk of HF and 70% (HR CI: 1.50, 1.91) increased risk of MI/stroke compared
to pts without a history of CV disease.
Potential limitations of this analysis include misclassification of outcome
and residual confounding.
In this retrospective database study, treatment with EBID resulted in
significantly lower risk of HF and MI/stroke during 4-y follow-up compared
with INS.
Non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) are
two pathologic conditions that are highly prevalent in Western countries
and that share multiple cardiometabolic risk factors. Presently, the published
research on the association between NAFLD (or liver function tests) and
AF is sparse. In particular, there is a lack of available information on the
relationship between NAFLD and AF in people with type 2 diabetes (T2DM),
a group of individuals in which these two diseases are highly prevalent. We
studied a hospital-based sample of 702 Caucasian patients with T2DM (M/
F=379/323, mean age 66 years) discharged from our Division of Endocrinology
during 2007-2011. The diagnosis of AF was confirmed in affected participants
by experienced cardiologists. NAFLD was defined by ultrasonographic
detection of steatosis in the absence of other liver diseases. Of the 702
patients included in the study, 514 (73.2%) of them had NAFLD and 85 (12.1%)
had persistent AF. NAFLD was associated with an increased risk of prevalent
AF (odds ratio [OR] 3.04, 95% CI 1.5-6.0, P<0.0001). Adjustments for age,
sex, BMI, hypertension, electrocardiographic left ventricular hypertrophy,
chronic kidney disease, statin use, prior history of coronary heart disease,
heart failure, valvular heart disease, chronic obstructive pulmonary
disease and hyperthyroidism did not appreciably weaken the association
between NAFLD and AF (adjusted-OR 4.39, 95%CI 2.0-9.3, P<0.0001). The
significance of this association was consistent in all subgroups evaluated. In
conclusion, this study is the first to document that NAFLD is associated with
an increased prevalence of AF in a large hospital-based sample of patients
with T2DM. This association appears to be independent of important clinical
risk factors for AF. Future research is needed to corroborate these findings
and to determine whether NAFLD predicts the incidence and persistence of
AF in people with T2DM.
1419-P
Temporal Trends in Subclinical Coronary Artery Disease (CAD)
Among Non-Elderly Adults: A Population-Based Study
1421-P
CARIN Y. SMITH, KENT R. BAILEY, VERONIQUE L. ROGER, PETER N. NEMETZ,
JANE A. EMERSON, PASQUALE J. PALUMBO, CYNTHIA L. LEIBSON, Rochester,
MN, Vancouver, BC, Canada
Gender Effect on Risk of First-Ever Ischemic Stroke and Early Mortality in Hospitalized Diabetic Patients
The argument that obesity and diabetes (DM) epidemics have not impacted
CAD prevalence is based on continued declines in hospitalized myocardial
infarction and heart disease deaths. This fails to account for subclinical CAD,
especially in the non-elderly. Using non-natural deaths (96% autopsy rate),
we previously showed that declines in CAD grade since 1981 ended in the
mid-1990s.
Our present aim was to predict population trends in CAD grade using
trends in CAD risk factors and applying associations between CAD risk
factors and grade in autopsied decedents.
We used Rochester Epidemiology Project resources to identify all Olmsted
County, MN, residents age 16-64 who died of non-natural causes 1981-2009
with CAD grade at autopsy (N=551) and a random sample of 1244 Olmsted
County residents age 16-64, 1981-2009. For each group, we reviewed all
medical records and estimated temporal trends in CAD risk factors, including
age, sex, blood pressure (BP), BP medication use, DM (qualifying glucose or
medication), body mass index (BMI), smoking, and hyperlipidemia. We used
multiple regression of CAD grade on risk factors in decedents to predict CAD
grade in the population sample, and tested for linear and non-linear temporal
trends in predicted grade.
In both groups, BP values and smoking declined over time (all p <.03);
while BP medication use, DM, BMI≥30, and hyperlipidemia increased (p
<.05, except DM in decedents). Predicted CAD in the population (estimated
grade/year [95% CI], p value) revealed an increased trend 1981-2009 (linear
slope =.0011 [-.0004, .0026], p=.15); a non-linear model provided a better fit
(p=.055), with a trend for decrease 1981-1986 (-.0139 [-.0321, .0043], p=.14)
followed by an increase 1987-2009 (.0026 [.0004, .0048], p=.022).
Despite continuing declines in smoking and BP values, an autopsy-based
model predicts an increased rate of subclinical CAD for a random sample
of non-elderly adults, possibly due to rising obesity, DM, and need for BP
medication.
LAURA POLICARDO, PAOLO FRANCESCONI, FRANCESCO CIPRIANI, ROBERTO
ANICHINI, LUCIA TURCO, FLAVIA FRANCONI, STEFANO DEL PRATO, GIUSEPPE
SEGHIERI, Firenze, Italy, Pistoia, Italy, Sassari, Italy, Pisa, Italy
Ischemic stroke occurs at higher rate among diabetic patients and diabetes
worsens stroke prognosis in terms of mortality and disability. Aim of this
study is to evaluate gender differences in the association between diabetes
and hospitalization for first-ever ischemic stroke (FEIS). For this purpose we
reviewed the database of all discharges from hospitals of Tuscany, Italy
(3,393,538 inhabitants, 2011 census), during the period 2003-2011. ICD9-CM codes 433.xx, 434.xx, 436.xx identified ischemic stroke, and 250.xx
diabetes mellitus. FEIS identified those discharged only once or discharged
for the first time in cases of multiple admissions. In total alive discharged
population with FEIS diagnosis (n=62,199; 30,557 males and 31,642 females)
age-adjusted odds ratio (OR: 95% CI) of FEIS was significantly higher in
diabetic patients and was greater in male diabetic patients than in females
[OR:1.38; (1.34-1.42) vs. 1.26; (1.22-1.30)]. Such increased risk was observed
in each age class, save for those>70yr where risk was higher in women,
declining progressively with age, except among women whose risk of
association FEIS-diabetes peaked in age class 51-60 yr [OR:2.10; (1.81-2.43)].
Adjusted OR of 30-days mortality risk was unmodified in age class ≤ 70 yr,
while in age class >70 yr was about 20% lower in male diabetic patients with
stroke than in non-diabetic subjects of same age class [OR:0.81; (0.72-0.91)],
and conversely was higher in women compared to diabetic men [OR:1.49;
(1.31-1.71)]. Finally, association diabetes-mortality in FEIS did not change
with time for both sexes. In conclusion hospitalization risk for FEIS is ~ 3040% higher in diabetic patients, and is significantly greater in diabetic men
than in women. Risk declines with age, reaching its maximum in females
during perimenopausal life. Thirty-days diabetes-associated mortality risk is
lower in male diabetic patients aged above 70 yr, is higher in women than in
men in this age class, being unmodified over time.
Supported by: Fondazione Cassa di Rsparmio di Pistoia e della Lucchesia
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A371
POSTERS
1418-P
Non-Alcoholic Fatty Liver Disease Is Associated With an Increased
Prevalence of Atrial Fibrillation in Patients With Type 2 Diabetes
Epidemiology/
Genetics
EPIDEMIOLOGY—CARDIOVASCULAR DISEASE
EPIDEMIOLOGY—CARDIOVASCULAR DISEASE
to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) have
been shown to be associated with dyslipidemia in adults. However there
are few general population studies examining this association in children. In
this context, we examined the association between serum PFOA and PFOS
levels and dyslipidemia in a nationally representative sample of US children.
A cross-sectional study was performed on 815 participants ≤18 years of age
from the National Health and Nutrition Examination Survey 1999-2008. The
main outcome was dyslipidemia, defined as total cholesterol >170 mg/dL, lowdensity lipoprotein cholesterol (LDL-C) >110 mg/dL, high-density lipoprotein
cholesterol (HDL-C) <40 mg/dL or triglycerides >150 mg/dL. We found that
serum PFOA and PFOS was positively associated with high total cholesterol
and LDL-C, independent of age, sex, race-ethnicity, body mass index, annual
household income, physical activity and serum cotinine levels. Compared to
subjects in quartile 1 (referent), the multivariable-adjusted odds ratio (95%
confidence interval) for high total cholesterol among children in quartile 4
was 1.16 (1.05-2.12) for PFOA and 1.53 (1.11-1.64) for PFOS. PFOA and PFOS
were not significantly associated with abnormal HDL-C and triglyceride
levels. Our findings indicate that serum PFOA and PFOS are significantly
associated with dyslipidemia in children, even at the lower “background”
exposure levels of the US general population.
1422-P
Comparative Safety and Effectiveness of Sitagliptin in Patients
With Type 2 Diabetes and Heart Failure
POSTERS
Epidemiology/
Genetics
DANIALA L. WEIR, A. SENTHILSELVAN, JASON R. DYCK, JASJEET K. SANDHUMINHAS, FINLAY A. MCALISTER, DEAN T. EURICH, Edmonton, AB, Canada
Sitagliptin belongs to a new class of antidiabetic agents called incretins,
which are hypothesized to have pleiotropic effects on the cardiovascular
system as well as heart failure specific effects. The objective of this study
was to determine if the use of sitagliptin was associated with any benefit or
risk on clinical outcomes in a population-based cohort of patients with type
2 diabetes and incident heart failure.
Using a large commercially insured US claims and integrated laboratory
database, 11,967 subjects with type 2 diabetes and incident heart failure
were identified through physician claims, hospital discharge abstracts,
and/or ambulatory care visits based on ICD-9 CM codes. Our populationbased cohort was followed from January 1, 2004 until death, termination
of medical insurance, or December 31, 2010. Time-varying multivariable Cox
proportional hazards models were used to asses differences in all-cause
mortality.
Average age of subjects was 56 years, 39.6% were female, and mean
duration of follow-up time was 1.94 years. In total, 653 subjects died
(5.5%). No association between all-cause death and sitaglitpin use was
observed compared to other glucose lowering agents. After adjustment
for demographics, clinical & laboratory data, pharmacy claims, health care
utilization and time-varying propensity scores, any sitagliptin use was not
associated with a statistically significant increase in mortality (adjusted HR
0.64, 95% CI 0.37-1.12) compared to no sitagliptin use. Similarly, compared
to metformin/sulfonylurea combination therapy, sitagliptin combination
therapy was not associated with an increase in mortality (adjusted HR 1.01,
95% CI 0.40-2.56).
Sitagliptin therapy was not associated with excess risk of all-cause death
among patients with type 2 diabetes and heart failure.
Supported by: 5T32HL090610-04; 5R03ES018888-02
1425-P
Relatively Small Increases in LDL-Cholesterol are Associated With
Elevation in Coronary Heart Disease Risk in Diabetes
SWAPNIL RAJPATHAK, GLENN DAVIES, SAMUEL S. ENGEL, North Wales, PA
While an elevated circulating level of low density lipoprotein cholesterol
(LDL-C) is a known risk factor for developing coronary heart disease (CHD)
among patients with type 2 diabetes, it is unclear whether relatively small
increases in LDL-C levels have a meaningful impact on this risk, especially
in the longer term. Using a Markov CHD risk model based on Framingham
risk equations, we projected the number of CHD events in the US population
with diabetes using data from the 2009-10 National Health and Nutritional
Examination Survey (NHANES) (age≥40 years; 50% females, mean LDL-C of
101 mg/dl; 25.7% with history of CHD), in relation to a 5, 10 or 15% increase
in LDL-C levels. CHD events for individual patient profiles from NHANES
were weighted by each individual’s sampling weight to provide national
estimates. CHD events included fatal and non-fatal myocardial infarction
and angina. For LDL-C increases of 5, 10 and 15%, the model projected a
relative increase of 2.7%, 5.3% and 7.9% in total CHD events over 5 years.
Over a 10 year period, these estimates were 2.7%, 5.4% and 8.1%. This
increase in CHD risk could potentially translate to additional 108,361 nonfatal and 12,040 fatal cases of CHD for a 15% LDL-C increase among US
diabetic population aged≥40 years over 10 years. These results suggest that
even relatively small increases in LDL-C may elevate CHD risk in diabetes
and could impose significant clinical and economic burden. Interventions
among patients with diabetes that may potentially increase circulating lipid
levels warrant cautious use in this high risk population.
1423-P
Compliance With Anti-Diabetic Medication Improves Cardiovascular Outcomes in Patients With Type 2 Diabetes
SANGMO HONG, KYUNGJOO KIM, MI KYUNG KIM, JEONG-TAEK WOO, YOUNG
SEOL KIM, SEI HYUN BAIK, MOON SUK NAM, KWAN WOO LEE, JINHEE KIM,
YURI KIM, YONGSOO PARK, Gyeonggi, Republic of Korea, Seoul, Republic of Korea,
Incheon, Republic of Korea, Suwon, Republic of Korea
Objective: Type 2 diabetes (T2D) is associated with increased mortality
and morbidity from macrovascular disease. We assessed compliance with
anti-diabetic drug therapy and estimated its effect in reducing the risk of
macrovascular complications in T2D patients recruited from a prospective cohort
study (Korea National Diabetes Program (KNDP) database (2005-2010)).
Research Design and Methods: We used the Korean Health Insurance
Review and Assessment Service (HIRA) database as an independent source
of data related to the KNDP cohort database in order to compensate for
the incompleteness of prospective follow-up due to compliance. Compliance
with anti-diabetic medication was assessed by calculating the rates of
prescription refills from the HIRA database for a uniform period of 1 year. Cox
regression models of the effect of drug compliance were also compared.
Results: Of the 3842 eligible patients, 261 (6.8%) experienced cardiovascular
events during the follow-up period. Indeed, in multivariate models drug
compliance in both genders had an independent effect on the development
of new cardiovascular events. According to a covariate-adjusted model, the
predictors of cardiovascular disease were age (p<0.001), duration of diabetes
(p<0.001), hypertension (p=0.008) and anti-diabetic drug compliance (p<0.001).
Furthermore, the third of patients with the highest drug compliance achieved
a reduction of 75% (95% CI = 0.17-0.36) in cardiovascular disease risk, and the
middle third achieved a reduction of 59% (95% CI = 0.30-0.57) compared to
patients with the lowest drug compliance.
Conclusions: This study has shown that improving compliance to antidiabetic medication reduces the risk of macrovascular complications in
patients with T2D.
1426-P
High Mortality and Cardiovascular Event Rates Within Type 2 Diabetes Mellitus (T2DM) Patients With Established Cardiovascular
Disease (CVD) or CVD Risk Factors in a Large U.S. Database
DAVID M. KERN, STEPHANIE DEVORE, YING WU, JENNIFER KIM, BOAZ HIRSHBERG, OZGUR TUNCELI, BINGCAO WU, Wilmington, DE
T2DM-related comorbid conditions, such as hypertension and dyslipidemia,
and prior CVD events contribute to the development of cardiovascular (CV)
complications, including stroke, myocardial infarction (MI) and death. This
study described CV outcomes and mortality among patients with established
CVD and CVD risk factors.
368,581 T2DM patients aged ≥40 years were identified in the HealthCore
Integrated Research Environment from 1/1/2007 to 4/30/2011 and were
followed from first diagnosis (index date) until loss of eligibility or death.
Patients were classified as established CVD [Group 1]: MI, stroke, peripheral
vascular disease, coronary heart disease, congestive heart failure, or
revascularization in the year prior to index; or CVD risk [Group 2]: age risk (men
≥55 years, women ≥60) and with a prior diagnosis for either dyslipidemia or
hypertension.
177,140 Group 1 (mean age: 68.1 y) and 191,441 Group 2 (mean age: 66.2
y) patients met the selection criteria. Both groups were 57% men. Patients
were followed up to 5 years, and outcomes were analyzed via Kaplan-Meier
analysis (figure 1).
Supported by: Korea Healthcare Technology R&D Project
1424-P
The Association between Perfluoroalkyl Chemicals and Serum
Lipid Levels in Children
SARAH D. GEIGER, JIE XIAO, ALAN DUCATMAN, STEPHANIE FRISBEE, KIM E.
INNES, ANOOP SHANKAR, Madison, WI, Morgantown, WV
Dyslipidemia in children is associated with accelerated atherosclerosis
and earlier cardiovascular disease development. Environmental exposure
&
For author disclosure information, see page 829.
A372
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—CARDIOVASCULAR DISEASE
High mortality rates and CV events were observed for both cohorts during
follow-up. Patients with established CVD had much higher mortality rates
compared with those with CVD risk alone - reaching more than 20% after 4
years. T2DM patients are at significant risk for mortality and CVD events.
1428-P
Comparative Effectiveness of Sulfonylurea and Metformin on Risk
of Cardiac Events in Middle-Aged Adults With Type II Diabetes Mellitus
1429-P
Usefulness of Fatty Liver Index as Predictor for Coronary Artery
Stenosis in Subjects With Low to Intermediate Framingham Risk
Score
Supported by: AstraZeneca
CHANG HEE JUNG, JOONG-YEOL PARK, JAECHAN LEEM, WOO J.E. LEE, HONGKYU KIM, Seoul, Republic of Korea
Historically, the Framingham risk score (FRS) has been the dominant
method of risk stratification. However, considerable number of subjects with
substantial atherosclerosis will be missed if they are excluded from further
screening because they are in the Framingham low to intermediate-risk
category. Fatty liver disease (FLD), especially nonalcoholic fatty liver disease,
are frequently associated with risk factors for atherosclerosis. Recently,
a simple scoring system called fatty liver index (FLI) was developed as a
predictive indicator of FLD. In this study, we aimed to evaluate whether FLI
can be useful tool for the detection of subclinical coronary atherosclerosis
detected by coronary multidetector computed tomography (MDCT) in subjects
with low to intermediate FRS. We collected the data of asymptomatic 1,272
subjects (≥20 yr of age; mean age 52.8 yr) who participated in a routine
health screening examination of Asan Medical Center (Seoul, Republic of
Korea). Significant coronary artery stenosis defined as >50% stenosis. The
Agatston score was used as the coronary artery calcium score (CACS) and
was categorized as followings: CACS ≤100 (none to mild) and CACS >100
(moderate to severe). We could observe that more subjects with significant
coronary stenosis and moderate to severe CACS were included in the group
with FLI≥60 (FLI +) than in the group with FLI <20 (FLI -). The odds ratios (ORs)
for the presence of significant coronary stenosis and moderate to severe
CACS were significantly higher in the group with FLI≥60 than in the group
with FLI <20 even after adjustment for various confounding variable including
surrogate measure of insulin resistance. Our results suggest that FLI as a
simple surrogate indicator of hepatic steatosis can be useful in identifying
subjects with significant subclinical coronary atherosclerosis even though
they are classified as Framingham low to intermediate-risk category.
1427-P
Neck Circumference as a Measure of Central Obesity: Associations
With Metabolic Syndrome Beyond Waist Circumference in Chinese
Population
JUAN LIU, ZHENZHEN HONG, AILING CHEN CHEN, YANBING LI, Guangzhou,
China
Neck circumference (NC), a simple and time-saving screening measure to
identify obesity is reported to be positively correlated with the factors of
the metabolic syndrome (MetS). This study was conducted to evaluate the
correlation between the NC and components of MetS and wether it add
informations to that provided by waist circumference (WC). Cross-sectional
analysis of a population sample of 333 men and 438 women, aged 40~65
years, was conducted. Eligible subjects were healthy subjects who voluntarily
received routine comprehensive check-ups including magnetic resonance
imaging(MRI) scan analyses of abdominal Adipose tissue from February to
June 2012 at Diabetic Center of the First Affiliated Hospital of Sun Yat-sen
University. MetS was identified based on modified criteria of the ATP-III. NC
was significantly and positively associated with WC and body mass index
(BMI) (rə0.6), visceral adipose tissue (VAT) area and subcutaneous adipose
tissue (SAT) area measured by MRI (rə0.3), serum triglyceride, blood pressure
and homeostatic model-assessed insulin resistance, and inversely with SAT/
VAT ratio (SVR) (rə-0.3) and HDL-cholesterol (rə-0.4) both in men and women.
Sex and age-adjusted NC was associated significantly with MetS, at a about
1.5-fold increased likelihood for 1 standard deviation (SD) increment. After
further adjustment for WC, smoking status, alcohol use and menopausal
(women only), a significant residual odds ratio (OR, 1.2 [95%CI 1.1; 1.5])
persisted in women, but not in men. The reciever operating characteristic
(ROC) cut-off value for NC, as an indicator for MetS, was calculated as
37.7cm in men and 32.7cm in women. NC was shown to be associated with
metabolic risk factors in Chinese men and women and contributed to MetS
likelihood beyond WC in women. We suggest the use of neck circumference
as a novel, simple, practical and reliable anthropometric index in predicting
MetS, especially in women.
ADA-Funded Research
&
1430-P
Prevalence of Aspirin Resistance in Diabetic Patients Is Associated
With Daily Dose: A Systematic Review
SCOT H. SIMPSON, AHMED ABDELMONEIM, DIMA OMRAN, TRAVIS FEATHERSTONE, Edmonton, AB, Canada
Clinical trials have shown that ≤100 mg aspirin daily is not effective for
primary prevention of cardiovascular events in diabetic patients. However,
For author disclosure information, see page 829.
Guided Audio Tour poster
A373
POSTERS
Considerable controversy exists about the differential effect of oral
diabetic agents on the risk of cardiovascular disease (CVD) and mortality
in patients with type II diabetes. The comparative risk of CVD and mortality
with metformin and sulfonylureas is not well-described in the overall
population of adults age 40-64. The purpose of this study was to evaluate
the relative likelihood of cardiac events and death associated with the
use of sulfonylurea and metformin monotherapy in middle-aged patients
with type II diabetes. A retrospective-cohort study, based on propensityscore matching, analyzed patients in a large nationally representative
administrative claims database. The sample consisted of Medicaid and
Commercial patients aged 40-64 years who were new users of metformin
or sulfonylurea (glyburide and glipizide) monotherapy between 2006 and
2010. Patients were continuously enrolled for 12-months in the health plan
before initiation of diabetic treatment. Multivariate survival analysis (cox
proportional hazards model) was performed and patients were followed to
the time of adverse event or up to 180 days after the index date, and were
censored if switched to another drug or disenrolled from the healthplan.
The study population included 20,093 patients identified as new users of
sulfonylurea (female = 51.1%, mean age = 53.7 [± 6.9]) and 20,093 patients
identified as new users of metformin (female = 48.9%, mean age = 53.8 [±
6.7]) after matching. Patients prescribed sulfonylurea had a significantly
higher risk of CVD and all cause mortality compared to metformin (HR =
1.25, 95% CI: 1.18-1.32) after controlling for potential confounders. This
study provides new evidence suggesting that use of sulfonylureas increases
the risk of cardiac events and mortality in middle aged patients with type
II diabetes, and indicates caution be used in prescribing these drugs in this
patient population.
Epidemiology/
Genetics
CHRISTIE TEIGLAND, ALEXIS PARENTE, SANDHYA MEHTA, BARTON JONES,
PING CHEN, JOHN SCOGGINS, Bowie, MD
EPIDEMIOLOGY—CARDIOVASCULAR DISEASE
10mg/day (n=25), rosuvastatin 5mg/day (n=35), or pisuvastatin 2mg/day
(n=26). We evaluated dietary TG increase=postprandial TG - fasting TG at
baseline (ΔTGbase) and 4 weeks after statin administration (ΔTGstatin), and
ΔTG ratio=(postprandial TG / fasting TG with statin) / (postprandial TG /
fasting TG at base).
Change of ΔTG by statin administration (ΔTGstatin - ΔTGbase) was
inversely correlated with ΔTGbase (Figure), and was significantly smaller in
patients group of ΔTGbase ≥ 60mg/dl than in the group of ΔTGbase < 60mg/
dl (-87.5±84.7 vs. 20.3±58.1, p<0.0001). ΔTG ratio was also smaller in the
former group than the later (0.72±0.27 vs. 1.25±0.55, p<0.0001).
Statins strongly suppressed postprandial TG increase, especially in
patients with greater postprandial TG increase. This suppressive effect of
statins, resulting in lowering sdLDL level all day long, might be a possible
mechanism of beneficial effects of statins.
pharmacologic evidence suggests these patients require >100 mg daily
for adequate antiplatelet activity. This systematic review examined the
relationship between prevalence of resistance in diabetic patients and
daily aspirin dose. We searched 3 electronic databases from inception to
July 2012 using database-appropriate terms for aspirin, resistance, and
diabetes; clinical trial registries; and reference lists of included studies.
Studies were included if resistance was determined using a platelet
response measurement and the prevalence of resistance was reported
according to daily aspirin dose and diabetes status. We included 19 crosssectional studies, 4 cohort studies, and 3 randomized controlled trials.
Platelet response was measured using light transmission aggregometry in
12 studies, PFA-100 in 10, VerifyNow in 3, and serum thromboxane B2 levels
in 1. Diabetic patients were more likely to have aspirin resistance compared
to non-diabetic patients (pooled RR 1.34; 95% CI 1.03-1.73). Prevalence of
resistance varied significantly (p<0.001) according to daily aspirin dose.
Aspirin Dose Group
75-100 mg
150-250 mg
300-325 mg
Studies
19
8
8
Patients
1370
248
230
Resistant, n (%)
335 (24%)
13 (5%)
39 (17%)
Although these observations need to be verified in a clinical trial, the possibility that 1 in 4 diabetic patients are resistant to a commonly used aspirin
dose could have significant implications on its overall effectiveness.
POSTERS
Epidemiology/
Genetics
1431-P
The Effect of Maximum Body Weight in Lifetime on the Development of Coronary Artery Disease in Type 2 Diabetes: MAXWEL-CAD
Study
SOO LIM, EUN SHIL HONG, MIN JOO KIM, EUN KY KIM, YOON JI KIM, EUN ROH,
TAE JUNG OH, MIN KYEONG KIM, SU MIN HONG, SUNG HEE CHOI, KYONG SOO
PARK, HAK CHUL JANG, Seongnam, Republic of Korea, Seoul, Republic of Korea
We investigated association of rate of weight gain with subclinical
coronary artery disease (CAD) in newly detected patients with type 2
diabetes (T2D).
Obesity is well known to be associated with CAD. However, the
relationship between the rate of weight gain to development of CAD in T2D
patients has received less attention.
With 1724 consecutive Korean subjects aged ≥30 years newly diagnosed
with T2D, we evaluated degree of coronary artery stenosis, multivessel
involvement, plaque characteristics, and coronary artery calcium score
(CACS) using 64-slice cardiac computed tomography angiography. Data
of body weight at age 20 years (Wt 20y) were obtained from participants’
document. Participants recalled their maximum weight (Wtmax) prior to T2D
diagnosis and age at maximum weight (Agemax_wt). The rate of weight gain
(Ratemax_wt) was calculated from magnitude of weight gain (ΔWt = WtmaxWt 20y) divided by ΔTime (Agemax_wt -20 years).
Prevalence of significant coronary artery stenosis (≥50%), multivessel
involvement (≥2), any plaques, and CACS ≥ 100 were 11.4%, 16.8%,
19.7%, and 12.8%, respectively. The Wt 20y and Wtmax were 60.1±10.5kg
and 73.0±11.5kg, respectively. The Agemax_wt was 41.3±10.7 years and the
log-transformed (Ratemax_wt +1) was 0.59 ± 0.56 kg/year. After adjusting
for cardiovascular risk factors including BMI, the highest quartile of logtransformed (Ratemax_wt+1) was significantly associated with coronary artery
stenosis, multivessel involvement and presence of any plaque, particularly
of mixed and non-calcified plaques.
This finding supports public health recommendation of preventing rapid
weight gain from early adulthood for reduction of vascular complications
in T2D.
1433-P
WITHDRAWN
1432-P
Statins Strongly Suppress Postprandial Increase of Serum Triglyceride, Especially in Patients With Greater TG Increase—Possible
Mechanism of Beneficial Effects of Statins
TADAMASA WAKABAYASHI, YOSHIHARU FUJIMORI, MEIKO SAKURADA, MASAYUKI YOSHIMURA, HIRONORI MURAOKA, MASARU HATANO, MASEI SUDA,
TAKASHI ENDO, TAKU IMAI, MASAYA SAKURADA, Chino, Japan, Narita, Japan,
Yamaguchi, Japan, Tokyo, Japan
Statins decrease small dense low density lipoprotein (sdLDL), which
production is stimulated in response to an increase of triglyceride (TG). We
think that it is important to suppress dietary increase of TG (ΔTG).
We evaluated fasting and 3-hour postprandial lipid profiles in 86 patients
with dyslipidemia (61 males, 25 females), at baseline and 4 weeks after
statin administration. Patients were randomly assigned to atorvastatin
&
For author disclosure information, see page 829.
A374
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—CARDIOVASCULAR DISEASE
1434-P
1436-P
Associations of Cardiovascular Disease With Microangiopathy in
Diabetes
Insulin Resistance and Hypertension in Nondiabetic Asian Indian
Adults
SATSUKI KAWASAKI, HARUO MISAWA, YASUSHI TAMURA, YOSHINOBU KONDO, SHINOBU SATOH, OSAMU HASEGAWA, SOTOSHI KATO, YASUO YERAUCHI,
Fujisawa, Japan, Chigasaki, Japan, Yokohama, Japan, Tokyo, Japan
VEERAPPA A. KOTHIWALE, ANKUR BATRA, Belgaum, India
There is a growing evidence showing a relationship between Insulin
resistance and hypertension. Human as well as experimental studies have
indicated the importance of reduced insulin sensitivity in etiopathogenesis
of hypertension in some cases of essential hypertension. This study was
performed to review the existing hypothesis that hypertension is an insulin
resistant state irrespective of the diabetic status in Asian Indian adults.
There is a scarcity of data probing this relationship in Asian Indian population.
Hence, one year cross sectional study was conducted on 180 non diabetic
adults of Asian Indian ethnicity who were grouped as normotensives(60),
prehypertensives (60) and hypertensives (60) according to JNC VII classification. Insulin resistance was calculated as fasting Homeostatic Model Index
(HOMA) using fasting plasma Insulin levels and was compared with blood
pressure in all three groups with relevant statistical methods.
We found that Normotensives had a mean HOMA index 2.17±0.66 while
Prehypertensives and Hypertensives had a mean HOMA index 2.91±1.27 and
4.59±1.87 respectively. Scheffe test for intergroup variability and One Way
ANOVA was performed for HOMA index which showed a highly significant
correlation with p< 0.001.
These results suggest that Insulin resistance is independently linked
with blood pressure in non diabetic Asian Indian adults. We suggest lower
intervention threshold and development of newer therapeutic strategies to
combat insulin resistance irrespective of the diabetic status in such adults.
The progression of diabetic microangiopathy is promoted by poor control
of blood glucose and blood pressure. Macroangiopathy is also caused by
poor blood glucose control and other factors such as lipid, blood pressure
and lifestyle. Conceptually the progression of both types parallel one
another in diabetes mellitus (DM), and retinopathy is reportedly a risk factor
of cardiovascular disease (CVD). This study examined the associations of
CVD and diabetic microangiopathy in patients with type 2 DM. Subjects
were 1003 ambulatory patients with type 2 DM (578 males, 425 females).
They were 63.7 ± 12.3 years old, suffering from diabetes for 136 ± 111.8
months, and were divided into two groups: a CVD (+) group of 387 patients
showing ischemic ECG findings as abnormal Q, ST depression, and negative T
or history of angina pectoris or myocardial infarction. The other CVD (-) group
of 616 patients had none of the above findings. Retinopathy was graded into
4 stages: none, (N); mild or moderate non-proliferative, (MNP); severe nonproliferative, (SNP); and proliferative, (P). Nephropathy was classified into
three Stages: 1, 2, and 3A or worse. Subjects were first screened for CVD,
retinopathy, nephropathy, and clinical background, and then estimates of the
extent of CVD, retinopathy and nephropathy were made. The progressive
stages of retinopathy and nephropathy were associated with CVD. For the
4 stages of retinopathy CVD (+) frequencies were: 35%, 47%, 50%, and
57%, respectively. For CVD (-) they were 65%, 61%, 50%, and 44%. (p <
0.0001). For the 3 stages of nephropathy, the CVD (+) frequencies were 32%,
42%, and 60% respectively. For CVD (-) they were 68%, 58%, and 40%. The
DM patients showed association of CVD with progressions of macro- and
microangiopathies. However, some patients showed no association despite
having progressive microangiopathy, suggesting the development and
progression of CVD and microangiopathy were also affected by different
illness-specific risk factors.
Cardiovascular disease (CVD) is the leading cause of death in adults with
type 1 diabetes(T1D), and the risk for CVD is particularly increased in young
women with T1D. This study examined carotid intima-media thickness(cIMT)
in the common carotid artery, a measure of atherosclerosis in premenopausal
females between 14 and 46 years of age with T1D and without diabetes
(non-DM).
Study participants with T1D (n=32, age 27±11 years, duration 18±10 years)
and non-DM controls (n=46, age 26±7 years) were enrolled in CVD risk
factor studies at the Barbara Davis Center. cIMT was measured bilaterally
via ultrasound, and the side with the maximum thickness was used in the
analysis. Other measured risk factors included body mass index (BMI),
systolic blood pressure (SBP), total cholesterol, and LDL. Correlations and
partial correlations were examined by T1D status, followed by multivariable
linear regression to evaluate the relationship between cIMT and T1D.
T1D females had a higher mean cIMT than non-DM females (0.55±0.08
vs. 0.51±0.06, p=0.01), a higher BMI (p=0.01) and higher SBP (p=0.0004). In
participants with T1D, cIMT was correlated with older age, higher BMI and
higher SBP, whereas in non-DM participants cIMT was correlated with age
and higher total and LDL-cholesterol.
In multivariate linear regression models, mean cIMT remained significantly
higher in young women with T1D when adjusting for BMI and LDL individually,
but was attenuated (p=0.07) when adjusted for SBP. In a model adjusting for
age, BMI, SBP, T1D, and LDL, the association between cIMT and both SBP
and LDL differed based on diabetes status (p=0.004 for both interactions),
with SBP only significantly related to cIMT among participants with T1D, and
LDL only significantly associated with cIMT among non-DM participants.
These findings suggest that risk factors for early development of
atherosclerosis during the premenopausal years may differ between young
women with T1D and similar aged non-DM women.
1435-P
Comparison of Left Ventricular Filling Pressures between Male Patients With Type 2 Diabetes With Normal versus Low Total Testosterone Levels
MATIAS TINETTI, JAVIER FARIAS, MARIANO FERRER, ADRIAN BARANCHUCK,
Buenos Aires, Argentina, Ontario, ON, Canada
The aims of this study were to compare in male patients with type 2 diabetes
without structural heart disease, the left ventricular filling pressures (LVF) in
those with normal and low total testosterone (LTT) levels Heart failure is
a complication of diabetic patients and LVF is increased before symptoms
appear. LTT mediated diastolic function abnormalities through regulation of
peripheral hemodynamics. Male patients with type 2 diabetes have LTT in
30% of cases. The relationship between LTT levels in male diabetic patients
and LVF is unknown We assessed diabetic patients (p) with tissue Doppler
imaging for evaluation of left ventricular filling pressures by passive transmitral left ventricular inflow velocity to tissue Doppler imaging velocity of
the lateral mitral annulus during passive filling (E/e’ ratio). Patients with
history of heart failure, myocardiopathies, left ventricular hypertrophy,
diastolic dysfunction (E/e´>15) and arrhytmias were excluded. We compared
them depending on low (< 3,5 ng/ml, group A) or normal (> 3,5 ng/ml, group
B) total testosterone levels. All patients were asymptomatic and without
history of cardiovascular disease.
Biochemical test and bioparametric results were measured. Data were
analyzed using Mann Whitney U test and x2 test. A total of 148 male p were
included. Mean age was 58 years (±5,8) and mean time of diabetes evolution
7 years (±3,1). Group A 47p (32%) and Group B 101p (68%). There was no
difference between groups regarding age, time of diabetes evolution,
hypertension, weight, heart rate, BMI or echocardiographic parameters .The
E/e’ ratio in group A was 8,05 (±1,9) vs. group B 6,1 (±1,7) p < 0,0001.
Patients with type 2 diabetes and LTT levels have higher E/e’ ratio, showing
pre clinic increased left ventricular filling pressures vs diabetic patients with
normal testosterone levels. This finding is independent of time of diabetes
evolution, hypertension, or other echocardiographic parameters.
ADA-Funded Research
&
1438-P
The Relationship of Age at Menarche and Menopause With Diabetes in Chinese Women
GANG CHEN, JUNPING WEN, Fuzhou, China
Context: Age at menarche and menopause were associated with cardiovascular disease (CVD), diabetes mellitus and osteoporosis in Caucasian
women. However, the associations were largely unexplored in China.
Objective: We assessed the relationship of age at menarche and menopause with CVD, diabetes and osteoporosis in Chinese women.
Design and Setting: A cross-sectional, population-based study was
conducted in Fujian, China from June 2011 to January 2012.
For author disclosure information, see page 829.
Guided Audio Tour poster
A375
POSTERS
LINDSEY M. DUCA, TALIA L. BROWN, RACHEL M. SIPPL, FRANZISKA BISHOP,
DAVID MAAHS, PAUL WADWA, JANET K. SNELL-BERGEON, Aurora, CO
Epidemiology/
Genetics
1437-P
Risk Factors for Carotid Intima-Media Thickness Differ Between
Young Women With and Without Type 1 Diabetes
EPIDEMIOLOGY—CLINICAL—DIAGNOSIS AND SCREENING
Participants: A total of 5831 Chinese women aged 21-92years were
entered into the investigation.
Main Outcome Measures: We measured oral glucose tolerance test, 12lead resting ECG and calcaneus quantitative ultrasound.
Results: Age at menarche was negatively correlated with diabetes risk
(OR=0.95, 95%CI=0.91-0.99) and CVD risk (only among postmenopausal
females, OR=0.95, 95%CI=0.91-0.99) and positively correlated with
osteoporosis (OR=1.08, 95%CI=1.00-1.17) after adjustment for age. Menopause
age was inversely associated with CVD risk (OR=0.97, 95%CI=0.95-0.99) and
osteoporosis risk (OR=0.96, 95%CI=0.93-0.98), but not diabetes risk. Further
adjustment for body mass index (BMI) and waist circumference (WC) eliminated
associations of age at menarche with diabetes risk (OR=0.96, 95%CI=0.921.01) and CVD risk (OR=0.92, 95%CI=0.91-1.00).
Conclusions: Early menarche seems to be associated with increased risk
of diabetes and CVD, decreased risk of osteoporosis. Early menopause may
increase the risk of CVD. Females who had age at menopause 50-54years
had a lower osteoporosis risk than the reference. This relationship of age at
menarche with diabetes and CVD appears to be mediated by BMI and WC.
History of early menarche and menopause may help in the identification of
women with increased risk of diabetes, CVD and osteoporosis.
height and weight were used for the DRT. Dysglycemia was defined as A1C
≥ 5.7% or 6.0% and diabetes as A1C ≥ 6.5%.
1161 subjects had complete data for analysis with means for age and
BMI of 50 yrs and 29 kg/m2. 31% were male. Prevalence of A1C ≥ 5.7%, ≥
6.0% and ≥ 6.5% were 37%, 17% and 5%, respectively. Sensitivity (SENS),
specificity (SPEC) and area under the curve (AUC) for detection of increasing
levels of A1C are shown in Table 1.
Table 1
A1C ≥ 5.7%
A1C ≥ 6.0%
A1C ≥ 6.5%
Threshold SENS SPEC AUC SENS SPEC AUC SENS SPEC AUC
SCOUT DS 50 AU
.63 .72 .73 .79 .67 .81 .95 .62 .90
ADA DRT 5
.69 .64 .71 .85 .59 .78 .95 .54 .84
RCG
100 mg/dL .52 .67 .65 .59 .64 .67 .74 .62 .75
SCOUT DS and the ADA DRT had significantly greater AUC and SENS relative to RCG for detecting A1C-defined dysglycemia and diabetes. SCOUT DS
had comparable AUC and SENS relative to the ADA DRT with significantly
higher SPEC. Both noninvasive tests significantly outperformed RCG for diabetes screening with the added advantages of not requiring blood or causing
pain.
&
1441-P
POSTERS
Epidemiology/
Genetics
1439-P
Use of Discounted Combination Oral Hypoglycemics Improve Other
Cardiometabolic Risk Factors in a Community Health Center Population
Capillary Glucose Testing after Oral Glucose Load: A Convenient
Screening Test for Type 2 Diabetes and Prediabetes in Latino Adults
JEFFREY D. SIMMONS, NNEAMAKA NWANKWO, CINDY VALIENTE, Miami
Springs, FL
At least 25.8 million people in the U.S. have diabetes (DM). Of these, 7
million are undiagnosed. About 79 million more have prediabetes (preDM).
DM disproportionately affects the elderly, as well as certain ethnic groups.
DM affects 11.8% of Hispanics, but only 7.1% of whites. Many at high risk
are not screened, often due to poor access to care. We need a reliable tool
for early diagnosis of DM and preDM.
Subjects were recruited from among Latino men and women, age 45 and
over, with no history of DM. After an overnight fast, subjects were given a
standard 75 g oral glucose tolerance test (OGTT), with venous blood drawn
prior to and 2 hours after glucose load. At 2 hours, a simultaneous capillary
glucose test (CGT) was done, A capillary glucose value of > 140 mg/dL was
considered a positive screen. Over 3 years, a total of 116 subjects were
enrolled and completed the study.
Subjects with abnormal glucose on OGTT (preDM or DM): 46 (39.7%)
Previously undiagnosed DM: 12 (10.3%)
PreDM: 34 (29.3%)
Subjects with abnormal glucose on CGT (preDM or DM): 62 (53.4%)
PETER R. BAGINSKY, MITCHELL BARNETT, Vallejo, CA
Miami Beach Community Health Center serves over 1000 Type 2 diabetics,
the majority of which are uninsured. The complexity of the diabetic medical
regimen and its associated cardiometabolic risk factors create a tremendous
burden on the patients and necessitate choosing among various therapies
based on financial considerations. Over 12 months ago, combination
sitagliptin-metformin became available at a discounted rate in our center.
We hypothesized that a combination therapy would allow for the patients to
afford other therapies and lower their entire cardiometabolic risk profile. We
reviewed the records of our patients who had been treated with combination
sitagliptin-metformin for at least 6 months and had measurements of body
weight (lbs), systolic blood pressure (sBP), low density lipoprotein cholesterol
(LDL), and glycosylated hemoglobin (A1c) before and after initiation. A
student t-test for paired samples was used to compare both samples. After 6
months of combination oral hypoglycemic therapy, patients lost an average
of 4.79lbs (37pts, range -20 to +7, p=0.000039), had a drop in sBP of 8mmHg
(35pts, range -104 to +7, p=0.048), drop in LDL of 24mg/dl (28pts, range -92
to +23, p=0.0001) and drop in A1c of 1.2% (40pts, range -9.1 to +1, p=0.0038).
Discounted combination oral hypoglycemics may allow for better reduction
in global cardiometabolic risk in patients who must choose therapies based
on financial considerations.
Comparison of Random Capillary Glucose, the ADA Diabetes Risk
Test and SCOUT DS for Diabetes Screening in At-Risk Populations
Sensitivity, Specificity, Positive Predictive Value (PPV), and Negative
Predictive Value (NPV) of a post-load CGT of >140 mg/dL to detect preDM or
DM (compared with OGTT):
Sensitivity (95% CI): 84.8% (71.1% - 93.7%)
Specificity (95% CI): 67.1% (54.9% - 77.9%)
PPV (95% CI): 62.9% (49.7% - 74.8%)
NPV (95% CI): 87.0% (75.1% - 94.6%)
Our findings show the use of a single fingerstick CGT after a glucose load
is a sensitive screen for preDM or DM. Of the 116 subjects, 46 (39.7%) were
found to have previously undiagnosed DM or preDM. The CGT identified
39 (84.8%) of these individuals. Clearly this test, will miss a few with abnormal glucose; particularly those with isolated impaired fasting glucose.
Nevertheless, it is a simple, low-cost and powerful screening tool. It will
initially identify most individuals with preDM. This test has advantages for
screening the underserved population. It requires only an oral glucose drink
and a glucose meter.
JOHN D. MAYNARD, ANDREA BARRACK, PAUL MURPHREE, PANAGIOTIS
LATHOURIS, NIKOLAOS TENTOLOURIS, STAUROULA LONDOU, KOSTAS TZEMOS, BYRON OLSON, MARWOOD EDIGER, CAROLE PALEY, MANDY SWANEPOEL, RICHARD POPE, Albuquerque, NM, Baton Rouge, LA, Athens, Greece, Steeton,
United Kingdom
ATLANTIC DIP: Are the IADPSG Criteria for GDM Missing Women
Who Would Previously have been Identified With GDM Using WHO
Criteria?
EPIDEMIOLOGY—CLINICAL—DIAGNOSIS AND
SCREENING
Guided Audio Tour: Clinical Epidemiology—Diagnosis and Screening (Posters: 1440-P to 1447-P), see page 15.
&
1440-P
&
1442-P
ADRIENNE M. HEEREY, LOUISE CARMODY, BREDA KIRWAN, FIDELMA P. DUNNE,
MARIA EGAN, Galway, Ireland
Screening at risk subjects for prediabetes and diabetes is an important
step in prevention efforts. We examined the accuracy of random capillary
glucose (RCG, common for mass screening) and two noninvasive screening
methods, SCOUT DS and the ADA diabetes risk test (DRT) for detecting
increasing levels of abnormal A1C.
We pooled data from studies performed in the US, UK and Greece that
shared methods and aims. A diabetes score was calculated from skin
fluorescence measured on the left forearm with SCOUT DS. A finger prick
was done to measure RCG and A1C. Age, sex, history of gestational diabetes,
family history of diabetes, history of high blood pressure, physical activity,
ATLANTIC DIP now uses IADPSG criteria (fasting glucose ≥ 5.1 mmol/L; 1
h ≥ 10 mmol/L and 2 h ≥8.5 mmol/L) to identify Gestational Diabetes Mellitus
(GDM) having previously used WHO criteria for diagnosis (fasting gluscose
≥6.1 mmol/L and 2h glucose ≥ 7.8 mmol/L). Potential missed cases of GDM
using the IADPSG criteria (i.e. with a 2 h glucose 7.8 to 8.5 mmol/L) and the
impact on maternal and neonatal health has not yet been investigated. We
included women from 2005 -2012 who had a 75g OGTT for GDM diagnosis.
Women were either part of a universal screening programme (2007–2010) or
selective screening. Maternal and neonatal complications for “WHO” GDM
&
For author disclosure information, see page 829.
A376
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—CLINICAL—DIAGNOSIS AND SCREENING
prevalence of diabetes and prediabetes were 10.6% (men 12.7%, women
8.5%) and 19.3% (men 23.6%, women 15.2%). When HbA1C was included as
a diagnostic test, prevalence of diabetes and prediabetes were increased to
12.7% (men 14.8%, women 10.5%) and 38.3% (men 40.7%, women 36.0%).
Mean values of HbA1C were 5.5% (SE 0.0%) of normal glucose tolerance,
5.8% (SE 0.0%) of impaired fasting glucose, and 7.4% (SE 0.2%) of newly
diagnosed diabetes, respectively. We concluded that using fasting glucose
only can be underestimated to define diabetes and prediabetes. National
standardization should be needed to use HbA1C as a diagnostic test of
diabetes and prediabetes.
women (i.e. with a 2h glucose 7.8-8.5mmol/l) were compared to women with
normal OGTT (NGT). The Pearson Chi square test was used with a p value of
≤ 0.05 as significant. Of 4,398 women who had a 75g OGTT, 2,707 (62%) were
diagnosed with NGT and 1,691 (38%) with GDM. 827 (19%) had GDM using
both criteria; 695 (16%) with IADPSG criteria alone and 169 (3.8%) with WHO
criteria alone. Rates of emergency Caesarean sections were significantly
greater in WHO GDM women (20%) compared to NGT women (14%) (P<0.05)
and WHO GDM women were more likely to develop polyhydramnios (2.6%
v 0.8%)(P<0.05). Neonatal hypoglycaemia (2.3% v 0.7%) and congenital
malformations (4.7% v 1.6%) were both significantly greater in offspring of
WHO GDM women compared to NGT women (P<0.05). To conclude, less than
4% of women would not now be identified with GDM using IADPSG criteria
but would previously be classified with GDM by WHO criteria. Maternal
complication rates for these women and their offspring are greater compared
to NGT women. Future prospective studies are necessary to ensure that the
2 h IADSPG threshold of >/=8.5 mmol/L is not now too high.
&
1443-P
Abnormal Glucose Tolerance in Women With Polycystic Ovary Syndrome (PCOS): Role of Sex Steroids and Obstructive Sleep Apnea
KARLA A. TEMPLE, ESRA TASALI, BABAK MOKHLESI, HARRY WHITMORE,
SYDEAKA WATSON, EVE VAN CAUTER, DAVID A. EHRMANN, Chicago, IL
Obstructive sleep apnea (OSA) is a risk factor for cardiometabolic
dysfunction that is highly prevalent in women with PCOS. We sought
to examine the effects of sex steroids upon glucose tolerance and OSA
prevalence and severity in women with and without PCOS.
Following an overnight polysomnogram (PSG), 175 women (PCOS n=129;
control n=46) (BMI (kg/m2): 38.6 + 0.6 vs 39.4 + 1.1, p=0.495; Age (yr): 28.2 +
0.5 vs 31.0 + 0.9, p=0.004) had a 2-h 75-g oral glucose tolerance test (OGTT):
progesterone, total and free testosterone were measured at time 0; glucose,
insulin, and C-Peptide were measured every 30 min for 2-h. All analyses
were adjusted for age, BMI, and ethnicity-based diabetes risk.
Nineteen (41%) control and 62 (48%) PCOS women had OSA (OR for
OSA=2.4, CI 1.1-5.6; p=0.03) after controlling for age, BMI, and race risk. OSA
was more severe in PCOS women as reflected by the mean apnea-hypopnea
index (AHI) during the PSG (4.7 + 0.1 vs 1.7 + 0.2, p<0.001). Eleven (24%)
control and 50 (39%) PCOS women had prediabetes (IFG or IGT) (p<0.01).
Glucose tolerance was decreased by the presence of both PCOS (p<0.001)
and OSA (p=0.002). Insulin levels and insulin secretion rates (ISR) during
the OGTT were increased in PCOS women (p<0.001 for AUC). Fasting and
120-min ISR were increased in the presence of OSA (p=0.001 and p=0.022
respectively).
Among women with PCOS, 2-h glucose levels were positively correlated
with OSA severity (p=0.017) and negatively correlated with progesterone
concentration (p=0.03); the correlation with testosterone concentration was
not significant (p=0.07). In contrast, these relationships were not significant
in controls (p=0.18, p=0.45, p=0.53 respectively).
Conclusions: Compared to controls, women with PCOS have a higher
prevalence of both OSA and prediabetes. Both severity of OSA and
progesterone levels are predictive of two-hour glucose values during an
OGTT in women with PCOS. Women with both PCOS and OSA are at greater
risk for developing diabetes.
Supported by: CDC
&
MARY RHEE, SANDRA L. JACKSON, DARIN E. OLSON, WENQIONG XUE, QI
LONG, J. SONYA HAW, DIANA BARB, ARUN V. MOHAN, ANNE TOMOLO, PHYLLIS WATSON-WILLIAMS, LAWRENCE S. PHILLIPS, Atlanta, GA, Decatur, GA
Since inpatient glucose levels are variable, their usefulness as a marker of
diabetes risk has been questioned, but is not well understood. To determine
potential predictive utility, we evaluated hospital glucose levels in 10,522
veterans using the VA Informatics and Computing Infrastructure (VINCI)
database - in patients hospitalized between 2000-2009 for ≥3 days on
medical/surgical services, with ≥1 primary care visit within 2 yr before and
annually for 3 yr afterwards, and with no diagnosis of diabetes (ICD-9 code
250.xx or a diabetes drug) before or during hospitalization. 7,556 patients
did not have diabetes (normal, NL) throughout, and 2,966 were diagnosed
after discharge - 719 DM 1yr, 568 DM 2yr, 550 DM 3yr, and 1,129 DM 4-5yr.
Patients had mean age 58.4 yr and BMI 33.8, and were 90% male, and 22%
black. Using 3 hospital glucose values per patient (minimum, maximum,
median) to offset variability in sample numbers, we examined sensitivity
and specificity of glucose levels to identify patients diagnosed with DM 1-3
yr after discharge. A glucose level of 170 mg/dl (equivalent to the NL group
95th percentile) was insensitive but specificity was 95% - highly predictive
of clinically diagnosed diabetes in the next 3 years. Conclusion: Although
hospital glucose values reflect multiple factors other than insulin resistance
and insulin secretion, levels above 169 mg/dl are highly specific for diabetes
within 3 years post-discharge, and should trigger screening for diabetes
after hospitalization.
Supported by: NIH (P50-HD057796), (R01HL075079), (P60-DK020595), (UL1RR024999); Kovler Foundation
&
1444-P
Diabetes and Prediabetes are Largely Increased when HbA1C Is
used as a Diagnostic Test
JA YOUNG JEON, BU KYUNG KIM, SEUNG JIN HAN, KWAN-WOO LEE, DAE
JUNG KIM, Suwon, Republic of Korea, Busan, Republic of Korea
Due to the inconvenience of performing an oral glucose tolerance test,
and day-to-day variability in glucose, HbA1C has now been recommended
by the American Diabetes Association as a method to diagnose diabetes.
Korean Diabetes Association also recommended HbA1C as a diagnostic
test. We evaluated the prevalence of diabetes according to fasting plasma
glucose (FPG) only or both FPG and HbA1C. The data from the Korea
National Health and Nutrition Examination Survey (KNHANES) 2011 were
analyzed. Among 5,811 subjects aged 30 years or older, 5,128 were selected
after excluding the data of fasting time < 8hrs and/or the missing values
of fasting glucose or HbA1C. Diabetes was defined as 1) FPG ≥126 mg/dL,
2) previous diagnosis by medical doctors, 3) current use of anti-diabetic
medications, and/or 4) HbA1C ≥6.5%. Prediabetes was defined as 1) FPG
of 100-125 mg/dL, and/or 2) HbA1C of 5.7-6.4%. When we used FPG only,
ADA-Funded Research
&
1446-P
Inpatient Glucose Levels Predict Clinical Diabetes After Hospitalization
For author disclosure information, see page 829.
Guided Audio Tour poster
A377
POSTERS
Postpartum glycemic screening in women with history of gestational
diabetes (GDM) identifies abnormal glucose after pregnancy and allows
for early identification of Type 2 diabetes. Little is known about national
patterns of post-partum screening in clinically and geographically diverse
settings. Using claims data from an insurance database comprising 48
million members in all 50 states, we identified women aged 15-44 with GDM
with one inpatient or 2 outpatient ICD-9 codes (648.8X) and continuous
enrollment 310 days pre and 1 year post-delivery in 2002, 2004, 2007, or
2010. We identified screening type (75g oral glucose tolerance test (OGTT),
fasting plasma glucose (FPG), HbA1C) and timing (< 6, 6-12, and 12-52 weeks).
Of the 11,463 women with GDM in the 4 years combined, 22% received any
form of screening in the year post-partum. On logistic regression adjusted for
race/ethnicity, age, geographic region, and number of pregnancies, older age
(OR 1.23, 95% CI 1.02-1.48 for >=40 vs. 15-<30 yrs), Asian race/ethnicity (OR
1.75, 95% CI 1.52-2.02, vs. white), and geographic region were associated
with any screening. Rates in the West were significantly higher than in all
other regions and rates in the Midwest significantly lower. Over the 4 time
periods, screening rates increased (OR 1.07, 95% CI 1.03-1.18 per period),
as did use of the recommended 75g OGTT (OR 1.31, 95% CI 1.20-1.44 per
period). However among those screened (N=2520), A1C alone was commonly
used (36% of all tests), and represented 15% of testing at <12wks. Use of
A1C was highest in women with black race/ethnicity (OR 1.47, 95% CI 1.042.09, vs. white) and in the Midwest and Northeast (ORs 1.66 and 1.66, 95%
CIs 1.32-2.10 and 1.24-2.23, respectively, vs. West). In sum, type and timing
of post-partum diabetes screening differ by geographic region, age, and
race/ethnicity. Rates of screening and use of the recommended 75g OGTT
have been increasing over time, however HbA1C is commonly used, even in
the immediate post-partum period.
Epidemiology/
Genetics
EMMA M. EGGLESTON, ROBERT LECATES, FANG ZHANG, JAMES F. WHARAM,
DENNIS ROSS-DEGNAN, EMILY OKEN, Boston, MA
Supported by: HRB
&
1445-P
Variation in Post-Partum Glycemic Screening in Women With a History of Gestational Diabetes
EPIDEMIOLOGY—CLINICAL—DIAGNOSIS AND SCREENING
HOSPITAL GLUCOSE
mg/dL
>= 100
110
120
130
140
141
150
160
170
180
190
200
however, the pathology is not well-known. We investigated that galectin-3
could be a predictor of worsening glucose tolerance.
We measured serum Galectin-3 level of 81 participant received OGTT
in 2005 and 2009. In 2005, the participants were NGT 46, IGT 30, DM 5.
The mean serum galectin-3 level of all participants was 1732 pg/ml. Nine
participants were worsening glucose tolerance (NGT to IGT, and IGT to
DM), the mean serum galectin-3 level of these participants was 3721 pg/
ml, it was significantly higher than non-worsening group of 1537 pg/ml. The
optimal cut-off level of galectin-3 to detect worsening glucose tolerance
was 2400 pg/ml using ROC analysis (sensitivity 78%, specificity 80%). In
a biphasic logistic analysis, galectin-3>2400 was a significant risk factor
of worsening glucose tolerance, the odds ratio was 14.8 (P<0.005, 95%CI
2.42-90.0, adjusted by age, gender, BMI, FPG, I.I., HOMA-IR). Galectin-3 level
positively correlated with high sensitive CPR (R=0.27, P<0.05).
These results suggested that high serum galectin-3 level predicts
worsening glucose tolerance. In conclusion, Galectin-3 is a good predictor
of worsening glucose tolerance.
DIABETES DIAGNOSIS WITHIN 3 YEARS
AFTER HOSPITALIZATION
SENSITIVITY
SPECIFICITY
78.0%
36.1%
62.3%
54.5%
48.5%
68.5%
37.4%
78.5%
28.6%
85.0%
27.7%
85.4%
21.9%
89.4%
17.1%
92.7%
13.4%
94.8%
10.6%
96.3%
8.2%
97.3%
6.5%
98.0%
Odds Ratio of risk factors worsening glucose tolerance
Risk factors
Odds Ratio
P value
Galectin-3>2400
14.8
<0.005
Age
1.04
0.57
Gender (male)
0.84
0.85
BMI
0.92
0.64
FPG
1.07
0.16
Insulingenic index
2.01
0.39
HOMA-IR
0.89
0.92
Supported by: U.S. Dept. of Veterans Affairs
&
1447-P
A Method of Diabetes Risk Assessment Based Solely on Information from a Nuclear Magnetic Resonance Spectrum of Plasma
POSTERS
Epidemiology/
Genetics
JAMES OTVOS, THOMAS O’CONNELL, Raleigh, NC
Risk of progression to Type 2 diabetes is currently assessed by fasting
glucose, with concentrations 100-125 mg/dL defining a high-risk “prediabetes” condition. However, the risk of individual patients with prediabetes varies widely. To identify the highest-risk patients who would
benefit the most from intervention, we developed a Diabetes Risk index (DRI)
that uses only information derived from a single nuclear magnetic resonance
(NMR) spectrum of a fasting plasma sample. This information includes
glucose and lipoprotein subclass/size parameters previously linked to insulin
resistance as well as novel metabolite information including the branchedchain amino acid, valine, and a unique NMR-based inflammatory marker that
provides a global measure of protein glycoslyation. We used NMR spectra
collected at baseline from the Multi-Ethnic Study of Atherosclerosis (MESA)
to develop the DRI score. The dataset consisted of 3185 participants, 280 of
whom developed diabetes during 5 years of follow-up. The Figure presents
the diabetes conversion rates of subjects within 6 glucose subgroups (dotted
line), and those for subjects in the upper and lower quartile of DRI within
each glucose stratum. As shown, the risk of developing diabetes at any given
glucose level is substantially greater for DRI in Q4 vs Q1. It thus appears that
a simple NMR-based diabetes risk score can effectively stratify risk without
the need for additional clinical information.
95%CI
2.42-90.0
0.90-1.20
0.13-5.22
0.65-1.29
0.97-1.18
0.40-10.3
0.07-10.7
1449-P
Mechanism of the Dawn Phenomenon in Patients With Type 2 Diabetes
KEISHI YAMAUCHI, YUKA SATO, TORU AIZAWA, Matsumoto, Japan
The Dawn phenomenon (DF) is an early-morning rise in blood glucose that
occurs before or shortly after waking without nocturnal hypoglycemia. It can
be troublesome for patients with diabetes. However, the definition of this
condition is unclear. In the study, we analyzed mechanism of DF by dividing
into before waking (3 a.m. to 6 a.m.) and after waking (6 a.m. to 8 a.m.) in
inpatients of our hospital with type 2 diabetes. We measured plasma glucose
concentration (PG) at 3 a.m., 6 a.m. and 8 a.m. (=fasting), fasting immunereactive insulin, others such as lipids and hormones. Those with insulin
therapy or high fasting plasma glucose (>11mmol/L) were excluded. We
defined that more than 5% of elevation of PG was the significant elevation,
and the elevation between 3 a.m. and 8 a.m. was that DF is positive (DF+).
Further we divided DF+ into a group starting of the elevation before waking
(BW) and the other after waking (AW). DF+ was found in 39%. Difference
of age between DF+ and DF negative (DF-) have that tendency, but is not
significant. Although there were no differences of HOMA−IR nor HOMA−β
between of DF+ and DF-, HOMA-IR of AW was notably higher than DF-’s
and BW’s and HOMA−β of BW was significantly lower than DF-’s and AW’s.
These results suggested that BW is related to insulin secretory ability and
AW may be subject to influence from insulin resistance. In this study, we
showed that BW and AW occur by a different mechanism, respectively and
may be useful of measuring PG at 3 a.m., 6 a.m. and 8 a.m. for estimating
the quality of DF.
Selected data of the study
All
Number
(male/female)
Age
HoMA-IR
HOMA-β
#, P
1448-P
Galectin-3 Is a Good Predictor of Worsening Glucose Tolerance
TSUYOSHI OHKURA, YOUHEI FUJIOKA, HIDEKI SHIOCHI, KEISUKE SUMI, NAOYA
YAMAMOTO, KAZUHIKO MATSUZAWA, SHOICHIRO IZAWA, HIROKO OHKURA,
MASAHIKO KATO, SHIN-ICHI TANIGUCHI, KAZUHIRO YAMAMOTO, Yonago, Japan
DF-
DF+
All
BW
AW
66
43
23
7
16
(45/21)
(28/15)
(17/6)
(5/2)
(12/4)
60.6±13.6 59.1±14.0 63.6±13.2 64.3±13.1
63.3±13.3
2.14±1.53 2.01±1.63# 2.13±1.33 1.30±0.88## 2.49±0.93
29.2±19.2 32.2±17.2* 22.7±16.3 10.1±3.9
28.2±15.9*
Galectin-3 was reported as a predictor for prognosis of heart failure,
Galectin-3 is a family of soluble beta-galactoside-binding lectin that play
many important regulatory roles in inflammation. In diabetic patients, it
was reported that serum galectin-3 level negatively correlated with HbA1c,
&
For author disclosure information, see page 829.
A378
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—CLINICAL—DIAGNOSIS AND SCREENING
non-HLA SNPs in DAISY and found that PTPN22, UBASH3A, INS and IFIH1
were significantly associated with development of islet autoimmunity (IA)
and/or progression from IA to diabetes. A total of 1607 non-Hispanic white
DAISY children were now evaluated for these 30 non-HLA single nucleotide
polymorphisms (SNPs) and thyroid peroxidase (TPO) antibody. Of those, 7%
(n=109) had thyroid autoimmunity defined as positive TPO antibody during at
least one study visit. In Cox PH models adjusting for HLA-DR3 genotype and
family history of type 1 diabetes, GSDM (rs2290400), SH2B3 (rs3184504) and
2 UBASH3A SNPs (rs11203203 and rs9976767) were associated with thyroid
autoimmunity (HR 1.36, 1.53, 1.44 and 1.43 respectively, all p < 0.03). PTPN22,
CTLA4 and IFIH1 were not significantly associated with thyroid autoimmunity
(HR 1.34, 1.10 and 0.8 respectively, p > 0.1), likely because of small sample
size. Additional shared non-HLA genetic loci may play an important role in
the early onset of autoimmune phenotypes in this cohort of young children
with high-risk HLA markers for type 1 diabetes.
1450-P
Serum Irisin Levels in New-Onset Type 2 Diabetes
YEON-KYUNG CHOI, KWI-HYUN BAE, JI-YUN JEONG, JUNG-GUK KIM, IN-KYU
LEE, KEUN-GYU PARK, HYUN-AE SEO, EUI-HYUN KIM, JAE-HAN JEON, Daegu,
Republic of Korea
Aims: Irisin has been identified as a novel myokine that drives brown-fatlike conversion of white adipose tissue. In this cross-sectional study, we
investigated whether serum irisin levels are decreased in patients with type
2 diabetes (T2D) compared to control subjects with normal glucose tolerance
(NGT), and assessed the association between serum irisin levels and various
metabolic parameters.
Methods: This population-based study included 104 subjects with NGT
and 104 subjects with new-onset T2D. Serum irisin and adiponectin levels
and metabolic parameters were measured. Multivariate logistic regression
analysis was performed to assess the association between irisin levels and
the development of T2D.
Results: Serum irisin levels were significantly decreased in the newonset T2D group compared with the NGT control group (p =0.003). In a
multivariable model adjusted for various metabolic parameters, increased
irisin levels were associated with reduced odds (OR 0.64, 95% CI 0.47-0.88,
p = 0.006) of prevalence of T2D. Furthermore, multiple regression analysis
showed that 2 hour plasma glucose was an independent variable influencing
serum irisin levels (p = 0.004).
Conclusion: In the present study, we found that serum irisin levels were
decreased in T2D patients and inversely associated with the development
of T2D, suggesting that irisin may play a crucial role in glucose intolerance
and T2D.
Supported by: JDRF (11-2010-206)
1453-P
Neck Circumference Correlates Better With Glucose Homeostasis
than Waist or Waist-to-Hip Ratio
1451-P
The Visceral Fat Accumulation Affects Plasma Free Amino Acid
(PFAA) Profile and the Index Generated from PFAAs can Distinguish
Visceral Obesity in Japanese Subjects
KENJI NAGAO, TAKAYUKI TANAKA, YUKO ISHIZAKA, TORU MITUSHIMA, MIZUKI TANI, AKIKO TODA, EIICHI TODA, MINORU OKADA, HIROSHI MIYANO,
HIROSHI YAMAMOTO, YASUSHI NOGUCHI, MINORU YAMAKADO, Kawasaki,
Japan, Tokyo, Japan, Chiba, Japan
Metabolic complications associated with obesity are prevailing among
Japanese subjects. While visceral fat plays a pivotal role in development of
an unfavorable metabolic and atherosclerosis risk, visceral fat accumulation
is not always apparent by measuring BMI or waist circumference in Asians
because of the physiological characteristics particular to those ethnicities.
Thus, high-throughput determination of the amount of abdominal adipose
tissue is needed. We have previously reported that PFAA levels were
altered by accumulation of visceral fat, not by subcutaneous fat, in 1,449
healthy Japanese subjects whose visceral fat area (VFA) was determined
using computed tomography imaging (Clinical Obesity 2012;2:29-40). The
following four categories, which were defined based on the BMI and VFA
values, were used: healthy subjects, HS (BMI<25 kg/m2; VFA<100 cm2);
apparent obese subjects, AO (BMI≥25 kg/m2; VFA<100 cm2); non-apparent
visceral obese subjects, NAVO (BMI<25 kg/m2; VFA≥100 cm2); and obese
subjects, Obesity (BMI≥25 kg/m2; VFA≥100 cm2). In this study, we further
analyzed these populations according to those four categories. A hierarchical
cluster analysis using Ward’s method toward each category revealed
that the formations of amino acid clusters were identical between NAVO
and Obesity, while those of HS and AO were different, indicating not only
absolute levels of amino acids but also relative concentrations among each
amino acid were affected by the VFA accumulation. A PFAA index to identify
high VFAs (≥100 cm2) was developed by multivariate logistic regression
model. The ROC_AUC of the generated indices were 0.78 to 0.83, and the
sensitivity to identify subjects with NAVO was much greater than that of the
waist circumference (73% vs. 46%, respectively). These indices, thus, can be
used as a predictor of elevated visceral obesity and a risk assessment tool
for metabolic complications in Asian populations.
Supported by: NIH/NIDCR (R01DE020111)
1454-P
How Does Adoption of the IADPSG/ADA Guidelines for Diagnosis
of Gestational Diabetes Affect Women’s Perceptions of Disease
Severity?
JOYCE W. TANG, KENZIE A. CAMERON, ALAN PEACEMAN, RONALD T. ACKERMANN, Chicago, IL
Adoption of IADPSG/ADA Guidelines for diagnosis of gestational diabetes
(GDM) (75g 2 hour glucose tolerance test (GTT)) increases the proportion of
pregnant women diagnosed with mild disease, and may lead more women
to question their diagnosis. Perceived misdiagnosis could affect likelihood of
obtaining follow-up care and adoption of healthy behaviors.
We conducted semi-structured phone interviews with women diagnosed
with GDM within 1 year of their delivery. We recruited patients with positive
GTT results from 4 obstetrics and 1 endocrinology clinic in Chicago, IL; 3
clinics used 2 hour GTT; 2 clinics used 1 hour + 3 hour GTT. Women rated
their agreement (5 point scale) with: “I had a mild case of GDM” and “I don’t
think I truly had GDM.” Women rated (4 point scale) their risk for recurrent
GDM and DM2, and compared pre- and post-pregnancy diet and exercise
habits (healthier/more active, no change, less healthy/less active). Receipt
of postpartum GTT was self-reported. Chi-square tests were used to test
potential associations.
Of 124 eligible patients, 74 completed interviews (33 Caucasian, 34
Hispanic, and 7 African-American); mean age was 34; 70% were diagnosed
1452-P
Association of Non-HLA SNPs With Thyroid Autoimmunity in Children at Increased Risk for Type 1 Diabetes
ALEXANDRA R. FOUTS, FRAN DONG, RANDALL WONG, JILL M. NORRIS, MARIAN J. REWERS, ANDREA K. STECK, Aurora, CO
While type 1 diabetes and autoimmune thyroid disease cluster in individuals
and families, shared non-HLA genetic markers have not been consistently
replicated except for PTPN22, CTLA4 and IFIH1. The Diabetes Autoimmunity
Study in the Young (DAISY) prospectively follows children at increased risk
for the development of type 1 diabetes. We have previously examined 30
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A379
POSTERS
BMI, fat%, WC and WHR are standard anthropometric measures
mostly associated with prediabetes and other cardiometabolic conditions.
However, the potential relative value of neck circumference (NC) is not
well characterized. This analysis compares the relative utility of NC with
standard anthropometric measures by comparing correlations with glucose
homeostasis measures. A total of 1,206 overweight/obese Hispanic adults,
aged 40-65 years free of diabetes were recruited. NC was measured below
the larynx, perpendicular to the neck; other anthropometric measures were
assessed following the NHANES protocol. Prediabetes was defined as
fasting plasma glucose of 100-125 mg/dL, 2-h glucose tolerance after OGTT of
140-199 mg/dL and/or hemoglobin A1c of 5.7-6.4%. Correlations and logistic
regression analyses were adjusted for age, gender, smoking status and
physical activity. NC was positively correlated with BMI (r=0.62), WC (r=0.60),
hip circumference (r=0.55), fat% (r=0.39) and WHR (r=0.21) (all p values
<0.0001). Correlations with most glucose parameters tended to be similar or
stronger for NC compared to WC and other anthropometric measures: 1-hr
OGTT (r=0.19), 2-hr OGTT (r=0.13), fasting insulin (r=0.45), 30-minute insulin
(r=0.28) and HOMA-IR (r=0.44) (all p values<0.01). However, fat% showed
the largest correlations with fasting glucose (r=0.16). Individuals classified
in the upper and middle tertiles of NC were more likely to have prediabetes
(OR=2.81, 95% CI: 1.88-4.20 and OR=2.16, 95% CI: 1.58-2.94, respectively)
compared with those in the lowest tertile; similar analyses on WHR showed
weaker associations (OR=1.99 and OR=1.40, respectively). These preliminary
results suggest that NC is an excellent alternative for assessing central
adiposity. It was highly correlated with central adiposity, insulin resistance,
and glucose abnormalities. In cases where WC measures are difficult or
impossible to measure, NC may be the measure of choice.
Epidemiology/
Genetics
KAUMUDI JOSHIPURA, FRANCISCO MUÑOZ, CRISTINA PALACIOS, CYNTHIA M.
PEREZ, San Juan, Puerto Rico
EPIDEMIOLOGY—CLINICAL—DIAGNOSIS AND SCREENING
The subjects were 367 pregnant women with plasma glucose 1h after
50-g OGTT of ≥140 mg/dl at 24-28 weeks of gestation. The 100-g OGTT was
performed as a diagnostic test 2-4 weeks after the screening test. HbA1c
was done at same time.
The mean HbA1c value in women with GDM was significantly higher
than women without GDM(5.66 ± 0.32% compared to 5.27 ± 0.22%). The
HbA1c cutoff value of ≥5.85% had sensitivity of 28.6% and specificity of
98.4% while an HbA1c cutoff value of ≤5.35% had sensitivity of 88.4% and
specificity of 68.7% in diagnosing GDM.
Using HbA1c as the initial test, if the level of HbA1c is ≥5.85%, then the
woman can be labeled as having GDM. If HbA1c level is ≤5.35%, then she
may be labeled as normal. For women with an HbA1c level lying between
5.35% and 5.85%, an OGTT should be performed to correctly identify women
with GDM. Using this methodology 88.4% of the GDM cases would have
been detected and only 1.6% of normal women would have been wrongly
labeled as having GDM. Also, this methodology would have obviated an
OGTT in 59.9% women in our study.
HbA1c in combination with OGTT has usefulness for diagnosis of GDM in
Korea and can obviate the need of OGTT in women in GDM.
via 2 hour GTT; 59% were managed with diet alone. Most women perceived
their case of GDM to be mild (82%); 23% believed they were misdiagnosed.
No significant differences by diagnostic test modality emerged (p>0.9 for
both). Women who agreed their diagnosis was mild or misdiagnosed were no
less likely than those who disagreed to perceive moderate or high future risk
for GDM and DM2 (p>0.6 for all), and were equally likely to obtain postpartum
GTT (p>0.3 for both) and adopt improved health habits postpartum (p>0.2 for
all).
Most women felt they had a mild case of GDM; almost a quarter questioned
their diagnosis. Those diagnosed under the IADPSG/ADA guidelines were no
more likely to perceive their disease as mild or misdiagnosed. These beliefs
did not impact future risk perceptions or health habits.
1455-P
Glycated Hemoglobin and Incident Type 2 Diabetes in Singaporean
Chinese Without Known Diabetes
POSTERS
Epidemiology/
Genetics
MARK A. PEREIRA, ANDREW O. ODEGAARD, WOON-PUAY KOH, DANIEL STRAM,
JIAN-MIN YUAN, MYRON D. GROSS, Minneapolis, MN, Singapore, Singapore, Los
Angeles, CA, Pittsburgh, PA
Studies are limited, especially in Asians, on glycated hemoglobin
(HbA1c) and risk of incident type 2 diabetes (T2D). We examined HbA1c
and incident T2D in the Singapore Chinese Health Study. A subset of 5,781
men and women aged 48-81 at the time of the blood draw (1999-2004)
reported never having a diabetes diagnosis. Over 5.5 years of follow-up
we observed 125 incident cases of T2D. Hazard ratios (HR) for incident
T2D according to HbA1c percentage were estimated with Cox regression.
Results are shown in the table. After adjustment in Model 1 for age, sex,
dialect group, year of interview, and education, T2D hazard ratios increased
strongly with increasing HbA1c values throughout the full HbA1c range. In
Model 2, adjustment for body mass index, hypertension, cigarette smoking,
and consumption of alcohol revealed similar results as Model 1. These
findings suggest HbA1c is a strong independent predictor of incident T2D
in South Chinese men and women. Risk for future T2D diagnosis increases
considerably even well within the range of HbA1c thought to be ‘normal’
(<6.0%). Studies are needed to more fully examine HbA1c as a predictor of
future T2D risk in Asian and other populations.
1457-P
Utility of Elevated 1-h Glucose Values for Assessment of Pathogenesis of Type 2 Diabetes in Japanese Individuals
YORIKO HEIANZA, YASUJI ARASE, SATORU KODAMA, SHIUN DONG HSIEH,
KAZUYA FUJIHARA, SHIRO TANAKA, AKIKO SUZUKI, OSAMU HANYU, KAZUMI
SAITO, HITOSHI SHIMANO, SHIGEKO HARA, HIROHITO SONE, Tsukuba, Ibaraki,
Japan, Tokyo, Japan, Mito, Japan, Kyoto, Japan, Niigata, Japan
It has not been fully clarified how well adding data on elevated 1-h glucose
values during an oral glucose tolerance test (OGTT) in addition to fasting
plasma glucose (FPG) and 2-h plasma glucose (PG) values would contribute to
understanding the relationship between the two most distinctive factors in
the pathogenesis of type 2 diabetes (T2DM), which are insulin sensitivity and
insulin secretion, in Asian individuals who are not predominantly overweight
or obese. To clarify this issue, we investigated 1503 Japanese individuals
without a history of treatment of diabetes. Participants were categorized
into 5 groups according to glycemic status using WHO criteria ((1) normal
glucose tolerance (NGT) with 1-h PG <155 mg/dL, (2) NGT with ≥155 mg/
dL, (3) impaired glucose tolerance (IGT)/impaired fasting glucose (IFG) with
1-h PG <155 mg/dL, (4) IGT/IFG with ≥155 mg/dL or (5) T2DM). Differences
in whole body insulin sensitivity (Matsuda index), early insulin secretion
(insulinogenic index, IGI) and β-cell function (disposition index, DI) during the
OGTT were evaluated across the glycemic categories. Regardless of having
NGT or IGT/IFG, those with elevated 1-h PG values had a markedly decreased
IGI. Compared to individuals with 1-h PG <155 mg/dL, the Matsuda index
and DI were lower in individuals with 1-h PG ≥155 mg/dL among both the
NGT or IGT/IFG groups. The DI of NGT with 1-h ≥155 mg/dL or IGT/IFG with
≥155 mg/dL did not greatly differ from that in T2DM. Introducing assessment
using 1-h PG ≥155 mg/dL values into the current WHO criteria contributed to
identifying individuals with a reduced early insulin response to oral glucose
and those with beta cells with reduced ability to compensate for insulin
resistance in Japanese individuals. These results would assist clinicians in
finding patients whose insulin secretion is markedly low and in formulating
an optimal approach to treatment to prevent a further progressive loss of
beta-cell function.
Supported by: NIH (R01CA55069), (R35CA53890), (R01CA80205)
1458-P
Glucose Absorption Patterns Differ in Men and Women With Impaired Glucose Regulation
KRISTINE FÆRCH, GIOVANNI PACINI, JOHN J. NOLAN, ANDREA TURA, DORTE
VISTISEN, Gentofte, Denmark, Padova, Italy
1456-P
The Usefulness of HbA1c for Diagnosis of Gestational Diabetes Mellitus in Korea
The oral glucose tolerance test (OGTT) is often used to determine glucose
intolerance, insulin resistance and beta cell dysfunction in populations at
risk. We examined whether glucose absorption patterns after an OGTT
differed between men and women with normal and impaired glucose
regulation. Moreover, we explored the relationship of glucose absorption
with body height because short and tall individuals may respond differently
to a fixed amount of oral glucose. Different aspects of glucose absorption
(total absorption, peak absorption, time to peak, and half-life of glucose in
the gut) were estimated from 12-point 3-hour OGTTs in 66 middle-aged men
and women with normal glucose tolerance (NGT, n=20), isolated impaired
fasting glucose (i-IFG, n=18) and isolated impaired glucose tolerance (i-IGT,
n=28). We found that during a standard 75 g OGTT: 1) individuals with i-IGT,
particularly women, had lower total glucose absorption than NGT individuals
(Fig 1A-B, P=0.003) and slower glucose absorption than i-IFG individuals
KIWON KIM, YEO JOO KIM, HYEONG KYU PARK, JEONG RAN BYUN, SANG JIN
KIM, Cheonan, Republic of Korea
Gestational diabetes mellitus (GDM) was defined as a carbohydrate
intolerance of varying severity with onset or first recognition during
pregnancy, irrespective of glycemic status after delivery. Current screening
for and diagnosis of GDM use oral glucose tolerance test(OGTT), based
on the International Association of Diabetes and Pregnancy Study Groups
(IADPSG) statement. However, it is a relatively complicated procedure and
is associated with high cost. The adoption of easier strategies that do not
require fasting or more than a single blood draw could help to diagnose
GDM easy and to increase the rate of GDM testing. We investigated the
usefulness of HbA1c for diagnosis of GDM.
&
For author disclosure information, see page 829.
A380
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—CLINICAL—DIAGNOSIS AND SCREENING
(Fig 1A, P=0.002); 2) individuals with i-IFG had earlier peak of glucose
absorption than NGT individuals (Fig 1A, P=0.013); and 3) glucose was more
rapidly absorbed in taller compared with shorter individuals (P for linear
relationship<0.001). Glucose absorption during a 75 g OGTT is disturbed in
individuals with impaired glucose regulation, and in particularly in women,
which may have implications for the interpretation of OGTT results.
sampled intravenous glucose tolerance test. A total of 115 participants
developed diabetes. ALT increased the C statistic of a multiple logistic
regression model that had age, sex, ethnicity, and impaired glucose tolerance
as covariates (0.780 vs. 0.802, p <0.001) and of a separate model that also
included waist, SI, and AIR (0.840 vs. 0.851, p = 0.030). In this last model, ALT
correctly reclassified a fifth of individuals with moderate and strong diabetic
risks with a net reclassification improvement of 0.135 ± 0.039 (p = 0.005) and
an integrated discrimination improvement of 0.022 ± 0.006 (p <0.001) (Table).
In summary, ALT is useful for classifying individuals at risk of future diabetes
independently of other risk factors.
Table. Predicted and observed risks of incident diabetes in models with and
without ALT
Model 1 plus ALT
Model 1
<1%
1 - 4%
>4%
%
yearly risk yearly risk yearly risk Reclassified
<1% yearly risk
Total (%) 230 (94.9%) 15 (6.1%)
—
6.1%
Observed
0.4
1.3
—
—
yearly risk
1 - 4% yearly risk Total (%) 57 (22.1%) 185 (71.7%) 16 (6.2%) 28.3%
Observed
0
2.1
9.6
yearly risk
>4% yearly risk
Total (%)
—
19 (10.6%) 160 (89.4%) 10.6%
Observed
—
4.0
7.8
yearly risk
1459-P
Relationship between Cadmium and Pre-Diabetes among U.S.
Adults in NHANES
AMISHA WALLIA, SYLVIA BADON, NORRINA ALLEN, MALEK EL MUAYED, Chicago, IL
Prior epidemiologic and experimental studies suggest a potential
relationship between cadmium exposure (Cd), an environmental pollutant,
and dysglycemia. We evaluated the relationship between urinary Cd, a
marker of exposure, and pre-diabetes (pre-DM) in participants of the crosssectional NHANES (National Health and Nutrition Examination Survey) study
from 2005-2010. Participants were excluded if they were < 40 years old or
were missing data. Pre-DM was defined as 2 of the following: A1c > 5.7%
& < 6.5%, 2 hour OGTT glucose >140 & < 200 mg/dL, FPG > 100 & < 126 mg/
dL. We used restricted quadratic spline models to describe the non-linear
association between urinary Cd and pre-diabetes [adjusted for age, race/
ethnicity, gender, BMI, education, survey years and smoking, a major source
of Cd]. Mean urinary Cd was 0.40 µg/g creatinine (n=1,292). Higher Cd levels
were associated with increasing odds of pre-DM (Fig). Compared with a Cd
level of 0.1 ug/g (10 th percentile), a level of 1.0 ug/g (90 th percentile) had
an OR of 2.13 (1.66-2.74) of having pre-DM. Smokers had higher Cd levels
(0.56 ug/g vs 0.32 ug/g for ever-smokers and never-smokers respectively);
however, the relationship between Cd exposure and pre-DM was consistent
among smokers and non-smokers separately. In conclusion, there appears to
be significant non-linear unimodal relationship between urinary Cd levels and
odds of pre-DM. Further studies examining this relationship are warranted.
Figure: Odds ratios for pre-DM (adj.)
SANDRA L. JACKSON, DARIN E. OLSON, K.M. VENKAT NARAYAN, JOSEPH LIPSCOMB, QI LONG, PETER WILSON, JENNIFER MICHAELS, RINCY VARUGHESE,
MARY RHEE, SONYA HAW, ARUN V. MOHAN, PHYLLIS WATSON-WILLIAMS,
ANNE TOMOLO, DIANA BARB, LAWRENCE S. PHILLIPS, Atlanta, GA, Decatur, GA
Diabetes prevention and care are limited by lack of screening. Screening
with a 50g oral glucose challenge test (GCT), with measurement of plasma or
capillary glucose 1 hour later, at any time, regardless of meal status - similar
to screening for gestational diabetes - has been shown to be accurate,
convenient, and cost-effective in volunteer subjects. We hypothesized that
the GCT would also be useful in high risk patients. In a VA primary care clinic,
subjects with BMI >25, age >45, or other risk factors had measurement of
A1c, plasma and capillary random glucose (RPG and RCG), and plasma and
capillary GCT (GCTpl and GCTcap). At a second visit, they had a diagnostic
75g OGTT. 1440 subjects had mean age 57 years and BMI 30.4, 94% were
men, and 74% were black. By OGTT criteria, diabetes was present in 10%
and high-risk prediabetes (IGT and/or IFG with glucose 110-125 mg/dl) in
22%. The GCTpl provided areas under receiver-operating characteristic
curves (AUC) of 0.84, 0.76, and 0.70 for detection of diabetes, dysglycemia
(diabetes or high-risk prediabetes), and high-risk prediabetes, respectively.
GCTcap performed similarly, with AUCs of 0.82, 0.74, and 0.69 (all p=ns vs.
GCTpl). In 958 patients with complete screening data, GCTpl and GCTcap
were significantly more accurate than A1c, RCG, and RPG for detection of
diabetes or dysglycemia (all p<0.05). Conclusions: Primary care patients with
BMI >25, age >45, or other risk factors have a high prevalence of previously
unrecognized diabetes and high-risk prediabetes - 32% in this study. GCT
screening with measurement of plasma or capillary glucose 1 hour after a
50g glucose load, followed, if abnormal, by an OGTT, would be convenient it could be done opportunistically, during office visits - and would be more
accurate than random glucose or A1c for identifying these problems.
Widespread use of GCT screening could improve management by permitting
early initiation of therapy aimed to prevent or delay the development of
diabetes and its complications.
1460-P
Alanine Aminotransferase Has Discriminatory Value for Detecting
Individuals at Increased Risk of Diabetes: The Insulin Resistance
Atherosclerosis Study (IRAS)
CARLOS LORENZO, ANTHONY J. HANLEY, LYNNE E. WAGENKNECHT, MARIAN J.
REWERS, STEVEN M. HAFFNER, San Antonio, TX, Toronto, ON, Canada, WinstonSalem, NC, Aurora, CO
Supported by: U.S. Dept. of Veterans Affairs
A marker of non-alcoholic fatty liver disease, alanine aminotransferase
(ALT) is a known predictor of incident diabetes in Cox or logistic regression
models. However, it is not known whether ALT adds discriminatory value
to other diabetic risk factors. Therefore, we examined the ability of ALT to
reclassify high-risk participants in the IRAS (n = 724; age, 40 - 69 years;
median follow-up, 5.2 years). We excluded participants with lipid-lowering
medications, excessive alcohol intake, and ALT >100 U/L. Insulin sensitivity
index (SI) and acute insulin secretion (AIR) were measured by the frequently
ADA-Funded Research
&
1462-P
The Relative Associations of β-Cell Function and Insulin Resistance
With Glycemic Status in Asian Indians: The MASALA Study
UNJALI P. GUJRAL, K.M. VENKAT NARAYAN, ALKA M. KANAYA, Atlanta, GA,
San Francisco, CA
Asian Indians are at high risk for type 2 diabetes mellitus (T2DM) at
lower BMI which has raised speculation about innate susceptibility to
For author disclosure information, see page 829.
Guided Audio Tour poster
A381
POSTERS
1461-P
Glucose Challenge Test Screening for Diabetes and Dysglycemia in
a High-Risk Primary Care Population
Epidemiology/
Genetics
Supported by: NHLBI; NCRR
EPIDEMIOLOGY—CLINICAL—DIAGNOSIS AND SCREENING
the prevalence of anti GAD antibody and to characterize the phenotype of
Egyptian patients with adult-onset, clinically diagnosed T2DM attending at
The NIDE Cairo Egypt.A total of 500 Egyptian patients clinically diagnosed as
T2DM and treated with insulin were studied.The inclusion criteria included:
diagnosis of T2DM at age of ≥35 years, the lack of a requirement for insulin
at least 6 months after the diagnosis of T2DM and age at recruitment < 70
years. Anthropometric and clinical data were compared amongst patients
with or without autoantibodies. Beside routine investigations, both C
peptide level & presence of glutamic acid decarboxylase antibodies were
also assessed in these patients.Out of the total of 500 patients, GADA were
found in 159 (31.8%). Age at diagnosis of DM, FPG and LDL & C peptide level
were significantly higher among patients without GADA while among those
with GADA the frequency of female sex was significantly higher. The female
sex & low C peptide level were predictors of presence of GADA among this
group of patients.We can conclude that the prevalence of GADA ( as a marker
of autoimmune diabetes) among Egyptian insulin treating patients with adultonset, clinically diagnosed T2DM is high (31.8%). The clinical phenotype may
not help to characterize these patients & the determination of GADA in
particularly in females & those with low C peptide level represents the best
tool for a correct classification and a necessary prerequisite for a correct
therapeutic appraisal.
β-cell dysfunction in addition to known insulin resistance. We assessed the
relative associations of β-cell function and insulin resistance with glycemic
status in a cohort (n=150) of Asian Indians in the United States.
After an overnight fast, a 5-sample oral glucose tolerance test (OGTT)
was completed. Normoglycemia (NGT), impaired fasting glucose (IFG),
impaired glucose tolerance (IGT), and T2DM were defined by ADA criteria.
The Matsuda Index (ISIM) and the Disposition Index (DI0) were used to
measure insulin sensitivity and β-cell function, respectively. After 2.2 years
of follow-up, participants had a 2-sample OGTT and HOMA-IR and HOMA-β
were measured. Standardized polytomous logistic regression was used to
examine associations with prevalent and incident glycemic states.
Mean age was 57.2±8.1 years, and mean BMI was 26.1± 4.6 kg/m2.
Compared to NGT, after controlling for age, sex, BMI, visceral fat, family
history of T2DM, hypertension, and smoking status, both log ISIM and log DI0
were significantly associated with prediabetes (OR 0.51, 95% CI: 0.27, 0.95)
and (OR 0.22, 95% CI: 0.09, 0.58) and T2DM (OR 0.35, 95% CI: 0.15, 0.87) and
(OR 0.003, 95% CI: 0.0001, 0.03), respectively. At follow-up, incidence rates
were: NGT to IGT; 82.0 per 1,000 p/y; to IFG; 8.4 per 1,000 p/y, to T2DM;
8.6 per 1,000p/y; IGT to T2DM; 55.0 per 1,000 p/y; IFG to T2DM; 64.0 per
1,000 p/y. Both the change in HOMA-IR (OR 2.49, 95% CI: 1.57, 5.26) and
HOMA-β (OR 0.32, 95% CI: 0.13, 0.77) were significantly associated with
incident glycemic progression from NGT to IFG, IGT, or T2DM or from IFG or
IGT to T2DM.
Both insulin resistance and β-cell are associated with prediabetes and
T2DM. The independent associations of both of these factors after adjusting
for visceral fat indicates an innate susceptibility in Asian Indians for T2DM
development.
Supported by: National Institute of Diabetes & Endocrinology (Egypt)
1465-P
Serum TSH Level Is Associated With Islet Beta Cell Function in Type
2 Diabetic Patients
DAN DAN ZHANG, FANG LIU, WEI LU, HAO YONG YU, WEIPING JIA, Shanghai,
China
Objective: This study was to investigate the characteristics of serum supersensitive thyroid-stimulating hormone (sTSH) level and its relationship with
pancreatic beta cell function in Type 2 diabete mellitus (T2DM) patients.
Methods: A total of 1804 patients were enrolled in this cross-sectional
study, including 1328 T2DM patients and 476 Non-diabetic controls, and they
were divided into quartiles with respecting to their sTSH levels. FT3, FT4, and
TSH were measured with chemiluminescent microparticle immunoassay.
The clinical characteristics and biochemical indexes including the fasting
and postprandial C-peptide levels (2h Cp) , their interpolation (ΔCp) and their
relationship with TSH were analyzed.
Results: FT3 and FT4 levels of diabetic patients were significantly higher
than that of controls (both P <0.05), but the TSH level of T2DM patients
was significantly lower than that of controls [(2.34±3.73 vs 4.00±9.70) mIU/L,
P=0.018]. In diabetic population, TSH level in females was significantly higher
than that of males [(2.73±3.79 vs 2.01±3.65) mIU/L, P=0.001], meanwhile, FT3
and FT4 level in females was lower than that of males (P=0.000, P=0.037).
There were significant differences in body mass index (BMI) and triglyceride
(TG) among TSH quartiles (all P<0.05). The levels of fasting C-p, 2h Cp,
and ΔCP in the fourth quartiles was significantly higher than other three
TSH quartiles (all P<0.01). However, HbA1c and GA in the fourth quartiles
was significantly lower than other three quartiles (all P<0.01). Spearman
correlation analysis showed that serum TSH level was positively correlated
with 0’CP, 120’CP, ΔCP and gender, but was negatively correlated with HbA1c
and GA ( all P<0.01). Multiple stepwise regression analysis further revealed
that gender and ΔCP were independent associated factors of sTSH levels
(all P<0.01).
Conclusions: There is gender difference of serum TSH level, and high
serum TSH level may hint increasing beta cell function in T2DM patients.
1463-P
POSTERS
Epidemiology/
Genetics
Supported by: NIH (K23HL080026); AHA (0855069F)
Altered Fatty Acid Metabolism in Healthy First Degree Male Relatives of 2DM Patients
JOZSEF PAUER, BARBARA BUDAY, BOTOND LITERATI-NAGY, MARTA VITAI,
LASZLO KORANYI, Balatonfured, Hungary
The epidemic of obesity is associated with multiplication of prediabetic
patients. The first degree relatives of 2DM patients have a life time risk
for development of diabetes. As genom studies have not identified 2DM
genes with strong predictive values, the need for a diagnostic procedure is
essential for identification of those with high risk of 2DM. Our aim was to
determine metabolic alterations in healthy men with (DR: n= 14) or without
(H: n= 14) first degree 2DM relatives. Volunteers with normal glucose
tolerance were adjusted according to age and BMI, insulin resistance
was determined with hyperinsulinemic-normoglycemic clamps and β-sejt
function by iv glucose tolerance test. Fasting glucose, insulin and FFA values
were not different among the groups, but in the 60 th min, at the end of ivGTT
glucose levels were higher (H:5.8 ± 1,5, vs. DR: 7,2 ± 1,4 mmol/l, p<0.05), the
injected glucose did not suppressed FFA levels ( H: 0,17 ± 0,1 vs DR:0,36 ± 0,2
mmol/l,p<0.001) and first phase insulin secretion (AIR: acut insulin respose)
was decreased in DR group (H:104±63 vs DR:59 ± 33; p<0.01). There were no
differences among the groups in total body-, muscle tissue- , and fat tissue
glucose disposal, leptin and resistin levels, but the adiponectin levels were
significantly lower in DR group (H: 5,28±2,3 vs. GD:2,86 ± 1,7 mg/ml, p<0.001)
and the FFA/adiponectin ratios were higher (H: 0,10±0,08 vs GD: 0,29± 0.2,
p<0.01). In the DR group the HDL cholesterol levels were lower ( H:1.5±0,4
vs GD: 0,97± 0,2 mmol/l,p<0.002) and the lipid profile was atherogen with
less small density and more high density LDL cholesterol fractions. In
conclusion the impairment of insulin secretion and fatty acid metabolism
are the earliest sign of diabetes risk in men with first degree 2DM relatives,
prior to the manifestation of insulin resistance and glucose intolerance.
The measurement of FFA/ adiponectin ratio could be a simple parameter to
screen adult male relatives of diabetic patients for identification of genetic
risk of diabetes.
Supported by: NSFC (81070650)
1466-P
A Chinese Risk Score Model for Identifying Abnormal Glucose Tolerance Without Oral Glucose Tolerance Test
QI FU, MIN SUN, ZHIXIAO WANG, MENGDIE CAO, ZHENXIN ZHU, WEI TANG, MEI
ZHANG, YU DUAN, WEI HE, TAO YANG, Nanjing, China
1464-P
Objective: To develop a risk score model for identifing abnormal gulocse
tolerance (AGT) based on routine clinical information without oral glucose
tolerance tests (OGTT) in the Chinese population, and minimize the number of
subjects needing further OGTT. Research design and methods: β coefficients
from multivariable stepwise logistic regression in the derivation cohort
(7953 participants without known diabetes of a community survey) were
used to develop the risk score models. The performance of the risk score
models was verified in the validation cohort (1455 subjects without known
diabetes of another survey). All subjects had completed questionnaires,
physical examination and OGTT. Performances of the risk score models were
compared by using receiver operating characteristic (ROC) curves. Results:
Pilot Study: The Prevalence of Positive Anti-GAD Antibodies Among
Egyptian Insulin-Treated T2DM Diabetic Subjects at the National
Institute of Diabetes and Endocrinology (NIDE) Cairo, Egypt
IBRAHIM EL EBRASHY, A. BASSYOUNI, G. SALAM, S.N. AMAM, A. ABDELLA, A.
MAHFOUZ, G. HUSSIEN, Cairo, Egypt
Several studies have been performed in order to evaluate the prevalence of
autoimmunity to β-cells in patients with adult onset diabetes and have been
based on screening for ICA and/or GADA. In these studies, the prevalence
of autoimmune diabetes ranged from 8 to 45%, according to different
populations and selection criteria. The aim of our study was to evaluate
&
For author disclosure information, see page 829.
A382
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—CLINICAL—DIAGNOSIS AND SCREENING
(58,605/95,529; 61.3%) despite having an HbA1c≥7%. Of the 36,924/95,529
(38.7%) patients who modified therapy, 13,031/36,924 (35.3%) added ≥1
drug, 11,483/36,924 (31.1%) switched drugs and 12,410/36,924 (33.6%)
reduced the number of drugs taken.
Adherence to ADA guidelines on HbA1c testing frequency and therapy
modification was poor in this study population of US T2DM patients.
Two risk score models for screening AGT were developed. The simple model
used non-invasive risk factors, and the full model contained additional
variables obtainable by invasive laboratory tests (consisting of age, height,
waist, systolic blood pressure, pulse, hypertesion, family history of DM,
fasting blood glucose, triglyceride/high density lipoprotein cholesterol). The
area under curve (AUC) of simple model was similar to fasting blood glucose
(FBG) and glycated hemoglobin (HbA1c). The full model has the largest
AUC (0.799 [0.789-0.809] and 0.730 [0.702-0.758], P <0.001 compared with
simple model, FBG, and HbA1c) in both derivation and validation cohorts. At
a cut-off point of 80, the sensitivity, specificity, and percentage that needed
subsequent OGTT were 75.97, 67.56 and 48.38%, respectively. Conclusions:
We developed a risk score model for screening AGT based on routine clinical
information. It could effectively identify high risk population of AGT and
remarkably reduce the number of subjects requiring OGTT.
Supported by: Chinese Society of Endocrinology
1467-P
Adiponectin Binds to C1q in Human Serum, and C1q-Adiponectin/
Total Adiponectin Ratio Correlates With Coronary Artery Disease in
Japanese Type 2 Diabetes
HIRONORI KOBAYASHI, AYUMU HIRATA, KEN KISHIDA, HIDEAKI NAKATSUJI,
SHIGEO TAKAHASHI, HIDEAKI TANAKA, SUGURU AKAMATSU, KIYONORI KATSURAGI, TOHRU FUNAHASHI, IICHIRO SHIMOMURA, Tokushima, Japan, Osaka,
Japan, Tokyo, Japan
Adiponectin (APN) is produced abundantly in adipose tissue, and its
circulating level is decreased in subjects with excess intra-abdominal fat.
Previously, several studies reported that APN binds to some molecules.
However, the precise forms of APN in human blood have not been fully
understood. The aim of this study is (1) to determine whether APN binds to
complement C1q, (2) to develop the specific enzyme-linked immunosorbent
assay (ELISA) system for measuring C1q-APN complex, and (3) to determine
the clinical significance between C1q-APN complex and coronary artery
disease (CAD) with Japanese type 2 diabetes mellitus (T2DM) patients.
The direct interaction between adiponectin and C1q was detected in
human serum by co-immunoprecipitation. We developed the specific ELISA
system for measuring C1q-APN complex in human serum. Serial dilution of the
C1q-APN complex was used to generate standard curve (R2=0.9998). Good
linearity was observed with the diluted human serum. The intra- and intercoefficients of validation (CV) were below 4.6% and 6.7%, respectively.
By using this ELISA system, we investigated the clinical significance of
C1q-APN complex in T2DM patients diagnosed with CAD. Serum levels
of C1q-APN/Total-APN ratio were higher in patients diagnosed with CAD
(10.47±0.59, mean±SEM, n=54) than those without CAD (8.88±0.60, n=53,
p=0.0482). Age- and sex-adjusted logistic regression analysis identified
serum C1q-APN/Total-APN ratio and hypertension as significant and
independent determinants of CAD. A high serum C1q-APN/Total-APN ratio
was associated with 3.965-fold increase in CAD prevalence.
These results indicated that C1q-binding APN complex exists in human
serum. High serum C1q-APN/Total-APN ratio correlated with CAD in T2DM
patients. This study suggested that measurement of C1q-APN complex
may be a useful biomarker to evaluate the pathogenesis of CAD in T2DM
patients.
1469-P
Utility of Hemoglobin A1c for Predicting New-Onset Diabetes in
Chinese Adults
Supported by: Grant-in-Aid for Scientific Research on Innovative Areas
1470-P
1468-P
Glycosylated Haemoglobin Level Predicts Incidence of Heart Failure Hospitalization Independently of Cardiorenal Functions or
Prevalence of Cardiovascular Diseases in Patients With Advanced
Diabetes
Adherence to ADA HbA1c Testing Frequency and Antidiabetic Therapy Guidelines: Real-World Patient Data
JEAN F. LIAN, YUANJIE LIANG, Princeton, NJ
The 2009 ADA guidelines recommend HbA1c testing every 3 months and
intensification of antidiabetic therapy for type 2 diabetes (T2DM) patients
with HbA1c≥7%.
This retrospective study evaluated adherence to these guidelines in the
US. Data from healthcare claims (2009-2011) were evaluated for patients
≥18 years with ≥2 T2DM diagnoses (ICD-9CM codes 250.x0, 250.x2) and
an initial HbA1c≥7%. An HbA1c test performed 3 months (+15 days) after a
previous HbA1c of ≥7% was considered adherent. An addition to or switch in
therapy within 30 (+15) days of an HbA1c of ≥7% was considered adherent,
with the assumption that HbA1c testing frequency was adherent. Only
patients with continuous enrolment for one year after their initial HbA1c test
were evaluated for adherence to testing frequency.
A total of 67,105/82,675 (81.2%) of all patients were not tested for HbA1c
values at the recommended frequency even once a year (Fig. 1). Adherence
decreased with subsequent tests. Only 4.0% of patients adhered to testing
frequency over one year. Most patients did not modify their existing therapy
ADA-Funded Research
&
ICHIRO KISHIMOTO, HISASHI MAKINO, YOKO OHATA, TAMIKO TAMANAHA,
MAYU TOCHIYA, AYAKO TANAKA, RYO KOEZUKA, Suita, Japan
Growing evidence indicates that dysglycemia is a risk factor for
cardiovascular disease, but the relationship between diabetes control and
the risk of heart failure (HF) remains poorly understood. In addition, if diabetes
control is associated with HF events independent of other comorbidities
such as hypertension, chronic kidney disease or coronary heart diseases
(CHD) has not been well determined. To examine the direct impact of
diabetes control on incidence of heart failure, we evaluated the association
between baseline HbA1c and risk of hospitalization for congestive HF in
diabetes patients taken cardiac/renal functions and prevalent comobidities
into account. In six hundreds asymptomatic patients with type 2 diabetes,
who were at high-risk for HF, the effect of baseline HbA1c level on the
hospitalization for HF was analyzed in a time-to-event manner. Hazard ratios
were calculated using a Cox-proportional hazards model with adjustments of
cardiorenal functional parameters and prevalence of cardiovascular diseases
For author disclosure information, see page 829.
Guided Audio Tour poster
A383
POSTERS
Although many different cutoff levels of hemoglobin A1c (A1C) in diagnosing
diabetes have been suggested in the past, the usefulness of different A1C
cutoffs for predicting diabetes in the Chinese population remained unclear.
This study, a follow-up to the two Shanghai Diabetes studies conducted
from 2010 to 2012, aimed to evaluate the effectiveness of A1C in predicting
new-onset diabetes in Chinese adults. All subjects underwent a 75-g oral
glucose tolerance test and HbA1c was assessed at baseline and followup. A total of 2747 non-diabetic subjects (A1c < 6.5%) aged 20-75 years old
were enrolled. Exclusion criteria included pregnancy, severe kidney damage
(eGFR<30 ml·min-1·1.73m-2), anemia (hemoglobin <120g/L in men and <110g/L
in women), serum hepatitis B surface antigen positive, anti-hepatitis C
antibody positive and abnormal serum alanine aminotransferase level (>
69 IU/L). Among them, a total of 206 individuals developed diabetes during
the average 8-year follow-up period. The incidence density of diabetes was
32.8/1000 person-year. After adjustment for age, fasting plasma glucose, 2-h
plasma glucose, and waist circumference (WC), the Cox proportional hazards
model showed that the subjects with A1C ≥ 5.5% had a 1.5-fold increased
risk of new-onset diabetes compared to those with A1C < 5.5% (P=0.035).
And the risk of diabetes incidence significantly increased with elevated
A1C level (the hazard ratio reached 3.3 for the A1C6.4%). A1C5.5-6.4%
detected 76.1% of all individuals at risk of subsequent incident diabetes. Our
study suggested that A1C was indeed useful for screening and identifying
individuals at a higher risk of diabetes among Chinese adults.
Epidemiology/
Genetics
WEIPING JIA, XUHONG HOU, JUNLING TANG, Shanghai, China
EPIDEMIOLOGY—CLINICAL—DIAGNOSIS AND SCREENING
was 1.42 (1.21-1.67). When stratified by smoking categories, a U-shaped
association between alcohol intake and diabetes risk was observed only
in (s-a) category (HRs of (a-b), (a-c) and (a-d) compared to (a-a) were 0.85
(0.64-1.12), 1.04 (0.85-1.27) and 1.14 (0.91-1.43), respectively). There was no
synergistic effect between these two lifestyle behaviors. In conclusion, the
risk of development of T2DM increases with smoking and alcohol intake
whereas there were no interactions. It is possible that the favorable effect
of moderate alcohol intake would be reversed by smoking.
at baseline. Subjects (mean age, 66.5 years; 68% men; mean HbA1c, 9.1%)
were followed up for 5 years on average. When the patients were split into
two groups according to HbA1c status at baseline with a cutoff point of
8.4%, the higher HbA1c group has significantly worse outcome than the
lower group (Log-rank P=0.031). In the Cox-proportional hazards model, the
overall hazard ratios of 1% increase of HbA1c were 1.22 (95% CI 1.09-1.36,
P=0.0006) after adjustments for age, gender, smoking, estimated glomerular
filtration rate, urinary albumin excretion corrected by creatinine, plasma
brain natriuretic peptide level and prevalence of hypertension, CHD or HF at
baseline. It is, therefore, concluded that uncontrolled diabetes is a significant
risk for HF hospitalization independently of the baseline cadiorenal functions
or cardiovascular comobidities.
1473-P
Ratio of Trunk to Leg Volume Is Better Associated With Mortality
than BMI or Waist Circumference
JOSEPH P. WILSON, ALKA KANAYA, BO FAN, JOHN A. SHEPHERD, San Francisco,
CA
1471-P
Body shape is a known risk factor for diabetes and mortality, but the
methods estimating body shape, BMI and waist circumference, are crude.
We determined whether a novel body shape measure, trunk to leg volume
ratio, was independently associated with mortality.
We used the National Health and Nutrition Examination Survey 19992004 to generate dual-energy X-ray absorptiomery-derived trunk to leg
volume ratio. Mortality data were linked with the National Death Index
through 12/31/2006.
Of 9862 adults with trunk to leg volume measures, 551(5.6%) died. The
figure shows the total mortality (%) in each quartile of trunk to leg volume
ratio by BMI category, with significant trends (p<0.001) for each category.
Even among those with normal BMI, those in the highest quartile of trunk
to leg volume ratio had a higher likelihood of death (5.5%) than those in the
lowest quartile (0.2%). In a logistic regression model adjusting for age, sex,
ethnicity, physical activity, and poverty index ratio, the odds of mortality
comparing the fourth to first quartile of trunk to leg volume ratio was 1.76
(95% confidence interval, 1.20-2.60), 0.75 (0.67-0.84, per SD kg/m2) for BMI
and was not significant for waist circumference.
A high ratio of trunk to leg volume showed a strong association to mortality
while BMI had a paradoxically inverse association. This novel body shape
measure may provide additional information to better stratify individuals at
risk for mortality, even among those with normal BMI.
Comparison of IFCC Calibrated HbA1c for the Glucose, Fructosamine
and HbA1c Study from Laboratory and Point of Care Testing
POSTERS
Epidemiology/
Genetics
SUSAN E. MANLEY, RACHEL A. ROUND, PETER G. NIGHTINGALE, STEPHEN D.
LUZIO, IRENE M. STRATTON, ROBERT CRAMB, STEPHEN C. GOUGH, JONATHAN
WEBBER, Birmingham, United Kingdom, Swansea, United Kingdom, Gloucester,
United Kingdom, Oxford, United Kingdom
WHO and IDF recommend using HbA1c ≥6.5% [IFCC units 48 mmol/mol] for
diagnosis of diabetes with pre-diabetes defined as 6.0% to 6.4% [42 to 47].
We have compared HbA1c results from several IFCC calibrated methods for a
research study relating HbA1c to glucose and fructosamine.
HbA1c was measured in 130 patients with diabetes on three IE HPLC
analysers - Tosoh G8, Menarini HA8160 and Bio-Rad Variant II NU; two point
of care systems - DCA 2000®+ analyser and A1cNow+™ disposable cartridges;
an affinity chromatography analyser - Primus Ultra2 and compared to an IFCC
secondary reference method - Menarini HA8160 calibrated according to
protocol for an IFCC SRM laboratory.
The median (IQ range) for HbA1c was 7.5(6.8 to 8.4)% [58(51 to 68)] on
IFCC SRM with minimum value 5.3% [34] and maximum 11.9% [107]. There
were significant positive offsets between IFCC SRM and Tosoh G8 analyser,
mean difference (1SD), +0.22(0.21)% [2.4(2.3)], r2=0.973, p<0.001, and BioRad Variant II NU analyser +0.33(0.17)% [+3.6(1.9)], r2=0.984, p<0.001 with
a very small negative difference for Menarini HA8160 analyser -0.03(0.11)%
[-0.3(1.2)], r2=0.992, p<0.001. The POCT methods were less precise with
negative offsets for DCA 2000®+ of -0.12(0.27)% [-1.3(3.0)], r=20.955,
p<0.001 and A1cNow+™ -0.69(0.68)% [-7.6(7.5)], r2=0.691, p<0.001 (n=115).
Small differences between IFCC calibrated methods across a wide range of
HbA1c values were confirmed in internal quality control and national external
quality assurance schemes. These offsets should be considered when
evaluating data for individuals/cohorts of patients from different analysers
especially when HbA1c is in the diagnostic range.
Supported by: Novo Nordisk, Inc.
1472-P
Combined Risk of Alcohol Intake and Smoking for Development of
Type 2 Diabetes in the General Population in Japan: The Ibaraki Prefectural Health Study
AYUMI SUGAWARA, TOSHIMI SAIRENCHI, KAZUYA FUJIHARA, FUJIKO IRIE,
HIROSHI WATANABE, HIROAKI SUZUKI, HITOSHI SHIMANO, OSAMU HANYU,
HIROHITO SONE, HITOSHI OTA, IBARAKI HEALTH PLAZA, Tsukuba, Japan, Shimotsugagun-Mibu, Japan, Mito, Japan, Niigata, Japan
It is established that smoking increases the risk of development of
type 2 diabetes mellitus (T2DM). Conversely, a U-shaped association was
reported between alcohol intake and risk of diabetes, suggesting that
moderate drinking could lower diabetes risk. However, the combined risk
of these two lifestyle behaviors has not been elucidated despite the close
association between rates of smoking and drinking. Data were obtained
from the database of the Ibaraki Prefectural Health Study, a communitybased cohort study. 63865 men aged 40 to 79 y who completed an annual
health checkup in 1993 were included. We excluded individuals with T2DM
(≥7.0 mmol/L fasting or ≥11.1 mmol/L nonfasting or treatment) at baseline
(n=3116), incomplete health checkup data (n=17155), and ex-smokers or exdrinkers (n=20671). Subsequently, 22923 men were eligible for analysis.
The observation period began in 1993 to the date of development of T2DM
or of the last health checkup in 2007. Smoking habits were classified into
3 categories: never smoker (s-a), smoking <20 cigarettes a day (s-b), and
smoking ≥20 cigarettes/d (s-c). Alcohol intake was divided into 4 categories:
never (a-a), drinking <15 g/d (a-b), 15- 30 g/d (a-c) and >30 g/d (a-d). Cox
proportional hazard models showed that compared to the combination of
(s-a) and (a-a), hazard ratio (95%CI) of the combination of (s-c) and (a-d)
Supported by: National Science Foundation
1474-P
Clinical Characteristics of People With Diabetes Mellitus in Guatemala (Central America): Do Guidelines Match Local Reality?
FABIOLA PRADO DE NITSCH, MARIO A. NITSCH, Guatemala City, Guatemala
We determined clinical characteristics and compared adequacy of
international guidelines for diagnosis and treatment of Guatemalan
diabetics. After informed consent, we obtained clinical history, weight,
height, fingerstick blood glucose and HbA1c. Total sample was 931 diabetcs,
70% female. Average age 58 yr. Age at onset: 5 to 95 yr. 33 % of sample was
younger than 45 years at onset of diabetes.
53% reported no symptoms at onset, 43% reported at least 1 classic
symptom. Average BMI: 28,44 (± 5,18) kg/m² in women, and 27,33 (± 4,36) kg/
m² in men. 58% had BMI < 30 kg/m², and 35% and 24% of men and women,
respectively, had BMI 18,5 - 24,99 kg/m². Diabetics with BMI < 25.0 kg/m²
had higher A1c values than obese diabetics. Prevalence of morbid obesity:
&
For author disclosure information, see page 829.
A384
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—CLINICAL—DIAGNOSIS AND SCREENING
2%. No cases of super obesity documented. Average HbA1c 9.24%. 48%
had A1c >= 9,0%, and 10% had A1c>= 14.0%. This sample differs in age
and symptoms at onset, BMI and HbA1c values from international reports.
No previous Guatemalan reports are available in the diabetic population.
Presence of symptoms is not a good indicator for screening in the Guatemalan
population. Overall, we documented poor glycemic control. Females, men
with normal BMI, subjects younger than 65 years of age or younger than 45
years at diagnosis, and subjects with diabetes duration >= 5 years had higher
A1c values than their counterparts, and thus a higher risk of microvascular
complications. We must start generating nationwide information to set up
diagnosis and treatment guidelines that ensure improvement of the poor
glycemic control found, since international guidelines do not match local
clinical reality. Differential diagnosis must include screening for LADA and
malnutrition related diabetes in the normal weight diabetic population. We
are working on developing new educational and prescribing strategies to
improve glycemic control and reduce risk of complications in this Latino
diabetic population.
1476-P
Type 2 Diabetes Mellitus and Hepatocellular Carcinoma-Tumour
Characteristics and Outcome
1475-P
Zinc Transporter 8 Antibodies Can Replace IA-2 Antibodies as a Serological Marker for Type 1 Diabetes in India
SHIVAPRASAD CHANNABASAPPA, PRASANNA KUMAR, MALA DHARMALINGAM, RAJNEESH MITTAL, Bangalore, India
A high frequency of patients(45%) with presumed diagnosis of T1D in India
lack GAD (GADA) and IA-2 autoantibodies (IA2A). As no data on ZnT8A in
Indian population are available, the aim of our study was to estimate the
prevalence of ZnT8A in T1D patients of Indian origin. 88 T1D patients <18yrs
of age and duration of T1D < 48 months were recruited. Sex-matched healthy
controls aged 2-18 years (n = 88) were also recruited. ZnT8A, GADA and
IA-2A were esimated using commercial ELISA (DLD diagnotika,Germany).
68(77.3%) of patients were positive for atleast one antibody. ZnT8A were
positive in 31.8% of patients. The prevalences of GADA and IA2A were
64.7% and 19.3% respectively. In newly diagnosed patients the prevalence
of Znt8A was 45%. ZnT8A were positive in 26% of patients negative for both
GADA and IA2A. Combined use of ZnT8A and GADA could detect 97% of
antibody positive patients. Exclusion of IA2A didnot significantly reduce the
proportion of patients with positivity for antibodies, implying that the utility
of IA2A was limited and redundant. This study shows that ZnT8 antibody is
a specific marker of juvenile-onset type 1 diabetes in India. The inclusion of
ZnT8A in the antibody panel for screening of T1D in Indians can significantly
increase the proportion of patients with antibody positivity to nearly 80%.
ZnT8A can replace IA2A for screening autoimmunity in Indian T1D patients
without loss of sensitivity or specificity.
1477-P
Preoperative A1C and Clinical Outcomes in Surgical Patients With
Diabetes
RAJESH GARG, PATRICIA UNDERWOOD, REZA ASKARI, BINDU CHAMARTHI, ALI
TAVAKKOLIZADEH, Boston, MA
Acute hyperglycemia is associated with poor clinical outcomes in surgical
patients. However, the impact of chronic hyperglycemia on surgical outcomes
is not clear. We conducted a retrospective data analysis to investigate
the effect of pre-operative A1C on clinical outcomes after surgery. Data
were obtained from our Hospital’s National Surgical Quality Improvement
Program (NSQIP) database and electronic medical records for 5 years, 2005
to 2010. Out of 1515 patients with diabetes, 364 had an A1C value (>6.5%)
available within three months before surgery. These were divided into three
groups: A1C 6.5-8%, 8-10% and >10%. Group wise patient characteristics
and main outcomes are shown in table 1. Univariate regression analysis
demonstrated that higher A1C was associated with increased length
of hospital stay (LOS) (beta=0.51, p=0.009). This relationship remained
significant after adjustments for age, gender, BMI, race, type of surgery and
smoking status (p=0.02). Further, individuals with A1C ≥8% had significantly
longer LOS compared to those without diabetes (7.6±6.9 vs 4.7±4.8 days;
p<0.05). LOS did not differ between A1C <8% and non-diabetic individuals
(5.4±5.7 vs 4.7±4.8 days; p=NS). There was no significant difference in other
outcomes. We conclude that A1C ≥8% is associated with increased LOS
after surgery. These data have implications for poorly controlled diabetic
patients undergoing elective surgery.
Table 1. Patient characteristics and main outcomes in A1C categories.
N
Age (years)
Gender (Female %)
Race (African American %)
BMI (kg/m2)
Surgery Type (Vascular %)
Length of Hospital Stay (days)
Deep surgical wound infections (%)
Mortality within 30 days (%)
Supported by: Endocrine Society of India
ADA-Funded Research
&
Diabetes
HbA1c
6.5-8%
217
60.5±13.6
115 (53%)
29 (13%)
36.0±10.6
50 (23%)
5.4±5.7
0.46%
2.76%
Diabetes
HbA1c
8-10%
98
58.2±13.4
48(49%)
17 (17%)
35.3±10.3
33 (34%)
7.9±6.9
2.04%
3.06%
Diabetes p value for
HbA1c>10% trend
49
54.0±12.2
25(51%)
10 (20%)
36.9±10.2
14 (29%)
7.0±6.8
2.04%
2.04%
0.009
NS
NS
NS
NS
0.0009
NS
NS
For author disclosure information, see page 829.
Guided Audio Tour poster
A385
POSTERS
Type 2 diabetes (DM2) is a risk factor for the development of hepatocellular
carcinoma (HCC). However, the influence of DM2 on the tumour phenotype
and survival in patients with HCC remains controversial. Therefore, we studied
the tumour characteristics in patients with DM2 (DM2 group) vs non-diabetic
patients (non-DM2 group) at the time of diagnosis of HCC, and correlated
these findings with established prognostic factors (CLIP- Score), decisions
of treatment and survival rates. We performed a single-centre retrospective
analysis of n=252 patients with HCC treated in the last 12 years. In DM2patients, we found not only a better Child Pugh liver status than in non-DM2patients at the time of diagnosis (no cirrhosis 26 vs. 23%, liver cirrhosis [A] 59
vs 47%, [B] 14 vs 23%, [C] 1 vs 7%; p= 0.0114) but also a lower CLIP- Score,
indicating a better prognosis, especially among patients with unifocal HCC
(CLIP- Score [0-1], 94 vs 73%, Score [2-6] 6 vs 27%, p= 0.0035). In line with
these findings, DM2- patients demonstrated higher survival rates, especially
among patients with bad prognosis due to advanced disease (Mean survival in
patients with CLIP- Score [2-6], DM2 vs non- DM2: 20 vs 11 months, p= 0,0155).
No differences in AFP- levels and frequency of portal vein thrombosis were
observed. Although both mean (103 vs 218 cm3, p=0.99) and total (178 vs 268
cm3, p=0,675) tumour volume were insignificantly smaller in the diabetic group,
DM2 patients with multifocal HCC demonstrated significantly more lesions as
non- DM2 patients (3,5 vs 2,9 n=104, p= 0,0278). No differences in treatment
decisions (surgery, TACE, RFTA, drug therapy) were observed between the two
groups. These results suggest that concomitant DM2 in patients with HCC is
associated with multifocality of tumour lesions. However, DM2 patients have
neither a worse prognosis at the time of diagnosis nor lower survival rates as
non- DM2 patients with HCC.
Epidemiology/
Genetics
NIKOLAOS PERAKAKIS, APOSTOLIA LAMPRINOU, WERNER VACH, NADINE
HENNECKE, ROBERT THIMME, HUBERT ERICH BLUM, KATHARINA LAUBNER,
GÜNTER PÄTH, JOCHEN SEUFERT, Freiburg, Germany
EPIDEMIOLOGY—CLINICAL—DIAGNOSIS AND SCREENING
1478-P
1480-P
Different Pathophysiological Phenotypes among Newly Diagnosed
Type 2 Diabetes Patients
Serum Resistin Is Associated With HOMA and Matsuda-DeFronzo
Insulin Sensitivity Index But Not Glucose Parameters During OGTT:
The Toon Health Study
POSTERS
Epidemiology/
Genetics
JACOB V. STIDSEN, REIMAR W. THOMSEN, JENS S. NIELSEN, JØRGEN RUNGBY,
SINNA P. ULRICHSEN, SØREN FRIBORG, IVAN BRANDSLUND, JENS S. CHRISTIANSEN, HENRIK T. SØRENSEN, HENNING BECK-NIELSEN, Odense, Denmark,
Aarhus, Denmark, Vejle, Denmark
HIROSHI ONUMA, RYOICHI KAWAMURA, ISAO SAITO, YASUHARU TABARA,
MAYO AIBIKI, YUKINOBU NOMI, YUKO KADOTA, AI OKAMOTO, TATSUYA
NISHIMIYA, YASUNORI TAKATA, WATARU NISHIDA, TETSURO MIKI, TAKESHI
TANIGAWA, HARUHIKO OSAWA, Toon, Japan, Kyoto, Japan
Type 2 diabetes (T2D) can be considered a syndrome with several different
pathophysiological mechanisms leading to hyperglycemia. Nonetheless,
T2D is treated according to algorithms as if it was one disease entity. We
investigated the prevalence of different pathophysiological phenotypes
among newly diagnosed T2D patients in Denmark. Based on baseline data
from a Danish national cohort study we investigated 1048 incident diagnosed
T2D patients. The diagnosis T2D was made by general practitioners based
on clinical judgement. Phenotypes were classified in the following groups:
latent autoimmune diabetes (LADA) (GAD antibody titer >= 20 IE/ml and not
T1D), secondary diabetes (recent history of pancreatitis, pancreatectomy or
pancreas amylase > 65U/l, and GAD negativity), insulinopenic/non obese
diabetes (f-P-C-peptide < 300 pmol/l and not LADA or secondary diabetes),
classic obesity-associated insulin resistant diabetes ( f-P-C-peptide >= 600
pmol/l or waist circumference >= 94 cm for men and >=80 cm for women),
steroid-induced diabetes (oral glucocorticoid-treated subjects) and a group
not fitting into these phenotypes. Median age of our new T2D patients was
61 years (range 21-95 years), 57% were men. We found that 3.0% newly
diagnosed T2D patients suffered from LADA, 3.9% from secondary diabetes,
4.1% had insulinopenic diabetes, 0.6% suffered from steroid induced
diabetes whereas 84.8% presented the classic obesity-associated insulinresistant phenotype. Only 3.6% could not be classified within any of these
5 phenotypes. We conclude that newly diagnosed T2D patients represents
several well-characterized pathophysiological phenotypes with various
mechanisms of hyperglycemia. This should be taken into consideration when
choosing the appropriate treatment for the individual patient diagnosed with
T2D. We suggest to measure f-P-C-peptide, GAD antibodies and pancreas
amylase in patients with newly diagnosed T2D.
Resistin, secreted from adipocytes, antagonizes the action of insulin in
mice. In humans, resistin is predominantly expressed in macrophages, and
its expression is induced by inflammation. However, the association of
serum resistin and insulin resistance is controversial in humans. The relation
between serum resistin and either insulin resistance or secretion based
on oral glucose tolerance test (OGTT) in general populations remains to be
elucidated.
The Toon Health Study is a cohort study for surveying risk factors for
cardiovascular diseases and diabetes in community based subjects. In this
study, 2,033 residents aged 30-79 years were enrolled from 2009 to 2012.
In 1,936 subjects, a 75g OGTT was performed and plasma glucose (PG) and
insulin were measured at 0, 1, and 2 hours. Serum resistin was measured by
ELISA. Resistin, homeostasis model assessment insulin resistance (HOMAIR), HOMAβ, and Matsuda-DeFronzo insulin sensitivity index (ISI-M) were
natural log-transformed for statistical analyses.
Serum resistin was positively correlated with HOMA-IR and HOMAβ, and
inversely correlated with ISI-M (correlation coefficient [R] = 0.14, 0.15, and
-0.12, respectively, all P<0.0001). A multiple regression analysis showed
that these associations did not change after adjusted for age, sex, and
BMI (standardized β=0.12, 0.12, and -0.09; P <0.0001, <0.0001, and 0.004,
respectively). Serum resistin was not associated with fasting PG, 1-h PG, 2-h
PG, and glucose area under the curve (AUC) during OGTT.
In summary, serum resistin was associated with HOMA-IR, HOMAβ, and
ISI-M but not glucose parameters during OGTT. Serum resistin appeared to
be asscociated with insulin resistance, but insulin secretion capacity could
have stronger effects on glucose tolerance.
Supported by: Danish Council for Strategic Research
1481-P
1479-P
Functional Status of Patients With Type 2 Diabetes Mellitus: Is It the
Diagnosis or Underlying Risk Factors Promoting Ill Health?
Effects of Recommendation Notices for Clinic Visits by Nationwide
Health Screening System in Japan
HAROLD E. BAYS, KATHLEEN M. FOX, SUSAN GRANDY, SHIELD STUDY GROUP,
Louisville, KY, Monkton, MD, Wilmington, DE
OSAMU HANYU, YORIKO HEIANZA, KAZUO FURUKAWA, RYO KAWADA, MASAHIKO YAMAMOTO, TAEKO OSAWA, HIROMI SUZUKI, SHIN-ICHI MINAGAWA,
TAKAHO YAMADA, AYAKO YAMADA, AKIKO SUZUKI, HIROHITO SONE, Niigata,
Japan
Adults with type 2 diabetes mellitus (T2DM) often have diminished
functioning. This may be due to the implications associated with the
diagnosis of T2DM or to underlying characteristics that predispose to T2DM
and ill health.
Adult respondents to the Study to Help Improve Early evaluation and
management of risk factors Leading to Diabetes (SHIELD) were classified
into 3 groups: (1) T2DM diagnosis at baseline in 2004, (2) newly diagnosed
with T2DM from 2005-2009 (ie, “at risk” for T2DM at baseline), and (3) no
T2DM diagnosis at baseline or from 2004-2009. Self-reported functioning
scales included SF-12 (physical and mental health), PHQ-9 (depression), IPAQ
(physical activity) and WPAI (work impairment). Regression models adjusted
for age, obesity, current smoking, cholesterol problems, heart disease and
hypertension.
In total, 1837 (26%) respondents reported T2DM at baseline, 473 (7%)
reported newly diagnosed T2DM during the study, and 4629 (67%) reported
no T2DM at study end. SF-12 physical health scores were similar for T2DM
(40.7) and newly diagnosed T2DM (41.6) (p >0.05) but worse compared with
no T2DM (46.5) (p<0.01). Depression scores and work impairment were
similar for T2DM and newly diagnosed T2DM (4.86 vs. 4.99 for depression;
11.9 vs. 12.8 for work impairment, p>0.05) but worse than no T2DM (4.03
for depression; 9.5 for work impairment, p<0.01). T2DM (12%) and newly
diagnosed T2DM (12%) respondents were significantly less physically active
than those with no T2DM (16%) (p<0.01). Age, obesity, cholesterol problems,
smoking and T2DM status consistently predicted scale scores after adjusting
for other predictors in the model.
This survey suggests that self-reported functioning scale scores may be
similar between T2DM respondents and those who subsequently developed
T2DM. Both groups had significantly worse scores compared with those with
no T2DM - an effect substantially correlated with age, obesity, cholesterol
problems and smoking.
Early detection and continued interventions for cardiovascular risk factors
including diabetes/prediabetes, hypertension, and dyslipidemia are crucial
to prevent atherosclerotic disease. Japan launched a nationwide health
screening system in 2008 to detect these asymptomatic disorders at an early
stage to provide continuous interventions. Subjects classified as at high risk
receive notices recommending clinic visits and are expected to make regular
clinic visits for interventions and check-ups thereafter. However, the effect
of these notices on actual clinic visit rates is unknown. We determined the
clinic visit rate after such notices from information on health records and
health insurance claims. Health records and insurance claims between April
2010 and March 2011 of 117,952 adults aged 40-74 y (59,567 males; 58,385
females) were obtained from the Japan Medical Data Center Co., Ltd. This is
a representative sample since these individuals resided throughout Japan.
Criteria for a clinic visit were systolic blood pressure >140 mmHg, diastolic
blood pressure >90 mmHg, low-density lipoprotein cholesterol (LDL-C) >140
mg/dL or Hb-A1c >6.5%. Subjects already diagnosed with hypertension,
dyslipidemia or diabetes were excluded. Proportions of screenees requested
to make a visit clinic were 16% for high blood pressure, 29% for high LDL-C
and 2% for high HbA1c. However, only 12% of those contacted for high blood
pressure, 12% for high LDL-C level and 32% for high HbA1c actually made
a clinic visit. Rates were lowest among younger subjects (40-49 y). Rates
of continuation of clinic visits 12 mo after the notice declined to 7% for
blood pressure, 5% for LDL-C and 16% for Hb-A1c, with rates also lowest in
subjects aged 40-49 y. These results indicated unsatisfactory and transient
results of notices for clinic visits based on nationwide health screening
especially in younger people. Further novel strategies should be developed
to improve consultation/continuation rates for intervention.
Supported by: AstraZeneca
&
For author disclosure information, see page 829.
A386
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—CLINICAL—DIAGNOSIS AND SCREENING
1482-P
1484-P
Serum Ficolin-3 as a New Biomarker Predicting the Development
of Type 2 Diabetes
WITHDRAWN
1485-P
1483-P
African Immigrant Men have a Lower Waist Circumference of Risk
than African American Men
Hyperglycemia and Hypoglycemia on Admission are Associated
With Adverse Outcomes Among Hospitalized Patients With or Without Diabetes
MICHELLE Y. O’CONNOR, MADIA RICKS, NATALIE L. RAMSEY, FRANCINE THOMAS, PETER T. KATZMARZYK, JIANHUA YAO, ANNE E. SUMNER, Bethesda, MD,
Baton Rouge, LA
ROGERIO S. RIBEIRO, DOMINGOS A.C. MALERBI, JOÃO R. SÁ, RICARDO B.
PERES, SIMÃO A. LOTTENBERG, MARIA L.M. COSTA, MAGDA T. YAMAMOTO,
CLAUDIA R. LASELVA, JOSE A.M. CARVALHO, São Paulo, Brazil
Whether the waist circumference (WC) of risk differs among populations
of African descent is unknown. Defining the “WC of risk” as the WC which
best predicts insulin resistance, WC of risk was compared in age-matched
African-American (AA) and African immigrant men. Data on 180 nondiabetic men (43% AA, age 36±9y, mean±SD) were analyzed. Africans lived
in US for 10±9y. In the first 5y after immigration, weight gain per year was
~3 kg. Insulin resistance was defined by the lowest quartile of the insulin
sensitivity index (SI<2.34). Receiver operating characteristic (ROC) curves
and the Youden Index were used to identify the optimal WC. BMI was lower
in Africans than AA (27.0±3.7 vs. 29.6±6.2 kg/m2, P<0.01). Adjusting for BMI,
WC did not differ by ethnicity (93±56 vs. 93±48 cm, P=0.4), but Africans had
higher VAT (P<0.01) and lower SAT (P<0.05). The WC which best predicted
insulin resistance in Africans was 93 cm (AUC-ROC: 0.71) and in AA was
100 cm (AUC-ROC: 0.78). At every level of WC, VAT was higher in Africans
than AA (Figure). Hence, the WC of risk is lower in African than AA men. In
Africans, rapid weight gain after immigration may account for higher VAT
and greater insulin resistance at a lower WC. Overall, for populations in
transition, the WC of risk may take time to determine.
Objective: To study the association between glucose abnormalities
on admission and adverse outcomes among hospitalized patients with or
without diabetes.
Methods: We retrospectively examined the frequency of hyper (>
10 mmol/l or 180 mg/dl) and hypoglycemia (< 3.9 mmol/l or 70 mg/dl)
and its association with adverse outcomes among 23098 non-pregnant
hospitalized adults who underwent capillary glucose (Abbott Xceed Pro,
CV 6%) screening on admission, representing 94% of total admissions in a
tertiary private hospital during 2011. Patients were classified according to
diabetes status. Adverse outcomes included length of stay (LOS), infection,
admission to intensive care unit (ICU) and mortality. For patients with
multiple hospitalizations, only the first admission was considered. Statistical
significance was defined as P<0.05.
Results: Among 2913 patients with diabetes, hyper and hypoglycemia
were detected in 982 (33,7%) and 99 (3,4%) admissions, respectively.
Hyperglycemia was associated with increased LOS (7,05±14 vs. 4,06±8 days),
infections (21,2 vs. 14,4%), ICU admissions (24,9 vs. 14%), and mortality (2,6
vs. 0,5%), compared to normoglycemia. Hypoglycemia was associated with
increased LOS and mortality (3%).
Among 20185 patients without diabetes, hyper and hypoglycemia
were detected in 871 (4,3%) and 628 (3,0%) admissions, respectively.
Hyperglycemia was associated with increased LOS (14,7 vs. 3,6 days),
infections (28 vs. 13%), ICU admissions (44 vs. 8%) and mortality (10 vs.
0,9%), compared to normoglycemia. Hypoglycemia was associated with
increased mortality (2%).
Conclusion: Capillary glucose screening on admission may detect
hyperglycemia and hypoglycemia and indicate poor prognosis in hospitalized
patients with and without diabetes.
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A387
POSTERS
It is reported that toll-like receptor, one of the membrane-bound pattern
recognition receptor (PRR) plays an important role in insulin resistance(IR).
Ficolin-3, a soluble pattern recognition receptor (PRR) within the lectin
component of the complement pathway, share the same structure and
function with MBL, was found to be significantly different between normal
glucose tolerance (NGT) and type 2 diabetic patients in our study. To
investigate whether serum ficolin-3 associates with type 2 diabetes (T2DM)
and predicts the incidence of T2DM independent of established risk factors
in Shanghai Diabetes Study.
1742 subjects with NGT, 209 subjects with impaired glucose regulation
(IGR),and 145 subjects with type 2 diabetes, whom were followed
prospectively to assess the development of type 2 diabetes for average
3 years. 130 subjects developed type 2 diabetes. Baseline serum ficolin-3
levels were measured with ELISA. The role of ficolin-3 in predicting the
development of type 2 diabetes over 3 years was investigated using logistic
regression analysis.
At baseline, serum ficolin-3 was significantly lower in T2DM and IGR
subjects, and independently correlated with the index of homeostasis model
(HOMA-IR). A decreased serum ficolin-3 was independently associated with
T2DM. In the prospective study, 130 incident diabetic subjects were identified
in the full cohort during 3 years follow up. Decreased serum ficolin-3 was
associated with increased type 2 diabetes risk after adjustment for age. The
association remained significant after adjustment for age, sex, BMI, waist
circumference. Furthermore, decreased serum ficolin-3 was associated with
type 2 diabetes risk particularly in individuals with female, hyperglycemia,
non-abdominal obesity, hypertention, and dislipidemia.
Decreased serum ficolin-3 was strongly and independently associated
with T2DM and lower ficolin-3 levels predicted the development of type 2
diabetes in this Chinese cohort.
Epidemiology/
Genetics
HAIBING CHEN, WEIPING JIA, Shanghai, China
POSTERS
Epidemiology/
Genetics
EPIDEMIOLOGY—CLINICAL—DIAGNOSIS AND SCREENING
1486-P
1488-P
Elevated Serum Ferritin Level Is Associated With the Development
of Diabetes in Healthy Korean Men: A 4-Year Retrospective Longitudinal Study
Random Exmination of Blood Glucose in Adults by Trained Volunteers in a Hospital Setting
CHANG HEE JUNG, JAECHAN LEEM, JOONG-YEOL PARK, HONG-KYU KIM, WOO
JE LEE, Seoul, Republic of Korea
Screening for dysglycemia can be conducted by trained volunteers
in a public location. The study was designed to examine the incidence of
dysglycemia and diabetes among screened, non hospitalized subjects in a
pubic setting. A diabetes screening station staffed by trained volunteers
was situated in the main entrance lobby of E. Wolfson Medical Center,
Holon. Volunteers measured height, weight, blood glucose (by glucometer)
and blood pressure (by sphygmomanometer). Screened subjects were asked
whether they had diabetes. Dysglycemia was defined as blood glucose 140<
200 mg/dl and diabetes as ≥200mg/dl. Screening was performed free of
charge. A total of 9994 individuals (54.1 females, 55±15.1 years) underwent
screening. Of these, 1589 (15.9%) reported known diabetes. Among the 7868
subjects without known diabetes, dysglycemia was detected in 1065 (13.5%)
and diabetes was found in 115 (1.5%). Compared to subjects with blood
glucose < 140 mg/dl, those with dysglycemia were significantly older (58±14
vs. 51.5±15.2 years, p< 0.001) and had elevated BMI (27.4±4.6 vs. 26.4±4.5
kg/m2, p< 0.001), systolic blood pressure (137.4±22.9 mmHg vs. 131.9±21.6
mmHg, p< 0.001) and diastolic blood pressure (80.3±16.2 vs. 78.8±14.3,
p=0.004). Compared to subjects with newly identified dysglycemia, those
with newly identified diabetes had significantly higher diastolic blood
pressure (86.4±23.3 mmHg, p< 0.001) but did not differ by age, BMI or
systolic blood pressure. Implementation of a screening program in public
places can identify people at high risk for dysglycemia and diabetes, who
are referred for diagnosis and treatment.
MONA BOAZ, YOSEFA BAR DAYAN, JULIO WAINSTEIN, Holon, Israel
Accumulating evidence, mostly from studies conducted in Western populations, has demonstrated strong association between ferritin concentrations
and the development of type 2 diabetes (T2D). In Asian populations, however,
there was no research to examine whether serum ferritin levels have been
actually associated with the prospective development of T2D. Considering
both the different levels of serum ferritin between different ethnicities and
the diverse effect of body composition according to the ethnicities on the
association between serum ferritin and the insulin resistance, it still remains
unclear whether elevated ferritin levels contribute to the development of
T2D in Asian populations. In this 4-year retrospective longitudinal study,
we aimed to investigate the role of elevated levels of serum ferritin in the
development of T2D in a healthy Korean male population. After excluding
ineligible subjects, we examined the clinical and laboratory data of 2,029
male subjects (mean age, 51.2 yr, range, 23-82 yr) without T2D who
underwent general routine health evaluations at the Asan Medical Center
(Seoul, Republic of Korea) in 2007 and had returned for follow-up examination
in 2011. During a 4-year period, 186 incident diabetes cases (9.2 %) were
identified. We could observe that incident T2D increased across the baseline
ferritin quartile categories (P for trend = 0.003). The odds ratios (ORs) for the
development of T2D were significantly higher in highest compared with the
lowest ferritin quartile categories, even after adjustment for confounding
variables including HOMA-IR (OR=1.25, 95% confidence interval 1.34-2.22,
P for trend=0.046). These results suggest that elevated levels of serum
ferritin is associated with the development of T2D in an Asian population
as well. To our best knowledge, this is the first prospective study on the
positive association between serum ferritin levels and incident T2D in an
Asian population.
1489-P
Evaluation of Different Methods in HbA1c Interference
NILGUN SEMA GENC, MUGE KANMAZ-OZER, BEYHAN OMER, FIGEN GURDOL,
NEVIN DINCAG, Istanbul, Turkey
Background: Hemoglobin A1c(HbA1c) assay is the most powerful marker to
determine the glycemic control in diabetic patients.In this study, we aimed
to evaluate the analytical performances of the Roche Tina-quant HbA1c
assay based on immunoturbidimetry(TINIA), TosohG8 cation-exchange
high-performance liquid chromatography and Premier Hb9210 boronate
affinity chromatography methods.Sebia capillary zone electrophoresis
was performed as the reference method.The degree of interference was
examined by high urea and triglyceride levels on HbA1c analysis.
Methods: This study comprised 204 whole blood samples obtained from
the diabetic and nondiabetic patients.HbA1c levels were quantified in
quadriplicate using four different methods.
Results: The results of precision studies (within-run and betweendays) were under 2.5% CV as specified by IFCC working group for the
HbA1c standardization.The Deming Regression analysis between capillary
electrophoresis and other methods were evaluated, good correlation was
seen between capillary electrophoresis and TINIA and boronate affinity
chromatography as well. HPLC method also showed a good correlation but
was not in good agreement, because the confidence interval for slope did
not contain zero and intercept value. The HbA1c results with either normal
or high urea and tryglycerid levels were examined to detect the interference
of these substances.No significant differences were seen between the
reference method and other methods studied.
Conclusion: HbA1c results of the diabetic patients are not affected by the
accompanied metabolic disorders such as uremia and hypertriglyceridemia.
Therefore, these conditions may be ignored during the clinical evaluation of
the patient.
1487-P
A1c ≥ 6.5% Misses the Majority of Diabetic Patients Defined by
Plasma Glucose
HORNG-YIH OU, JEAN HUANG, RUDRUIDEE KARNCHANASORN, WEI FENG,
RAYNALD SAMOA, KEN C. CHIU, LEE-MING CHUANG, Tainan, Taiwan, Sylmar, CA,
Kansas City, KS, Duarte, CA, Taipei, Taiwan
Diagnosis of diabetes mellitus (DM) was originally made on blood glucose
from a fasting sample or oral glucose tolerance tests, based on the risk of
retinopathy, namely 126 mg/dL for fasting plasma glucose (FPG) and 200
mg/dL for 2-hour post-challenged plasma glucose (2hPG). In 2012, the ADA
officially adapted a hemoglobin A1c (A1c) ≥ 6.5% into its criteria for the
diagnosis of DM, which was also based on the risk of retinopathy. In this
study, we examined the performance of A1c in the diagnosis of diabetes as
compared to the diagnosis by FPG and 2hPG.
This study consisted of the participants of the NHANES 2005-2010. Only
the subjects aged 18 years old or older that had an A1c, FPG, and 2hPG were
enrolled into this study (n=5,796). After all established cases of diabetes
were excluded, 5,745 subjects were remained in this study. Consistent with
current ADA guideline, DM was defined as either FPG ≥ 126 mg/dL or 2hPG
≥ 200 mg/dL.
In this sample, 479 subjects (8.34%) were found to be diabetes. Among
them, only 119 subjects (24.84%) had an A1c ≥ 6.5%, while 360 subjects
(75.16%) had an A1c < 6.5%. As compared to the DM subjects with A1c ≥
6.5%, the diabetic subjects with A1c < 6.5% were leaner (29.92±6.43 vs.
32.98±6.82 kg/m2, mean±STD, P=0.00001). However, no difference was
found in gender distribution, age, systolic and diastolic pressure, and family
history of DM. For diabetic subjects with BMI of 20.00-24.99 kg/m2, 84.81%
of them had A1c < 6.5%.
We found that A1c was correlated with FPG very well (r=0.6987,
P<0.000001) and also with 2hPG very well (r=0.5906, P<0.000001). Jointly
FPG and 2hPG accounted for 51.11% of variation in A1c (P<0.000001). Based
on this relationship with FPG of 126 mg/dL and 2hPG of 200 mg/dL, A1c was
6.1037%.
In summary, A1c ≥ 6.5% will detect less than 25% of subjects with DM
defined by either FPG or 2hPG with very low sensitivity in lean subjects.
This study suggests that to be consistent with FPG and 2hPG cutoffs, a new
diagnostic criterion for DM, such as an A1c > 6.1% as defined in this study,
is required.
1490-P
Meal Tolerance Test Is More Valuable than Glucagon Stimulation
Test in Type 2 Diabetes
YOUHEI FUJIOKA, TSUYOSHI OHKURA, KEISUKE SUMI, HIDEKI SHIOCHI, NAOYA
YAMAMOTO, KAZUHIKO MATSUZAWA, SHOICHIRO IZAWA, HIROSHI KINOSHITA, HIROKO OHKURA, MASAHIKO KATO, SHINICHI TANIGUCHI, KAZUHIRO YAMAMOTO, Yonago, Japan
Glucagon stimulation test (GST) is a standard method of evaluating
endogenous insulin secretion. However, GST has adverse effects and takes
effort. In contrast, meal tolerance test (MTT) has no adverse effect and
cheaper than GST. The aim of this study is to evaluate the properties of GST
and MTT in type 2 diabetes patients. We enrolled sixty-nine patients of type2
diabetes (mean: age 61.3, M/F: 34/35, BMI: 24.2, HbA1c: 9.5) and performed
GST and MTT. We performed MTT by using a normal diabetes food of 30kcal/
day per ideal body weight, which contains 60% of carbohydrates, protein 20%,
&
For author disclosure information, see page 829.
A388
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—DIABETES COMPLICATIONS
lipid 20%. In MTT, patients continued oral hypoglycemic agents and insulin
treatment as usual, but we excluded patients taking glinide from subjects to
exclude influence of the medicine. In MTT, we measured plasma glucose (PG)
and serum C-peptide immunoreactivity (CPR), and plasma insulin level before
and 120minutes after meal load. We calculated increment of CPR (ΔCPR) by
subtracting fasting CPR (FCPR) from 6 minutes after glucagon injection and
120 minutes after meal load. The mean fasting PG (FPG) was 161 mg/dl, the
mean FCPR was 2.2 ng/ml, the mean GSTΔCPR was 2.1 ng/ml, and the mean
MTTΔCPR was 3.0 ng/ml. The mean MTTΔCPR was significantly higher than
the mean GSTΔCPR (P<0.01). To consider influence of glucotoxicity to both
test, we performed ROC analysis by FPG. The optimal cut point of was under
157 mg/dl to define MTT superior to GST (sensitivity 0.75, specificity 0.67,
AUC 0.70). MTT could examine insulin secretion including incretin effect by
the meal load, and it may be one of the reasons why MTTΔCPR is higher than
GSTΔCPR. Therefore, MTT could evaluate the endogenous insulin secretion
ability more than GST. However, MTT is affected by the glucotoxicity than
GST. We had better consider to perform GST in the hyperglycemic state,
especially FPG is 157mg/dl or more. We need to use GST and MTT properly
by a level of FPG. In conclusion, MTT is more valuable as an insulin secretion
test in type 2 diabetes patients than GST.
1492-P
Abnormal Glycoregulation in Chinese Patients With Graves Disease
1491-P
Relationship between Body Weight (BW) Gain from Early Adulthood
and Incident Type 2 Diabetes (T2DM): A Meta-Analysis
SATORU KODAMA, CHIKA HORIKAWA, KAZUYA FUJIHARA, RYOKO TAJIMA,
YORIKO HEIANZA, YOKO YACHI, KAORUKO T. IIDA, HITOSHI SHIMANO, OSAMU
HANYU, HIROHITO SONE, Mito, Japan, Tsukuba, Japan, Tokyo, Japan, Niigata, Japan
Our aim of this meta-analysis is to ascertain the shape of the relationship
between BW gain and risk of future T2DM. Electronic literature searches
were conducted for prospective studies investigating T2DM risk in relation
to BW change from early adulthood (18-24 y) to cohort entry using MEDLINE
and EMBASE. Excluded were studies that included participants with diabetes
or were <25 y of age. For 7 eligible studies, the natural logarithms of relative
risk (ln RR) of diabetes in all risk groups with BW gain compared with a
referent group that maintained BW were plotted against their corresponding
mean dose of BW gain standardized into body mass index (BMI) units. Linear
and spline regression analyses were applied for ascertaining the shape
of the scattered plots. Linear regression analysis indicated that RR (95%
confidence interval) for a 1 kg/m2 incremental increase in BMI was 1.18 (1.151.22). Spline curve revealed higher goodness of fit compared with linearity
(R2=0.85 vs. 0.75, P for difference <0.001). However, no critical point of BW
gain above which T2DM risk rapidly increased was detected (Figure). Results
of this meta-analysis suggested that T2DM risk continuously increased with
BW gain without a cut-off value below which the increase in T2DM risk was
avoided.
EPIDEMIOLOGY—DIABETES COMPLICATIONS
Guided Audio Tour: Epidemiology of Diabetes Complications (Posters: 1493-P
to 1499-P), see page 15.
&
1493-P
Epidemiology of Hypoglycemia and Its Impact on Health-Related
Quality of Life in Type 2 Diabetes Mellitus (HYPO-Cyprus)
CHRISTINA THERAPONTOS, PETROS MAVROGENIS, SIEW HWA ONG, STAVROS
POULOUKAS, CHRISTOS PASTELLAS, MARINELLA KYRIAKIDOU-HIMONAS,
PANAYIOTIS KOUTSIDES, GEORGE OLYMPIOS, MICHALIS PICOLOS, ANDREAS
STYLIANOU, COSTAS TOUFEXIS, POLYKARPOS EVRIPIDOU, THEODOROS LOIZOU,
Nicosia, Cyprus, Basel, Switzerland, Limassol, Cyprus, Larnaca, Cyprus
HYPO-Cyprus was a cross-sectional epidemiological study designed to
evaluate the incidence of hypoglycemia and its impact on health-related
quality of life (HRQoL) as a function of patient perspectives, HRQoL scores,
treatment satisfaction and current health status.
500 adult Cypriot type 2 diabetes mellitus (T2DM) patients were asked to
report their hypoglycemia frequency and experience (using Hypoglycemia
Perspectives Questionnaire), HRQoL (using Audit of Diabetes Dependent
Quality of Life-19 questionnaire), treatment satisfaction (using Treatment
Satisfaction questionnaire) and current health status (using EuroQol-5
Dimensions questionnaire).
Demographical and clinical characteristics (including HbA1c value and
current medication) were also recorded. Hypoglycemia was reported by
45.0% of patients, with a frequency of 0.71±1.37 events in the past 7 days
and 2.39±14.39 severe events in the past year. 59.8% of hypoglycemic
patients were uncontrolled (HbA1c≥7%).
On average, patients who experienced hypoglycemia were less concerned
about symptoms (p<0.05), used more compensatory behaviors (p<0.001) and
scored higher on awareness of hypoglycemia (p<0.001) than patients who
did not. The reported HRQoL score for hypoglycemic patients was lower
than non-hypoglycemic patients (average weighted impact score: -2.50
versus -1.99, p<0.01), with significant differences in travel (p<0.05), holidays
(p<0.05), physical activities (p<0.001), sex life (p<0.05), self-confidence
(p<0.01), motivation (p<0.05) and financial situation (p<0.05). Satisfaction
with treatment (p<0.05) and current health (p<0.001 for EQ-5D descriptive
system; p<0.05 for EQ VAS) were also reduced in hypoglycemic patients.
In conclusion, hypoglycemia: 1) was reported by approximately one
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A389
POSTERS
We selected 85 patients with Graves’ disease in our hospital from August
2010 to June 2012, and divided them into 3 groups, primary treatment
group (GD1group), treatment group (the course was 2±0.5month, symptom
uncontroled,GD2group), titration period group (the course was 4±1.5 months,
thyroid hormones were within normal, symptom controlled, GD3 group), and
also 30 healthy persons as control (NC group). All patients were treated by
ATD for 6 months and evaluated before and after the treatment.
At baseline, BG level of GD groups at 30, 60, 120, 180min after OGTT
were markedly higher than the NC group (P<0.01). BG and insulin level rose
to a peak level at 30min and 60 min respectively, and then declined with
the time. BG and insulin level post treatment were decreased significantly
(P<0.01), but still higher compared with NC group (P<0.01). At baseline,BG
and insulin level of GD1 group and GD2 group were significantly higer than
GD3 group (P<0.01). BG and insulin level of GD groups post treatmen had no
difference (P>0.05). At baseline, the ΔI30/ΔG30 of GD groups were significantly
lower than NC group (P<0.01), and there was not markedly increase after
treatment(P>0.05). SG, SI of GD groups at baseline were significantly higher
than NC group (P<0.01), and decreased significantly (P<0.01) after treatment,
but still higher than NC group(P<0.01). At baseline, the ΔI30/ΔG30 of GD groups
had no difference (P>0.05), the SG, SI of GD1 group and GD2 group were
significantly higher compared with GD3 group (P<0.01), and these index had
no differenc post tretment (P>0.05).These results suggest most of patients
with Graves’ disease might manifest with fasting hypoglycemia, impaired
glucose tolerance (IGT), insulin resistance, and hyperinsulinemia. Insulin
resistance and β-cell dysfunction coexist in patients with Graves’ disease.
Treatment by ATD can improve insulin resistance, but islet βcell function will
remained low for a very long period.
Epidemiology/
Genetics
QINGXIAN HUANG, QIAN LIU, WEIKAI HOU, KUN WANG, SHAN YU, LI CHEN,
Jinan, China
EPIDEMIOLOGY—DIABETES COMPLICATIONS
half of the studied T2DM sample; 2) was associated with higher levels of
uncontrolled diabetes and 3) had a negative impact on HRQoL of Cypriot
T2DM patients.
&
Supported by: Novartis Pharmaceuticals Corporation
SHUBARNA AMIN, S. JOSEPH KIM, BAIJU R. SHAH, Toronto, ON, Canada
&
This study examined the risk of chronic kidney disease (CKD) in South
Asian and Chinese people after diabetes diagnosis, compared to the general
population.
Using population-level healthcare databases in Ontario, Canada, all
769,554 people diagnosed with diabetes from January 1996 to December
2007 were followed until March 2012 for CKD using physician claims and
hospitalization data with validated algorithms. South Asian and Chinese
patients were identified by surname; all other patients were in the general
population. Groups were compared using Cox regression models, adjusting
for demographic differences, hypertension and cardiovascular disease.
A comparison group without diabetes was also examined, and the effect
modification of diabetes on CKD risk was tested using an interaction term.
Compared to the general population, South Asian [HR 0.84 (95% CI 0.800.87)] and Chinese [0.91 (0.87-0.95)] people had a lower risk for CKD after
diabetes diagnosis. However, these ethnic differences in CKD risk were no
different from ethnic differences in CKD risk in the comparison population
without diabetes (p for interaction term=0.06 for South Asians, 0.6 for
Chinese).
South Asian and Chinese patients had a lower risk of CKD after diabetes
diagnosis than those in the general population. These ethnic differences
mirrored the ethnic differences in CKD risk of people without diabetes,
suggesting no diabetes-specific effect of ethnicity on CKD risk.
1494-P
Falling or Static National Rates of Diabetes-Related Outcomes from
2005 to 2011 Despite Increasing Prevalence
POSTERS
PAUL L. DRURY, PAULINE W. GILES, EMMANUEL JO, Palmerston North, New Zealand, Wellington, New Zealand
Epidemiology/
Genetics
1496-P
Ethnic Differences in the Risk of Chronic Kidney Disease After Diabetes Diagnosis
Despite rapid and substantial increases in the national diabetes (DM)
population at risk in New Zealand (NZ), anecdotally we have not seen the
anticipated rise in adverse outcomes for renal and vascular morbidities.
We have therefore assessed the annual number of lower-limb amputations,
renal replacement therapy access procedures, cardiovascular (CV) events
and strokes occurring throughout NZ over the 6 year period 2006-2011 using
standard data collection and coding methods. All such events, identified
by ICD-9 or ICD-10 coding, can be linked by a unique national patient
identifier available for >98% of people. We used a detailed algorithm, the
NZ Virtual Diabetes Register (VDR), to define the population with DM; this
identifies individuals as having DM based on their specific healthcare facility
and therapy usage with ≥ 90-95% sensitivity and specificity. Diabetes
prevalence using the VDR rose from 138,200 (end-2005) to 208,076 (end2011), an increase of 50.6% over 6 years - 7.0% compound per annum (p.a.),
while total national population rose only 7.3% (4.12 to 4.42 million) over this
period.
Lower limb amputations in people with DM remained roughly static
between 648 and 782 events annually while, as a rate per 1000 people
with DM, this fell sequentially from 0.47% to 0.39% p.a. (-17%; P<0.05).
Renal access procedures also remained static between 422 and 548 events
annually (0.24-0.33% p.a.; p=NS) with no clear trend. Both the absolute
number and rate of CV events fell progressively from over 13,000 to below
11,000 (9.48 to 5.74% p.a., -39% ; r= -0.97; p<0.005). Stroke events rose in
absolute numbers from 2600 to 3300 but the rate fell from 1.90 to 1.73%
p.a.(-9%; r= -0.90, p<0.02).
We conclude that, despite a 50% increase in diabetes prevalence, national
major end-point rates are currently either static or falling, particularly so for
CV events. This probably largely reflects more systematic care, wider use of
CV and renal preventative therapy together with improved footcare.
&
1495-P
The Effects of Smoking on Glycemic Control and Microvascular
Complications in Type 1 Diabetes in the Diabetes Control and Complications Trial (DCCT)
&
BARBARA H. BRAFFETT, MADELINE M. RICE, HEATHER YOUNG, JOHN M. LACHIN, Washington, DC
1497-P
Diabetes Status and Incidence of Cancer After Age 65, U.S. 1988–
2007
Several studies have demonstrated the significant effects of smoking on
the risk of microvascular complications, however, few have also examined
the mediating effects of HbA1c. Using publicly available data from the wellcharacterized cohort of 1,441 subjects with type 1 diabetes who participated
in the Diabetes Control and Complications Trial (DCCT), we describe the
acute and long-term risks of smoking on glycemic control and microvascular
complications (nephropathy and retinopathy).
Over a mean of 6.5 years of follow-up, the DCCT recorded self-reported
smoking behaviors, glycemic exposure based on HbA1c values, and
complication status. Generalized linear mixed models were used to assess
whether time-dependent measurements of smoking predict HbA1c levels.
Cox proportional hazard models were used to assess time-dependent
smoking exposures as predictors of nephropathy and retinopathy. All models
were adjusted for potential baseline confounders.
During the DCCT, current smokers had consistently higher HbA1c values
compared with former and never smokers (0.35% mean difference vs.
never smokers; 0.29% mean difference vs. former smokers). Additionally,
current smokers had a 42% higher risk of retinopathy and 34% higher risk
of nephropathy compared with never smokers. The significant associations
between smoking and complications were fully attenuated after adjusting
for HbA1c. Former smokers did not differ significantly from never smokers
with respect to HbA1c and the risk of complications.
Smoking is associated with poor glycemic control and an increased risk
of microvascular complications in individuals with type 1 diabetes. Our data
suggest that the negative effects of smoking on glycemic control may be a
mechanism by which smoking leads to complications of type 1 diabetes. The
harmful effects of smoking on HbA1c and the risk of complications may not
persist after quitting smoking,
SHARON H. SAYDAH, KAI M. BULLARD, GIUSEPPINA IMPERATORE, EDWARD
GREGG, LISA RICHARDSON, JEFFERY JOHNSON, Washington, DC, Atlanta, GA,
Alberta, AB, Canada
Although many studies reported the association between diabetes and
cancer, few studies have examined the difference in cancer incidence
between pre-diabetes and diabetes (DM) status and fewer have focused
on the population aged 65 years and older. This study’s objective was to
determine the risk of cancer incidence among the Medicare population
by elevated glucose status. We used data from the National Health and
Nutrition Examination Surveys (NHANES:1988-1994 and 1999-2004), linked
CMS Medicare files through 2007. We included 4,552 adults aged ≥65 years
at the time of NHANES interview with no prior history of cancer and no
enrolment in a Health Maintenance Organization prior to 2007. Diabetes
status was defined as follows: treated DM (DM + antidiabetic medication);
untreated DM (DM + no medication, or no DM + A1c>=6.5%); prediabetes
(no DM + A1c 5.7-6.4%); normoglycemia (no DM + A1c<5.7%). Cancer
incidence was defined by ICD-9CM codes 140-209.3 or 230-234.9 as an
admitting or principal diagnosis. Overall cancer incidence among NHANES
participants over 65 years and in Medicare was 25.7 per 1000 person years.
There was no significant difference in unadjusted cancer incidence by
glucose status (Table). In adjusted proportional hazards models, there was
no significant increased risk of cancer incidence for any group compared to
the normoglycemia group. These results do not suggest an increased risk of
cancer incidence among the older adult Medicare population regardless of
elevated glucose status.
&
For author disclosure information, see page 829.
A390
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—DIABETES COMPLICATIONS
Adults with cancer diagnosed during follow-up,
unweighted n
Cancer incidence, all sites (per 1000 person-years)
Relative hazard (95% CI), adjusted for age, sex,
race/ethnicity, education, and survey period
25.7
(23.1-28.3)
--
24.8
(21.6-27.9)
1.00
(reference)
27.0
(23.1-30.9)
1.14
(0.94-1.37)
&
30.0
24.8
(20.8-39.2) (17.5-32.0)
1.17
1.05
(0.82-1.65) (0.77-1.44)
1500-P
Stroke Incidence and its Long-Term Impact on Mortality in a Population-Based Cohort With Newly Diagnosed Diabetes and Impaired
Glucose Tolerance in China: The Daqing Diabetes Study
1498-P
YALI AN, PING ZHANG, JINPING WANG, EDWARD GREGG, BO ZHANG, HUI LI,
QIUHONG GONG, YANYAN CHEN, XIAOYAN XING, MICHAEL ENGELGAU, GOJKA
ROGLIC, YINGHUA HU, PETER H. BENNETT, GUANGWEI LI, Beijing, China, Atlanta,
GA, Daqing, China, Geneva, Switzerland, Phoenix, AZ
Low Bone Mineral Density (BMD) Is Associated With Insulin Resistance and Poor Metabolic Profiles: Role of Body Fat and Osteocalcin
(OST)
ANNY H. XIANG, ZANGHUA CHEN, MARY HELEN BLACK, MIWA TAKAYANAGI,
THOMAS A. BUCHANAN, RICHARD M. WATANABE, Pasadena, CA, Los Angeles, CA
While stroke is a leading cause of death in China and the numbers of
persons with diabetes and impaired glucose tolerance (IGT) are large and
growing, the incidence and risk of death attributable to stroke among
Chinese adults with these conditions have not previously been quantified.
We examined incidence of stroke and related mortality over a 23 year
period in a cohort of 630 persons with newly diagnosed diabetes (NDM), 576
with IGT, and 519 with normal glucose tolerance (NGT), who were identified
initially in 1986 by screening 50% of the community aged 25 years and over
in Da Qing, China. Stroke incidence and related mortality were ascertained
up to December 31st, 2009 in some 95% of the cohort.
Stroke, fatal or non-fatal, occurred in 218 (36.8%) persons with NDM, 177
(32.7%) with IGT and 121 (24.6%) with NGT. Stroke incidence was higher
in men than in women with NDM (29.0 vs. 18.5/1000 person-years) and
IGT (22.1 vs. 13.7/1000 person-years), but not with NGT (12.9 vs. 11.4/1000
person-years). The age-adjusted hazard ratios for NDM vs. NGT were 2.15
(95% CI 1.59-2.92) in men and 1.47(95% CI 1.05-2.08) in women.
Among those who developed a stroke, death occurred in 145 (66.5%) with
NDM, 82 (46.3%) with IGT, and 36 (29.8%) with NGT. Case-fatality rates
from stroke (per 1000 person-years) were 130.6 in men and 153.9 in women
with NDM, 95.5 and 56.7 in men and women with IGT, and 56.4 and 46.6 in
men and women with NGT. Age- and sex- adjusted case-fatality rate ratios
were 2.42 (95% CI 1.67-3.69) for NDM vs. NGT and 1.54 (95% CI 1.04-2.29)
for IGT vs. NGT.
In China, diabetes and IGT lead to considerable excess risk for stroke and
excess mortality due to stroke. Persons with diabetes or IGT face double
jeopardy by having both a higher stroke incidence and a higher case-fatality
rate after a stroke.
.
Bone has emerged as an endocrine organ and may play a role in glucose
homeostasis partially through fat and OST. We tested whether BMD is
associated with metabolic parameters in 1239 subjects from the BetaGene
study. Phenotyping included BMD and percent body fat (%BF) by DXA,
fasting and 2-hr glucose and insulin, delta 30min insulin (ΔIns30), insulin
sensitivity (SI) and acute insulin response (AIR) assessed by oral- (OGTT)
and intravenous- (FSIGT) glucose tolerance tests. Carboxylated and
uncarboxylated osteocalcin (cOST, uOST) were measured in a subset of 729
subjects. The cohort had mean+SD age of 35+8 years and BMI of 29.5+5.9
kg/m2, and fasting glucose ≤126 mg/dl; 73% were female. After adjustment
for age, sex, height and weight (to remove weight bearing effects), BMD was
positively associated with SI (p=0.0004), negatively associated with %BF,
waist circumference, 2-hr glucose, fasting and 2-hr insulin, ΔIns30 and AIR
(all p<0.01). Adjustment for %BF reduced the BMD correlations with SI by
44%, 2-hr glucose by 19%, fasting and 2-hr insulin by 11% and 47%, ΔIns30
by 22% and AIR by 33%. Adjustment for %BF did not eliminate the significant
associations (adjusted p <0.048). Further adjustment for cOST insignificantly
altered the correlations <±5% in the subset with OST. Adjustment for uOST
reduced the BMD correlations with ΔIns30 by 18% and AIR by 34%, but only
changed the BMD correlations modestly for SI, 2-hr glucose, fasting and 2-hr
insulin (6%, -16%, 7%, 9%, respectively). Directions of observed associations
were consistent between males and females. Thus, our results indicate that
low BMD is associated with insulin resistance and poor metabolic profiles
in Mexican Americans without overt diabetes. %BF explained nearly half of
the associations for insulin resistance and 2-hr insulin, suggesting some of
the effect on BMD may be mediated through body fat. uOST, not the cOST,
appears to play a role for the relationship between BMD and acute insulin
response.
1501-P
Supported by: NIH/NIDDK (5RO1DK-61628)
&
Duration of Type 2 Diabetes, Independent of Age and Metabolic Status, Is a Predictor of Global Cognitive Decline
1499-P
DIVYA YOGI-MORREN, SARAH STRANJFORD, LAURENCE KENNEDY, MARWAN
HAMATY, JOHN P. KIRWAN, JOHN GUNSTAD, SANGEETA R. KASHYAP, Cleveland, OH, Kent, OH
Physical Functioning and Mortality in Type 2 Diabetes: Insights
from TRIAD
KELLY R. YLITALO, LAURA MCEWEN, PEARL LEE, ANDREW J. KARTER, WILLIAM
H. HERMAN, Ann Arbor, MI, Oakland, CA
Clinical studies have noted a greater prevalence of global cognitive
impairment, incidence of cognitive decline and Alzheimer’s disease in type 2
diabetes (T2D). The clinical factors that underlie cognitive decline in T2D are
not well understood. We performed a prospective, longitudinal cohort study
in which 47 adults with T2D (58.0±12 years, 59.6% female, BMI 34.5±9 kg/
m2, HbA1c 7.4±0.7%,
T2D duration 11.2±9y, 40% insulin users) and age and gender-matched,
healthy non-diabetic subjects (no comorbidities/no medications) completed
the Webneuro computerized cognitive test battery, which assesses executive
function, attention and memory. Tests were performed at baseline and at
follow up within 1 yr to determine the impact of Metabolic Syndrome and its
management on cognitive function outcomes.Each clinic visit documented
historical data, physical parameters, and biochemical data. At baseline,
cognitive impairment was common in the T2D patients, with 13% exhibiting
impairment (greater than 1 SD below control performance) in memory, 50%
in attention, and 35% in executive function. Partial correlations between
years of diabetes and test performance were performed adjusting for
demographics and clinical characteristics (laboratory levels of HbA1c,
triglycerides, LDL, diagnosis of hypertension, and BMI). Results showed
Diabetes is a risk factor for mortality. Subjective health status, including
self-reported physical functioning, may also be a marker for mortality. This
study examined the association between self-reported physical functioning
and mortality in people with diabetes, and determined if this association
differed by race/ethnicity. We studied 7,894 type 2 diabetic patients who
participated in Translating Research Into Action for Diabetes (TRIAD), a
prospective study of diabetes care in managed care. At baseline in 2000,
participants completed a questionnaire and had medical record reviews.
Physical functioning was assessed with the Short Form Health Survey
(SF-12). The National Death Index was searched annually for deaths over
10 years of follow-up (2000-2009). At baseline, mean age was 61.7 years,
50% were non-Hispanic white, 22% were black, and 16% of participants
reported “good physical functioning” (better than norms for U.S. adults).
Over 10 years, 28% of participants died (2,111/7,894); 39% (856/2,111) due
to cardiovascular disease. Relative to those with good functioning, those
with poor physical functioning had a 37% higher all-cause death rate,
after adjusting for age, sex, race/ethnicity, education, income, body mass
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A391
POSTERS
n, unweighted
Person-years, mean
(95% CI)
Follow-up person-years, median (IQR)
index, smoking, and comorbidities (Hazard Ratio (HR)=1.37; 95% Confidence
Interval (CI): 1.15, 1.63). Similarly, those with poor physical functioning had a
42% higher adjusted cardiovascular death rate compared to those with good
functioning (HR= 1.42; 95% CI: 1.06, 1.90). Although blacks were less likely
than whites to report good functioning (p<0.01), the association between
functioning and mortality was consistent across race/ethnicity. In this
managed care population with diabetes, self-reported physical functioning
was a robust predictor of mortality, in addition to traditional biological risk
factors, for all race/ethnic groups. Physical functioning assessments are
easy to perform and may be useful benchmarks for tailoring the care of
persons with chronic disease.
Normoglycemia Prediabetes Untreated DM Treated DM
2231
1294
358
669
8.2
8.0
7.9
5.8
(7.8-8.6)
(7.6-8.4)
(7.1-8.6) (5.4-6.3)
7.0
6.9
6.8
5.0
(4.3-12.2)
(4.2-11.9) (3.8-11.3) (3.2-7.6)
470
270
80
92
Epidemiology/
Genetics
Total
4552
7.8
(7.5-8.2)
6.7
(4.0-11.3)
912
EPIDEMIOLOGY—DIABETES COMPLICATIONS
longer duration of diabetes was associated with poorer performance on
basic attention (Digit Span, r=-0.41 p<0.04), working memory (Working
Memory, r=-0.40, p<0.04), and executive function (Switching of AttentionLetter/Number, r=0.41, p<0.04). We conclude that executive function and
attention impairments characterize cognitive decline in middle aged adults
withT2D compared to age and gender matched controls. Duration of diabetes
is a predictor of cognitive dysfunction independent of metabolic factors and
age. Alternative strategies for diabetes education in the population are
warranted.
than one quarter or no assigned NAqt than among those with full NAqt
(HR=1.3, 95% CI 1.1-1.6 and HR=1.2, 95% CI 1.1-1.4, respectively) and similar
in those with at least one quarter NAqt. Survival among NA with diabetes on
hemodialysis is positively associated with NAqt. Those with less than onequarter NAqt have the lowest median survival time among NA.
1502-P
LIZHENG SHI, XIN YE, MEI LU, ERIC Q. WU, HARI SHARMA, DARREN THOMASON, VIVIAN FONSECA, New Orleans, LA, Parsippany, NJ, Boston, MA
1504-P
Long-Term Clinical Outcomes Associated With LDL-C and HbA1c
Goal Achievement in Patients With Type 2 Diabetes Mellitus
(T2DM)
Management of Comorbid Type 2 Diabetes and Low Testosterone in
Primary Care (UK)
There may be incremental clinical benefits associated with dual-goal
achievement (hemoglobin (HbA1c) <7% and LDL-cholesterol (LDL-C) <100mg/
dL) in T2DM patients compared with single-goal achievement.
Adult T2DM patients with ≥2 measurements of LDL-C and HbA1c were
identified from the South Central Veterans Affairs Health Care Network
(01/2004-06/2010). Multivariate Cox proportional hazards models were
used to evaluate time to the first clinical event associated with time-varying
goal achievement status. Clinical events included composite endpoint of
microvascular complications (retinopathy, nephropathy, or neuropathy),
cardiovascular endpoint (cardiovascular death, stroke, or myocardial
infarction), and acute coronary syndromes (ACS), as well as surgical
procedures (percutaneous coronary intervention and coronary artery bypass
graft (CABG)).
A total of 75,646 patients were included (median follow-up: 4.5 years).
Compared with only LDL-C goal achievement, dual-goal achievement was
associated with lower risks of microvascular complications, ACS, and
surgical procedures. Compared with only HbA1c goal achievement, dual-goal
achievement was associated with lower risks of cardiovascular endpoint
and CABG.
In this analysis of US Veterans with T2DM, dual-goal achievement was
associated with incremental clinical benefits compared with only HbA1c or
only LDL-C goal achievement.
POSTERS
Epidemiology/
Genetics
STEPHAN LANES, BRADLEY H. CURTIS, CHARLES WENTWORTH, KRISTINA
BOYE, CINIRA LEFEVRE, MELISSA GAWLIK, DARA SCHUSTER, GLENN MATFIN,
Lexington, MA, Indianapolis, IN, Windlesham, United Kingdom, Minneapolis, MN
While the increased prevalence of low testosterone (LT) in men with type
2 diabetes (T2DM) is well established, uncertainty exists regarding the
interrelationship between these two conditions (causal or association).
This retrospective cohort study utilized the validated Clinical Practice
Research Database (CPRD) a UK primary care electronic health record
database. We obtained detailed files for males with clinically diagnosed
LT or T2DM containing all medical records available from the primary care
physician (GP). Data (2000-2010) were examined for baseline characteristics
including labs, allowing calculation of incidence of LT according to prior
T2DM or vice versa. Patients were included in the incident T2DM and LT
cohorts if they had no history of diagnosis of the condition prior to a 1-year
enrollment index date.
We identified 75,772 men with incident T2DM (Mean Age 62; BMI 31) and
20,509 men with incident LT (Mean Age 36; BMI 29) of a total evaluable
population of approximately 3.5m men. In men with T2DM, incidence of
clinical LT was 1.72 times (95% CI 1.59, 1.86) greater than the incidence in
those without T2DM; whereas prevalent LT did not predict an increased risk
of developing T2DM; RR 0.94 (95% CI 0.90, 0.98). Only 1% of patients with
T2DM had a total testosterone test. Among men with newly diagnosed LT,
12% had a testosterone test in the year prior to diagnosis and 29% had a
testosterone test in the year following diagnosis. In addition, 4,488 (< 25%)
of incident LT patients received testosterone replacement treatment (TRT)
during the study period.
In the UK primary care setting, clinical LT occurred nearly twice as
frequently among patients with T2DM, even in the setting of extremely low
screening rates. In addition, appropriate TRT and monitoring of testosterone
levels after LT diagnosis was also low, indicating a gap between current
guidelines and practice. Given the potential for improved quality of life with
LT treatment, education of men with T2DM and the GP on the comorbid
nature of T2DM and LT is warranted.
Supported by: Daiichi Sankyo, Inc.
1505-P
The 9p21 Myocardial Infarction High Risk Locus Does Not Associate With Peripheral Vascular Disease in Patients With Type 2 Diabetes Mellitus
Supported by: Eli Lilly and Company
1503-P
MEDA E. PAVKOV, NILKA R. BURROWS, PYONE CHO, KAI M. BULLARD, PAUL W.
EGGERS, ANDREW S. NARVA, Atlanta, GA, Bethesda, MD
ELEONORA RUSSO, DANIELA LUCCHESI, LAURA PUCCI, SALVATORE DE COSMO,
MONIA GAROFOLO, VERONICA SANCHO BORNEZ, SIMONA GEORGIANA POPA,
ROSSELLA RUSSO, ROBERTO MICCOLI, VINCENZO TRISCHITTA, GIUSEPPE
PENNO, STEFANO DEL PRATO, Pisa, Italy, San Giovanni Rotondo, Italy, Craiova,
Romania
Diabetes is the leading cause of kidney failure among Native Americans
(NA), however, those NA treated with dialysis have better survival than
other racial/ethnic groups. We analyzed records from the US Renal Data
System with hemodialysis initiated in 1995-2009 to assess survival among
NA with diabetes listed as the primary cause of kidney failure. Kaplan-Meier
method was used to compare survival by NA blood quantum (NAqt), and
Cox regression analysis to compute adjusted hazard ratios (HR) for death
due to any cause. The study included 5,635 persons of which 60% had full
NAqt, 20% had less than full but greater than half NAqt, 5% had one quarter
to half NAqt, 3% had less than one quarter NAqt, and 12% reported NA
ancestry but had no blood quantum information in the Indian Health Service
database. Median follow-up time was 3.6 years (interquartile range 1.5 to
6.2 years). Median survival time was less with lower NAqt: 4.6 years (95%
CI 4.4-4.7 years) in those with full NAqt to 3.2 years (95% CI 2.5-3.5) in those
with <25% NAqt, and 2.8 years (95% CI 2.5-3.1) in those without assigned
NAqt (p <0.001). Compared with hemodialysis patients with full NAqt,
unadjusted HR of death was 1.1 (95% CI 1.02-1.3), 1.2 (95% CI 1.01-1.4), 1.3
(95% CI 1.1-1.6), and 1.3 (95% CI 1.1-1.5) in those with lesser or no assigned
NAqt, respectively. After controlling for demographic factors, comorbidities,
health insurance status, smoking, and erythropoetin treatment in a Cox
regression analysis, the risk of death remained higher in those with less
Chr9p21 locus is a robust CHD genetic marker. Associations were
reported with carotid artery plaque, stroke, aneurysms, heart failure, CVD
mortality, while no association was found between Chr9p21 and CV risk
factors, suggesting that the locus exerts a direct effect on CV risk. We
explored the association between the Chr9p21 (SNP rs2383206) and ABI
and peripheral artery disease (PAD, i.e. ABI <0.9) in 937 unrelated Italian
T2DM (M/F 550, 58.7%/387, 41.3%). Genotyping was performed by TaqMan
assay implemented on HT7900 Applied Biosystems platform. Patients
were 59.2±7.5 yrs old with a diabetes duration (DD) of 10.4±9.0 yrs, BMI
29.4±5.4 kg/m2; sBP 142±19, dBP 82±10 mmHg, HbA1c 7.7±2.7% (median
value 7.45%; first and third quartiles 6.75 and 8.25%); 132 patients (14.1%)
had PAD. Genotype distribution was: AA (n. 146) 15.6%; GA (n. 452) 48.2%;
GG (n. 339) 36.2%. The sample was in Hardy-Weinberg equilibrium. There
was no difference among genotypes in age, DD, smoking, BMI, sBP, dBP,
HbA1c, total-, LDL- and HDL-C, triglycerides, uric acid, fibrinogen, urinary
A/C ratio and eGFR (MDRD). No association was found between rs2383206
and ABI as a continuous trait (AA: 1.06±0.19; GA: 1.05±0.17; GG: 1.04±0.16;
p=NS). Furthermore, no association was apparent between rs2383206 and
PAD prevalence (AA 15.1%; GA 13.5%; GG 14.5%; p=0.867). No interaction
was observed between rs2383206 and HbA1c above the median value or
within the fourth quartile. No differences emerged between genders or in
Survival on Dialysis among Native Americans With Diabetes by
Level of Indian Ancestry, United States, 1995–2010
&
For author disclosure information, see page 829.
A392
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—DIABETES COMPLICATIONS
subjects with vs. those without family history of CHD. In logistic backward
regressions, PAD was associated with age, sBP, smoking (p<0.0001 for all),
dBP (inversely), male gender (p=0.001 for both), HbA1c (p=0.022) and A/C
ratio (p=0.035) (model 1) or CHD (p<0.001) (model 2), but not to rs2383206. In
this cohort of Italian T2DM, the rs2383206 SNP, previously associated with
CHD and shown to interact with glycaemic control, was not associated with
continuous ABI and PAD phenotypes.
Among PWD, a disproportionate percent of Black (41%), low income
(48%), less educated (44%) and not insured (48%) had significant tooth loss
compared to White (30%), high income (11%), highly educated (14%) and
insured (27%). Oral treatment decreased with lack of insurance and reduced
education or income level.
Serious dental issues occur even among PWD who seek regular oral
health treatment and indicate a need to communicate the importance of
proper oral health care to PWD.
1506-P
Adiponectin and Retinopathy in Type 1 Diabetes
Odds Ratios (OR) and (95% Wald Confidence Intervals) for DR Severity
Characteristic
Model 1 Model 2 Model 3 Model 4
Age at exam,
0.99
1.01
1.00
0.99
per 1 yr
(0.96-1.02) (0.98-1.05) (0.97-1.04) (0.96-1.03)
Male
1.78
2.21
1.72
1.50
(1.13-2.81) (1.35-3.62) (1.01-2.93) (0.87-2.61)
Log 9-20 yr ADPN,
1.79
1.58
1.74
1.55
per 1 unit
(1.21-2.65) (1.04-2.40) (1.13-2.66) (1.00-2.41)
Mean HbA1c,per 1%
3.18
2.95
2.99
(2.45-4.11) (2.27-3.84) (2.29-3.90)
eGDR,
0.80
0.86
per1 mg · kg-1 · min-1
(0.70-0.93) (0.74-1.00)
Systolic BP,
1.09
per 3 mmHg
(1.02-1.16)
Log UACR,
per 1 unit
Model 5
1.00
(0.96-1.03)
1.68
(0.99-2.84)
1.44
(0.94-2.20)
3.13
(2.41-4.06)
1508-P
Handgrip Strength Is Associated With Glomerular Filtration Rate in
Patients With Diabetes Type 2
PATRICIO LOPEZ-JARAMILLO, DANIEL COHEN, DIEGO GOMEZ-ARBELAEZ, HERTZEL GERSTEIN, JACKIE BOSCH, SALIM YUSUF, ORIGIN INVESTIGATORS, Bucaramanga, Colombia, Hamilton, ON, Canada
Deterioration of renal function is a common complication of diabetes
type 2 (DM2). Grip strength (GS) is associated with better renal function
and lower mortality in individuals with chronic kidney disease. DM2
patients are a group at risk of strength deficits since lower strength predicts
Insulin resistance and the onset of DM2, in turn are associated with the
deterioration of muscle function and strength. The association between
strength and renal function in DM2 has not been evaluated. In a subanalysis
of the ORIGIN trial of CVD outcomes and mortality in DM2 and pre DM2, we
examined the association between GS and estimated glomerular filtration
rate (eGFR).
GS was assessed and eGFR was determined using the MDRD formula
in 12516 patients (35% female), mean age 63.6 (±7.8) with either impaired
glucose tolerance/impaired fasting glucose (12%), or DM2 (88%),. Significant
trends (P<0.001) consistent with a positive relationship between eGFR (mL/
min) and age adjusted GS quintiles (GSa), were noted for males and females
separately (fig.1).
We found a graded association between strength and an important marker
of renal function in an international cohort of Pre DM2 and DM2 patients.
Our analysis cannot determine causality, but strength or strength training
interventions are associated with better endothelial function, inflammatory
profile and insulin sensitivity pathways and lower oxidative stress, factors
which may mediate positive associations with renal function.
Model 6
1.02
(0.98-1.05)
2.50
(1.48-4.20)
1.31
(0.85-2.03)
2.56
(1.95-3.37)
1.11
(1.04-1.18)
1.82
(1.43-2.32)
Supported by: NIDDK (R01DK36904)
1507-P
Gum Disease and Diabetes in Michigan, an Overlooked Connection
H.C. MICHELLE BYRD, CHRIS FUSSMAN, DAWN L. CRANE, BETH ANDERSON,
SARAH LYON-CALLO, Lansing, MI
Diabetes increases the susceptible to oral health diseases like periodontitis
which can lead tooth loss and bone disease. We report the prevalence of
oral health treatment and outcome among adult persons with diabetes
(PWD) based on results from the 2008 and 2010 Michigan Behavioral Risk
Factor Surveys (MiBRFS).
Questions related to oral health, diabetes, and behavioral factors were
included within the 2008 and 2010 MiBRFS. The diabetes definition excluded
prediabetes or gestational diabetes. Questions included oral health
treatment (dental visit and cleaning), teeth missing due to infection, and
dental coverage.
Prevalence of significant tooth loss was statistically higher among
PWD vs. persons without for all ages (Figure 1). Despite similar oral health
treatment compliance, this prevalence among PWD age 18-44 was 4 times
higher than those without diabetes. Older PWD tended to have oral health
treatment less often and a higher percent of significant tooth loss than those
without diabetes.
ADA-Funded Research
&
Supported by: Sanofi (NCT00069784)
For author disclosure information, see page 829.
Guided Audio Tour poster
A393
POSTERS
The role of adiponectin (ADPN) in type 1 diabetes (T1DM) complications is
unclear and few studies have examined the relationship between retinopathy
(DR) and prospectively measured ADPN. The Wisconsin Diabetes Registry
Study cohort, followed since T1DM diagnosis through 20 years, provided
this opportunity. Subjects with DR grading by fundus photographs at the
20-year exam and ADPN tested in -80oC stored samples from 1, 4, 7, 9 or
20-year exams were included. Twenty-year examinees (n=304) participated
in (mean) 3.43 total exams yielding 1043 stored plasma samples tested and
99% (n=301) had 20-year DR grading. The relationship between ADPN and
DR by 20 years was assessed by ordinal logistic regression of DR severity
categories: none-minimal, mild-moderate and vision-threatening DR, and
logistic regression of a dichotomous (yes/no) indicator of progression from
4 or 9 to 20 years. Mean ADPN levels at 1-4, 7-9 and 9-20 years, and overall,
were investigated. A positive relationship between higher ADPN during
9-20 years diabetes and 20-year severity was no longer significant when
systolic BP or urine albumin-creatinine ratio at 20 years were considered.
Unadjusted mean ADPN at earlier durations was not significantly related to
DR severity or progression. Higher ADPN at later diabetes coincides with DR
severity, kidney function and higher BP at 20 years diabetes duration. Our
findings support a possible compensatory response of increased ADPN tied
to endothelial dysfunction- or inflammation-based processes.
Epidemiology/
Genetics
TAMARA J. LECAIRE, MARI PALTA, RONALD KLEIN, BARBARA E.K. KLEIN, Madison, WI
POSTERS
Epidemiology/
Genetics
EPIDEMIOLOGY—DIABETES COMPLICATIONS
1509-P
1511-P
Characterization of the Risk for Urinary Tract Infections in Patients
With Type 2 Diabetes
Disease Burden of Urinary Tract Infections among Type 2 Diabetes
Mellitus (T2DM) Patients: A U.S. Database Study
KRISTY IGLAY, ALEX Z. FU, YING QIU, SAMUEL S. ENGEL, RAVI SHANKAR, MICHAEL J. DAVIES, KIMBERLY G. BRODOVICZ, Whitehouse Station, NJ, Washington, DC
SHENGSHENG YU, ALEX Z. FU, YING QIU, SAMUEL S. ENGEL, RAVI SHANKAR,
SWAPNIL RAJPATHAK, LARRY RADICAN, KIMBERLY G. BRODOVICZ, Whitehouse
Station, NJ, Washington, DC, North Wales, PA
Type 2 diabetes (T2DM) is associated with increased rates of infections,
with urinary tract infections (UTI) among the most commonly encountered.
The incidence and risk of UTI in patients (pts) with or without T2DM were
assessed in a retrospective US cohort study. Pts ≥18 years old with a T2DM
diagnosis in 2010 were identified using the MarketScan database. Index
date was first date with diagnosis in 2010. Pts were excluded if they had
T2DM diagnosis or antihyperglycemic medication use in the year prior to
index date. Pts without T2DM were matched on age, gender, index date,
and geographic region. Eligible pts had medical records for 1 year before
(baseline) and after (follow up) the index date. UTI diagnosis (UTI, cystitis, and
pyelonephritis) during follow up was assessed using ICD-9 codes. Logistic
regression adjusted for patient characteristics and comorbid conditions was
used to assess the likelihood of experiencing UTI. A total of 89,790 matched
pairs were selected. The mean age at index date was 56 years and 51% were
male. Pts with T2DM had more pre-existing comorbid conditions compared
to pts without T2DM. In the 1-yr follow up, 7.6% of all pts were diagnosed
with UTI, with more pts with T2DM compared to those without T2DM (9.4%
vs. 5.7%; p<0.0001). The proportion of women with T2DM experiencing
UTI was greater than those without T2DM (14.0% vs. 9.1%; p<0.0001). A
lower proportion of men had UTI, but the difference between T2DM and no
T2DM was significant (5.0% vs. 2.4%; p<0.0001). In a logistic regression,
pts with T2DM had a greater likelihood of experiencing UTI during follow
up (adjusted odds ratio [OR] = 1.54 [95% CI 1.47, 1.60]; p<0.0001). When
stratified for gender, the odds were still significantly greater for pts with
T2DM (women: OR = 1.43 [1.36, 1.50]; men: OR = 1.91 [1.76, 2.07]; p<0.0001
for both). Recurrence of UTI was also higher with T2DM (1.6% vs. 0.6%;
p<0.0001) during follow up. In conclusion, pts with T2DM were more likely to
experience a UTI and recurrent UTIs compared to pts without T2DM.
While the association between type 2 diabetes mellitus (T2DM) and
urinary tract infection (UTI) is known, the economic burden has not been
adequately quantified. Healthcare resource utilization and costs for T2DM
patients with (prevalent cohort [PC]) and without (incident cohort [IC]) a
history of UTI were assessed in a retrospective cohort study using a US
commercial health insurance claims database (MarketScan). T2DM patients
aged ≥18 years with continuous enrollment for ≥1 year prior to, and after,
the first observed T2DM diagnosis (between 1/1/2009-9/30/2010) were
included. Patients with type 1 diabetes or gestational (including pregnancy)
or other forms of secondary diabetes were excluded. Cases of UTI, cystitis,
and pyelonephritis were identified using ICD-9 codes. The final study cohort
comprised 93,919 T2DM patients. UTI prevalence was 7.6% (n=7,143) and
8.3% (n=7,835) at baseline and at the end of the follow-up, respectively.
During the follow-up period, 33.9% of the PC had ≥1 UTI while 6.2% of the
IC had ≥1 UTI (p<0.0001). After controlling for patient characteristics and
baseline comorbidities, age 75+ (odds ratio [OR]=1.36 vs. age 55-64, [95% CI:
1.26, 1.47]), female gender (OR=2.9, [2.75, 3.06]), and history of UTI (OR=5.81,
[5.48, 6.15]) were the strongest predictors of UTI. Compared to the IC, the PC
was more likely to have UTI related inpatient visits (11.4% vs. 9.8%, p=0.038),
outpatient visits (96.9% vs. 95.2%, p=0.0005), and more outpatient visits per
patient (2.60 vs. 1.62, p<0.0001). The associated outpatient cost per patient
per year was also higher for the PC than IC ($630.8 vs. $415.9, p=0.001 for
payers, $62.92 vs. $48.54, p=0.0006 for patients). There was no significant
difference in inpatient cost for either payers or patients. In conclusion,
among T2DM patients, UTI was associated with increased healthcare
utilization and higher costs, especially for those with previous UTI.
1512-P
Differential Expression of IRS-1 in Visceral and Subcutaneous
Adipose Depots in Morbidly Obese/Type 2 Diabetic Subjects: Their
Correlation With Biochemical Profile With 2 Novel Variations Sequenced in Asian Indians
1510-P
Treatment Gaps in Chinese Type 2 Diabetes Patients With Chronic
Kidney Disease: The Joint Asia Diabetes Evaluation (JADE) Program
MUKTI SHARMA, KALPANA LUTHRA, SANDEEP AGGARWAL, ANOOP MISRA,
NAVAL VIKRAM, New Delhi, India
ROSEANNE O. YEUNG, YUYING ZHANG, RISA OZAKI, ANDREA O. LUK, NICOLA
BROWN, YI SUI, YU CHEUNG, KAM PIU LAU, CHIU CHI TSANG, W.B. CHAN,
HARRIET CHUNG, REBECCA WONG, ALICE P.S. KONG, RONALD C. MA, FRANCIS
C. CHOW, PETER TONG, JULIANA C. CHAN, WING-YEE SO, HONG KONG JADE
STUDY GROUP, Hong Kong, China
To look for differential expression of IRS-1at regional fat-depots (visceral
and subcutaneous) in morbidly obese diabetic patients, and correlate
genotype-phenotype traits if any in above subjects.
A total of 35 morbidly obese (BMI>40Kg/m2) in presence of co-morbidities
and 16 controls (BMI<25Kg/m2) adipose tissue were obtained from subjects
undergoing Bariatric and elective abdominal surgery respectively. RealTime qPCR performed for gene expression. Biochemical parameters were
assessed. Sequencing of IRS-1in morbid obese/diabetic subjects along with
controls was carried out to identify novel variations.
We observed a decrease in mRNA expression of IRS-1in adipose tissue
of visceral and subcutaneous depots in morbidly obese subjects than
controls (non-obese), with a marked reduction in visceral as compared to
subcutaneous adipose tissue of morbidly obese diabetic subjects (p=0.02).
A salient finding of this study was presence of two novel variations, not
reported previously: one, in codon 1102 GAG>AAG, a non-synonymous
mutation, encoding lysine instead glutamate in morbidly obese subjects with
insulin resistance, second a deletion at codon 658 in three morbidly obese/
insulin resistant and one non-obese with high levels of insulin (Accession
numbers: JX912162, JX912163, JX901287, JX901288, JX901289).
Our observation of a substantial reduction in expression ofIRS-1in visceral
and subcutaneous adipose tissues of morbidly obese diabetic subjects,
strongly suggest that the IRS-1expression may serve as a novel molecular
marker for predicting tissue insulin responsiveness. Novel variations at
codons 658 and 1102 of IRS-1 were present only in morbidly obese, insulin
resistant subjects, suggesting their crucial role in insulin resistance and
obesity in these subjects and need to be functionally characterized.
CKD amplifies the risk of cardiovascular disease (CVD) although control of
risk factors can reduce the risk of morbidity and mortality in these patients.
The JADE Program is a quality improvement (QI) initiative, augmented by a
web-based program with decision support protocols, validated risk engine,
and personalized diabetes feedback reports. Between 2007-2012, 15314
patients were enrolled from 6 hospital and community clinics in Hong Kong.
In this cross-sectional cohort, 9.2% (95% CI:8.7-9.7) had at least stage 3
CKD and were more likely to be female (49.1 vs. 45.2%), older (69.0±10.1 vs.
58.2±11.1yrs), with a longer disease duration (median 7 vs. 6yrs). CKD patients
had higher A1C (7.8±1.7 vs. 7.5±1.5%, P<0.001), systolic blood pressure (BP)
(146±22 vs. 134±18 mmHg, P<0.001), and lower LDL-C (2.5±0.9 vs. 2.6±0.8
mmol/L, P<0.001). CKD patients were more likely treated with insulin (19.4
vs. 8.9%), statins (60.4 vs. 38.3%) and renin-angiotensin inhibitors (55.2
vs. 35.9%). They also had higher rates of CVD (22.6 vs. 9.2%), stroke (15.3
vs. 5.8%), peripheral vascular disease (16.3 vs. 3.4%), retinopathy (44.4 vs.
25.3%), and neuropathy (12.5 vs. 3.6%) (all P<0.001).Patients with CKD were
less likely to reach target A1C (36.0 vs. 43.7%) and BP (21.3 vs 36.6%), but
more likely to reach target LDL (60.5 vs. 49.5%) (all P<0.001). Up to 2012,
280 CKD patients had undergone repeat assessment, of which LDL target
<2.6mmol/L achievement improved from 58.4% to 67.6% with absolute LDL
falling from 2.5±0.9 to 2.3±0.9mmol/L and HDL increased from 1.1±0.3 to
1.23±0.4 mmol/L (all P<0.001) after a follow up time of 1.5±0.5 years. We did
not detect any significant changes in A1C or BP in these patients. Our findings
highlight the treatment gaps in these high risk CKD patients, which can be
detected using a structured, integrated care program in a high-volume clinic
setting, and provide useful information for future QI implementation
Supported by: Dept. of Biotechnology (N-881)
Supported by: Asia Diabetes Foundation
&
For author disclosure information, see page 829.
A394
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—DIABETES COMPLICATIONS
in previous research between diabetes and endometrial cancer incidence
may be largely confounded by body weight.
1513-P
Kidney Failure and Diabetes Mellitus Related Hospital Admissions
in California: 2000–2010
1515-P
KALANI S. RATNASIRI, Davis, CA
The aim of this study was to determine prevalences of diabetes mellitus
(DM) and concurrent kidney failure (KF) (acute, chronic and unspecified)
among people (> 20 years) admitted to hospitals in California from 2000 to
2010. The analysis was undertaken on the hospital data compiled by the
California Office of Statewide Health Planning and Development (OSHPD).
Diagnoses of > 32.3 million de-identified hospital admissions recorded in
the OSHPD database were screened, employing ICD9CM codes specific
to DM (as primary or any listed diagnosis) and KF. Trends were evaluated
using regression models. The prevalence of DM among hospital admissions
(as primary or any listed diagnosis) increased significantly from 16.6% in
2000 to 24.7 % in 2010, an increase of 48.7%. After adjusting for covariates
(gender, age, race/ethnicity, payer source), DM related admissions had
increased by 55.0% from 2000 to 2010 (odds ratio 1.55 [95% CI 1.54 - 1.56]).
The prevalence of KF among hospital admissions (as primary or any listed
diagnosis) increased significantly from 3.9 % in 2000 to 16.7 % in 2010, a 3.3
fold increase. After adjusting for covariates (as above) this increase was 4.8
fold [4.80 - 4.87]. Among admissions for DM, the unadjusted prevalences of
KF were 9.7 % and 34.1% which was a 3.5 fold increase. These data suggest
that between 2000 and 2010 there have been significant increases in the
number of admissions with both DM and KF with a disproportionate increase
in the latter.
Prevalence of Metabolic Syndrome (MetS) and Associated Co-Morbidities in Hong Kong Chinese Patients With Type 2 Diabetes: The
Joint Asia Diabetes Evaluation (JADE) Program
Supported by: Asia Diabetes Foundation
1514-P
1516-P
Association between Diabetes, Diabetes Treatment and Endometrial Cancer
Role of Serum Immunoglobulin G (IgG) Antibody against Periodontal
Bacteria in Type 2 Diabetes and Pre-Diabetes
JUHUA LUO, KAREN MARGOLIS, LEWIS KULLER, ROWAN CHLEBOWSKI, JEAN
WACTAWSKI-WENDE, SHIRLEY BERESFORD, CHU CHEN, LORENA GARCIA, MICHAEL REGIER, Bloomington, IN, Minneapolis, MN, Pittsburgh, PA, Los Angeles, CA,
Buffalo, NY, Seattle, WA, Davis, CA, Morgantown, WV
DEEPIKA SHRESTHA, YOUNHEE CHOI, JIAJIA ZHANG, LINDA J. HAZLETT, ANWAR T. MERCHANT, Columbia, SC, Daegu, Republic of Korea
Periodontitis, a chronic low grade, poly-microbial infection of the gums,
is associated with diabetes and pre-diabetes but the role of specific
periodontal microorganisms is understudied. We evaluated serum IgG
antibodies against 19 periodontal bacteria in relation to type2 diabetes
(n=990; Mean A1C= 7.6%) and pre-diabetes (n=2059; Mean A1C= 5.9%) in
the NHANES III (1988-1994) dataset among 7366 participants aged 40 or
more. Four antibody clusters were derived using cluster analysis. Cluster 1
consisted of A. actinomycetemcomitans, T. forsythia, T.denticola, S. noxia, E.
corrodens, V. parvula and C. rectus; Cluster 2 of P. intermedia, P. nigrescens,
P. melaninogenica, and P. gingivalis mix; Cluster3 of A. naeslundii and E.
nodatum and; Cluster4 of S. intermedius, S. oralis, S. mutans, F. nucleatum,
M.micros and C. ochracea. In the surveylogistic regression models that
included all four clusters, clusters 1 and 3 were not associated with diabetes
and pre-diabetes. Cluster 2 was positively associated with diabetes after
adjusting for age, sex, education, ethnicity, smoking and drinking alcohol,
but not for pre-diabetes. Cluster 4 was inversely related to diabetes and prediabetes, even after adjustment for known confounders. Specific periodontal
microorganisms may have qualitatively different associations with diabetes
and pre-diabetes and deserve further study.
Endometrial cancer is the most common female gynecologic cancer
among westernized countries with increasing incidence over the past two
decades. A growing body of evidence suggests that diabetes is a risk factor
for endometrial cancer incidence. However, the majority of these studies
use case-control designs and no epidemiological study has examined the
association between metformin treatment and endometrial cancer risk.
The objective of this study was to assess the relationships among diabetes,
metformin treatment and endometrial cancer risk in postmenopausal women
participating in the Women’s Health Initiative (WHI) - a large prospective
study. A total of 88,107 women aged 50-79 years who were free of cancer and
had no hysterectomy at baseline were followed through September 30,2010.
Over a mean of 11 years follow-up, 1,241 endometrial cancers developed.
Information on diabetes therapy was collected via a face-to-face review
of current medication containers that participants brought to the baseline
visit. Endometrial cancers were confirmed by central medical record and
pathology report review. Multivariate Cox proportional hazards regression
models were used to estimate hazard ratios for diagnosis of diabetes and
metformin treatment as risk factors for endometrial cancer. Compared with
women without diabetes, women with self-reported diabetes, and the subset
of women with treated diabetes, had significantly higher risk of endometrial
cancer. However, these effects were observed only without adjusting for
BMI. After further adjusting for BMI, the associations between diabetes,
diabetes treatment, diabetes duration and the risk of endometrial cancer
became non-significant. In conclusion, there is no significant association
between diabetes, diabetes treatment and endometrial cancer risk in
postmenopausal women. Our results suggest that the relationship observed
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A395
POSTERS
The JADE Program is an integrated quality improvement initiative
augmented by a web-based program with built-in clinical decision support
protocols, validated risk stratification engine, and personalized patient
feedback reports. Between 2007 and 2012, 15314 patients were enrolled
from 6 hospital- and community-based clinics. Of these, 54.2% (95% CI:
53.4%-55.0%) had MetS using the International Diabetes Federation
criteria. Compared to non-MetS patients, MetS patients were of similar age
(59.9±11.6 vs. 58.3±11.2yrs) but predominantly female (53.0% vs 37.1%), with
longer disease duration (9.4±8.2 vs. 8.5± 7.7yrs). The MetS patients were less
likely to achieve the A1C goal of <7% (38.0% vs. 48.0%) and had higher A1C
(7.66±1.53% vs. 7.37±1.56%) (both P<0.001). Patients with MetS were more
likely to be treated with insulin (10.6% vs. 9.0%), statins (44.5% vs. 35.6%)
and renin-angiotensin inhibitors (44.2% vs. 30.2%) (all P<0.001). They also
had higher rates of coronary events (11.8% vs. 8.9%), stroke (7.9% vs. 5.4%),
peripheral vascular disease (5.4% vs. 3.7%), chronic kidney disease (11.8%
vs. 6.3%), end stage renal disease (0.9% vs. 0.4%), sensory neuropathy
(5.0% vs. 3.7%), retinopathy (28.4% vs. 25.5%) and malignancy (4.7% vs.
4.1%) (P<0.001). As of 2012, 2226 MetS patients have completed a repeat
assessment after a mean of 1.3±0.4 years, and demonstrated significant
improvements in rates of risk factor target attainment: A1C <7% increased
from 39.6% to 42.3% (P=0.014), BP <130/80mmHg increased from 24.6%
to 35.2% (P<0.001), and LDL-C <2.6mmol/L increased from 47.3% to 59.4%
(P<0.001). Impressively, 21.2% of patients also no longer fulfilled criteria
for MetS (P<0.001). Our findings suggest that a structured, integrated care
program augmented by information technology improves target attainment
in diabetes patients with MetS in a high-volume clinic setting.
Epidemiology/
Genetics
YUYING ZHANG, ROSEANNE O. YEUNG, RISA OZAKI, ANDREA O. LUK, NICOLA
BROWN, YI SUI, YU CHEUNG, KAM PIU LAU, CHIU CHI TSANG, W.B. CHAN,
HARRIET CHUNG, REBECCA WONG, ALICE P.S. KONG, RONALD C. MA, FRANCIS
C. CHOW, PETER TONG, WING-YEE SO, JULIANA C. CHAN, HONG KONG JADE
STUDY GROUP, Hong Kong, China
EPIDEMIOLOGY—DIABETES COMPLICATIONS
most common sites of infection leading to hospitalization were lower
respiratory tract, skin and soft tissue, and urinary tract (Table 1). Comparing
with non-diabetic men, diabetic men were associated with significantly
increased risks of necrotizing fasciitis, skin and soft tissue, and bone and
joint infections. For diabetic women, urinary tract and lower respiratory
tract were the most common infection sites. As compared with non-diabetic
women, diabetic women were associated with significantly higher risks of
necrotizing fasciitis, skin and soft tissue, bone and joint, urinary tract, postoperative clean wound, and septicemia. Despite similar fatality with nondiabetics, diabetic patients had higher hospital cost and length of stay.
Association of the serum IgG titers in different clusters in relation to diabetes
and pre-diabetes
Models
DIABETES
PRE-DIABETES**
Cluster1 Cluster2 Cluster3 Cluster4 Cluster2 Cluster4
Model1:Odds Ratio(95% CI)
1.02
1.08
0.97
0.86
1.01
0.87
P-value
(0.98-1.06) (1.04-1.14) (0.92-1.02) (0.79-.93) (0.97-1.05) (0.83-0.92)
0.2763
0.0006
0.2558
<.0001
0.6063
<.0001
Model2:Odds Ratio(95% CI)
0.99
1.05
1
0.92
0.99
0.93
P-value
(0.96-1.04) (0.99-1.11) (0.95-1.06) (0.85-.99) (0.95-1.03) (0.88-0.98)
0.9753
0.0554
0.9901
0.0475
0.5335
0.005
Model3:Odds Ratio(95% CI)
0.99
1.06
1
0.92
0.99
0.94
P-value
(0.95-1.04) (1.00-1.12) (0.95-1.06) (0.84 -1) (0.96-1.04) (0.89-0.98)
0.8638
0.0248
0.9982
0.0491
0.8547
0.014
Model4:Odds Ratio(95% CI)
1
1.05
0.99
0.88
1
0.94
P-value
(0.96-1.03) (1.00-1.11) (0.94-1.05) (0.80-.98) (0.95-1.04) (0.89-0.98)
0.9843
0.0517
0.9478
0.0165
0.963
0.0133
Model1 with no adjustment for confounders; Model 2 adjusted for age (continuous), sex, education, ethnicity; Model3 adjusted further for smoking and
drinking alcohol; Model4 further to physical activity, BMI (continuous), waist
circumference [WC] and dentist visit. Note:** Cluster 1 and Cluster 3 were
insignificant in all four models for pre-diabetes.
Supported by: Taiwan Dept. of Health
1517-P
1519-P
Celiac Autoimmunity Is Associated With Lower Blood Pressure and
Renal Risk in T1D
Skin Accumulation of Advanced Glycation End-Products (AGEs)
Highly Correlates With Severity of Renal Complications in Patients
With Diabetes
POSTERS
Epidemiology/
Genetics
CHRISTINA CRISTALDI, RACHEL G. MILLER, VINCENT C. ARENA, INGRID LIBMAN, YIHE HUANG, DOROTHY J. BECKER, TREVOR J. ORCHARD, Pittsburgh, PA
RYO KAWADA, OSAMU HANYU, KAZUO FURUKAWA, MASAHIRO ISHIZAWA,
MASAHIKO YAMAMOTO, TAEKO OSAWA, TAKAHO YAMADA, SHINITI MINAGAWA, HIROMI SUZUKI, AYAKO YAMADA, YORIKO HEIZNZA, AKIKO SUZUKI,
HIROHITO SONE, Niigata, Japan
Though the long-term consequences of undiagnosed celiac disease in
individuals with T1D are unclear, celiac disease has been associated with
an increased risk of end-stage renal disease (ESRD) independent of T1D. We
thus evaluated whether celiac autoimmunity augments the development of
microalbuminuria (MA; AER 20-200µg/min) and diabetic nephropathy (DN;
AER > 200µg/min) in the 22 year prospective, observational, Pittsburgh
Epidemiology of Diabetes Complications (EDC) Study of childhood onset
diabetes diagnosed within years 1950-1980 and first examined 1986-88.
Serum samples from 451 of the 658 participants have so far been screened
for tissue transglutaminase IgA (TTGIgA) antibodies and IgA levels. This
sample, when compared to the remaining participants, included more
diagnosed with T1D in the years 1950-59. Of these 451, 32 (7.1%) had a
positive TTGIgA ≥ 20 units; half of whom (n=16) had a strongly positive
TTGIgA (>30 units). There were no differences in diagnosis date of T1D,
diabetes duration, age of onset, race, sex, A1C, lipid profile, height, weight,
BMI, smoking status, and anti-hypertensive therapy in those with strongly
positive versus negative celiac antibodies. The strongly positive group at
baseline had a lower systolic blood pressure (106 ± 15 vs 115 ± 17; p=0.03)
and 25 year cumulative incidence of DN than those with negative antibodies
(17% vs 49%; p=0.04). However, adjustment for blood pressure and year of
T1D diagnosis eliminated the statistical significance (p=0.23). None of those
with positive celiac serology developed intestinal lymphoma. These results
suggest that positive, yet untreated, celiac autoimmunity, in a long term
survivor population of older participants with childhood onset T1D, does not
increase the risk of MA, DN, or ESRD and may even be associated with lower
blood pressure and renal risk after 25 years duration. Further evaluation and
screening of remaining participants will help resolve the extent to which
these results reflect a survivor bias.
Reducing sugars such as glucose react nonenzymatically with protein
amino groups to form advanced glycation end products (AGEs). Although
the roles of AGEs in the pathogenesis and progression of diabetic vascular
complications, dementia, and aging have been studied, the relationship
between AGEs and diabetic complications in Asian subjects has been
little studied. Accumulation of AGEs on the vascular wall on or under the
skin is reported as skin autofluorescence (AF) with a skin AF reader. Skin
AF is determined by a spectrometer across the 420-600 nm range on the
theforearm. We examined the relationship between skin AF of diabetic
patients and biochemical variables or status of vascular complications to
clarify factors determining skin AF. Skin AF was measured using the AGE
Reader (DiagnOptics, Groningen, Netherlands) in 140 outpatients with
diabetes who went to Niigata Univ. Hosp. in 2009-2010. Mean age was
60±13.2 y, HbA1c was 7.9±1.8%, BMI was 24.8±4.7 kg/m2, duration of
diabetes was 13.7±10.4 y, and skin AF was 2.6±0.6 arbitrary units. There were
significant correlations between skin AF and age (P=0.00), BMI (P=0.29),
duration of diabetes (P=0.26), retinopathy stage (P=0.37), nephropathy
stage (P=0.001), eGFR (P=0.00), total plaque score (P=0.01), maximum
intima-media thickness (P=0.001), and maximum plaque thickness (P=0.005).
In multivariate analyses with skin AF as the dependent variable, stage of
nephropathy (P=0.007) and eGFR determined (P=0.00) skin AF independently.
Stage of retinopathy and ischemic heart disease were not related to skin AF.
These results imply that accumulation of AGEs on the vascular wall may be
closely related to diabetic nephropathy. In conclusion, the close association
between skin AF and diabetic nephropathy seen in this analysis warrants
future prospective studies to elucidate whether skin AF could be a predictor
of nephropathy and cerebral infarction.
Supported by: R01DK034818
1518-P
1520-P
Risk of Infection Incidence, Fatality, and Medical Resource Utilization in Adult Diabetic Patients—A Nationwide Study
Microalbuminuria: Association With Gray Matter Atrophy in Cognitive Circuits in Type 2 Diabetes
CHIA-HSUIN CHANG, JIUN-LING WANG, JOU-WEI LIN, LI-CHIU WU, MEI-SHU
LAI, LEE-MING CHUANG, Taipei, Taiwan, Kaohsiung, Taiwan, Douliu City, Taiwan
DISHA MEHTA, MARIA-ZUNILDA NÚÑEZ, ANDREW GALICA, AMIR ABDULJALIL,
BRAD MANOR, MEDHA MUNSHI, PETER NOVAK, SARA MONTI, VERA NOVAK,
Boston, MA, Santiago, Dominican Republic, Columbus, OH
The relative contribution of individual site of infections leading to
hospitalization among diabetic patients remained unclear. A retrospective
study using the Taiwan National Health Insurance claims database was
conducted to identify all hospitalizations related to infections in 20052007. Infections were categorized into specific sites. The incidence, fatality,
hospital cost, and length of stay of overall and individual site of infections
were calculated. Standardized ratio was estimated to compare the risk
among diabetic with non-diabetic patients.
Diabetic men and women had approximately 2-fold increased risk of
overall infection as compared with non-diabetics. For diabetic men, the
Microalbuminuria is a marker of renal microvascular disease that is
associated with global brain atrophy and neurovascular changes in type 2
diabetes mellitus (T2DM). These changes in brain structure and function
increase the risk of cognitive decline and dementia in this population. In this
study, we aimed to determine the regional effects of microalbuminuria on
brain tissue volume in older adults with and without T2DM. We performed a
secondary analysis of data from 255 men and women aged 65±7yrs, which
included 112 T2DM participants with DM duration (11.48±9.39yrs), HbA1c
&
For author disclosure information, see page 829.
A396
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—DIABETES COMPLICATIONS
1521-P
1523-P
Relationship between Diabetic Neuropathy and Sleep Apnea Syndrome—A Meta-Analysis
Diabetic Kidney Disease (DKD) in UK Patients With Type 2 Diabetes
(T2D)
KAZUYA FUJIHARA, SATORU KODAMA, CHIKA HORIKAWA, AYUMI SUGAWARA,
YORIKO HEIANZA, HITOSHI SHIMANO, YOKO YACHI, KAZUMI SAITO, OSAMU
HANYU, HIROHITO SONE, Mito, Japan, Tsukuba, Japan, Niigata, Japan
JAVIER CID RUZAFA, ROSIRENE PACZKOWSKI, KRISTINA S. BOYE, GIAN LUCA DI
TANNA, MATTHEW J. SHEETZ, ROBERT DONALDSON, MATTHEW D. BREYER,
DAVID NEASHAM, JAMES R. VOELKER, London, United Kingdom, Indianapolis, IN
A high prevalence of sleep apnea syndrome (SAS) has been reported
in patients with diabetes. However, it is not conclusive whether diabetic
neuropathy (DN) is one of the causes of that high prevalence. Our aim of
this study is to compare the prevalence of SAS between diabetic patients
with and without DN. Systematic literature searches were conducted for
cross-sectional studies that reported the number of patients with DN and
SAS using MEDLINE and EMBASE. Odd ratios (ORs) for SAS related to DN
were pooled with the Mantel-Haenszel method. Eleven eligible studies were
included in this meta-analysis. The Figure shows a forest plot of ORs with
95% confidence intervals (CIs) for SAS in patients with DN compared with
those not having DN. Overall, the pooled OR (95% CI) for SAS was 2.03 (1.203.43). A higher OR was observed in younger patients (mean age, ≤55 ) than
in those >55 y (OR, 16.0 [95% CI, 4.07-62.9] vs. 1.50 [95% CI, 0.93-2.44];
P for interaction, 0.01). This current meta-analysis showed that a higher
prevalence of SAS was observed particularly in young diabetic patients with
neuropathy compared with those without neuropathy, suggesting that DN
is a main contributor to SAS and that the effect of aging is small in diabetic
patients. Further research is needed to elucidate the mechanisms by which
DN leads to the development of SAS.
Diabetes is a major cause of chronic kidney disease (CKD). We evaluated
patients with T2D and presumed DKD using the Clinical Practice Research
Datalink and classified them based on estimated glomerular filtration rate
(eGFR) and albuminuria stages. We describe demographic factors for the
prevalent patients as of 1 Oct 2006 (Table 1) and report the number of
patients at each eGFR and albuminuria stage (Table 2). Presumed DKD was
identified by Read codes indicating T2D plus CKD Read codes or >3 months
of albuminuria or eGFR<60mL/min/1.73m2, except CKD from other etiology.
We identified 111,030 prevalent patients with T2D, of whom 37% had
presumed DKD, and 19,594 incident DKD patients with T2D through 31 Dec
2011.
A substantial proportion of patients with T2D have DKD. The proportions
with albuminuria data, on angiotensin converting enzyme inhibitors or
angiotensin receptor blockers were low, suggesting a gap between clinical
practice and medical evidence during the study period.
Table 1. Baseline characteristics of UK patients with T2D prevalent DKD
(n=41,273)
eGFR 1 eGFR 2 eGFR eGFR eGFR 4 eGFR 5 eGFR
3a
3b
Missing
N
935 7113 21331 9364 2264 232
34
Age (years) Mean
51
65
69
75
78
74
68
Gender (%) Male
41.9 48.2 63.1 66.5 67.8 69.0 50.0
Ethnicity (from HES) (%) 86
92
94
95
95
89
75
White
Blood pressure (%)
52.2 53.2 52.3 52.3 54.1 41.8 38.2
Below 140/85
HbA1c (%) >6.5%
73.2 68.8 65.6 64.5 65.3 52.6 17.6
ACE inhibitors,
70.5 66.2 63.2 70.9 68.6 49.6 41.2
ARB, or both (%)
Table 2. Baseline albuminuria quantitative test results and eGFR stages, pats
with T2D prevalent DKD
Quantitative
Quantitative
Quantitative
Quantitative
normoalbuminuria, microalbuminuria, macroalbuminuria, albuminuria missing,
n (%)
n (%)
n (%)
n (%)
eGFR 1
136 (14.5%) 206 (22.0%)
20 (2.1%)
573 (61.3%)
eGFR 2
1404 (19.7%) 694 (9.8%)
40 (0.6%) 4975 (69.9%)
eGFR 3a
4380 (20.5%) 501 (2.3%)
45 (0.2%) 16405 (76.9%)
eGFR 3b
1662 (17.7%) 399 (4.3%)
32 (0.3%) 7271 (77.6%)
eGFR 4
303 (13.4%) 141 (6.2%)
35 (1.5%) 1785 (78.8%)
eGFR 5
12 (5.2%)
11 (4.7%)
9 (3.9%)
200 (86.2%)
eGFR Missing
0 (0.0%)
1 (2.9%)
0 (0.0%)
33 (97.1%)
1522-P
A Population-Based Prevalence Survey and Risk Factor Analysis of
Diabetic Retinopathy in Beijing Changping District
MING-XIA YUAN, ZHONG XIN, JIN-KUI YANG, Beijing, China
This study describes the prevalence and risk factors of DR in a Chinese
population in Beijing Changping district. In a total of 8,155 Chinese between
18-79 years of age, who participated in the 2010 Health Examination Survey
ADA-Funded Research
&
Supported by: Eli Lilly and Company
For author disclosure information, see page 829.
Guided Audio Tour poster
A397
POSTERS
Supported by: NIH/NIDDK (5R21-DK084463-02); NIH/NIA (1R01AG028076-A2)
Epidemiology/
Genetics
in Beijing representing a population of 1,600,000 citizens in the disgrict,
3760 subjects whose FPG ≥ 5.6mmol/L were invited to the studyand 2551
subjects completed physical examination and laboratory measurements
including fasting plasma glucose (FPG), OGTT-2h plasma glucose (2hPG) and
hemoglobin A1c (HbA1c). The grade of DR was assessed with two 45° color
digital retinal images. Of the 2551 persons, 280 with known diabetes, 334
with newly-diagnosed diabetes and 853 with impaired glucose regulation
(IGR) were identified. The prevalence of DR in diabetes and IGR subjects was
9.9% and 1.2%, respectively. The prevalence of retinopathy was much lower
in newly-diagnosed diabetes (2.7%) than in known diabetic subjects (18.6%).
In diabetic patients, independent risk factors for retinopathy were longer
diabetes duration [odds ratio (OR) 1.49 (95% CI 1.38, 1.62), for every one year
increase], FPG [OR 1.32 (95% CI 1.22, 1.43), per mmol/L], 2hPG [OR 1.18 (95%
CI 1.12, 1.24), per mmol/L], HbA1c [OR 1.66 (95% CI 1.45, 1.90), per 1%], and
higher systolic blood pressure [OR 1.16 (95% CI 1.02, 1.31), per 10 mmHg].
The results suggest that the prevalence of DR in patients with diabetes and
pre-diabetes was much lower in this study than that reported in Western
countries. The major risk factors for retinopathy are longer duration of
diabetes, hyperglycemia, and hypertension.
(7.17±1.20 ), and 143 controls. 3D magnetization prepared rapid acquisition
with gradient echo (MPRAGE) MRIs were acquired to quantify regional gray
matter (GM) and white matter (WM) volumes. Least square models were
used to analyze the relationship between urine albumin creatinine ratio and
brain volumes adjusted for age, gender, hypertension years and glucose
levels. T2DM patients had borderline higher microalbuminuria levels as
compared to controls (p=0.06). In the T2DM group, microalbuminuria was
associated with GM atrophy of the middle temporal gyrus (Left(L)-p=0.002;
Right(R)-p=0.004), insular cortex (L-p=0.01) and supramarginal gyrus (Lp=0.01). The atrophy in WM was predominantly of the frontal lobe region
of the superior frontal gyrus (L, R-p=0.02), inferior frontal lobe (L-p=0.014)
and hippocampus (p=0.032). No significant relationships were observed
in controls. Our cross-sectional results indicate that in T2DM patients,
microalbuminuria is associated with tissue atrophy within numerous brain
regions associated with cognitive function, independently of glucose
and HbA1c levels. Prospective studies are thus needed to determine if
microalbuminuria underlies brain atrophy and cognitive decline within this
vulnerable population.
EPIDEMIOLOGY—NUTRITION
1524-P
Outcome
Beta (SE)1
Pr > |t|
Log[Predicted Fiber Intake
from ME model (g)]
Log[IL-6 (pg/mL)]
0.01 (0.35)
0.96
Log[CRP (mg/dL)]
-0.13 (0.32)
0.67
Log[Fibrinogen (mg/dL)]
-0.01 (0.05)
0.82
PWV (m/sec)2,3
-0.50 (0.47)
0.29
AIx (%)3,4
6.42 (7.46)
0.35
BrachD (% change/mmHg)3
0.77 (0.74)
0.31
1From multivariable linear regression models adjusted for predicted total
energy intake from the ME model, age, gender, race/ethnicity, diabetes duration, smoking, and physical activity. Standard errors estimated using bootstrapping.
2Carotid-femoral.
3Additionally adjusted for time between assessment of diet (baseline
SEARCH visit) and arterial stiffness (ancillary study visit).
4Normalized to heart rate of 75 beats/min.
Protection from Fracture Risk in Long Term Type 1 Diabetes: 50-Year
Medalist Study
POSTERS
Epidemiology/
Genetics
HILLARY KEENAN, SARA TUREK, STEPHANIE HASTINGS, GEORGE L. KING, Boston, MA
Individuals with type 1 diabetes (T1D) have demonstrates a 12-fold
increased risk of fragility fractures over their age-matched peers. As
hospitalization for fracture is highly associated with decreased quality
of life, morbidity and and mortality this is an important, yet little studied
diabetic complication particularly amongst those with extreme duration
T1D. The 50-Year Medalist Study has extensively characterized over 800
individuals with a mean age of 69 y and duration of 55 y of T1D. Early
examination of self-reported rates of hip, vertebral, and wrist fractures
show extraordinarily low rates (0.33%, 0%, and 1.7%, respectively) in
stark contrast to the 12-fold increase expected. To further examine these
findings, 55 participants received DXA scans, 29 females, 26 males with a
mean ±SD HbA1c of 7.2±0.8% and 7.0±1.2%, age 62.1±6.5 y and 66.7±6.8
y, and duration of 52.9±2.7 y and 55.8±5.1 y, respectively. BMI for this age
group was low with 25.0±5.2 kg/m^2 for females and 27.3±4.4 kg/m^2 for
males. T-scores, indicative of risk for fracture, for female 1/3 radius (1/3R)
was -1.1±1.3, lumbar spine (LS) 0.1±1.2 and for the femoral neck (FN) -1.3±0.8.
For males the 1/3R, T-score was -1.1±1.3, the LS was -0.1±1.9, and at the
FN -1.3±0.8, none in the osteoporotic range. Total vitamin D, D2, D3 and
calcium did not correlate with T scores among female or male, except for D3
among male and the LS T-score (R=0.5, p=0.03). There was no association of
T scores with HbA1c, BMI, age or duration in either gender, p>0.05. As BMIs
were low in male and female, the lower than expected risk T scores are
likely not due to increase weight bearing as seen in T2D patients. These pilot
data demonstrate protection from fracture, and low risk in this group with
long term T1DM suggestive of a protective factor preventing bone health
deterioration.
&
SHIRO TANAKA, YUKIO YOSHIMURA, CHIEMI KAMADA, SACHIKO TANAKA,
CHIKA HORIKAWA, RYOTA OKUMURA, HIDEKI ITO, YASUO OHASHI, YASUO
AKANUMA, NOBUHIRO YAMADA, HIROHITO SONE, Kyoto, Japan, Tokushima,
Japan, Ibaraki, Japan, Tokyo, Japan, Mito, Japan, Niigata, Japan
Foods rich in fibre, such as vegetables and fruits, prevent cardiovascular
disease among healthy adults, but such data in patients with diabetes are
sparse. We investigated this association in a cohort with type 2 diabetes
aged 40–70 years whose HbA1C values were ≥6.5%. After excluding nonresponders to a dietary survey, 1414 patients were analysed. Baseline
dietary intake was assessed by the Food Frequency Questionnaire based on
food groups. Primary outcomes were times to coronary heart disease (CHD)
and stroke. Mean daily dietary fibre in quartiles ranged from 8.7 to 21.8 g and
mean energy intake ranged from 1442.3 to 2058.9 kcal. Mean daily intake
of vegetables and fruits in quartiles ranged from 228.7 to 721.4 g. During
the 8-year follow-up, incidents according to quartiles of dietary fibre were
22, 15, 13, and 18 for stroke and 21, 24, 27, and 24 for CHD. Table 1 shows
the results of Quartile Cox regression, showing inverse associations. There
were no significant associations with CHD. The HR per 1 g increase was
smaller for soluble dietary fibre (0.48, 0.30–0.79, p<0.01) than for total (0.82,
0.73–0.93, p<0.01) and insoluble dietary fibre (0.79, 0.68–0.93, p<0.01).
The incidence rate of stroke was estimated to be lower than 0.90 per 1000
patient-years among patients consuming over 25 g daily of dietary fibre. In
conclusion, increased dietary fibre, particularly soluble fibre, and vegetables
and fruits reduce incident stroke but not CHD.
EPIDEMIOLOGY—NUTRITION
Guided Audio Tour: Nutritional Epidemiology in Diabetes (Posters: 1525-P
to 1531-P), see page 17.
&
1526-P
Intakes of Dietary Fiber, Vegetables, and Fruits and Incidence of
Cardiovascular Disease in Japanese Patients With Type 2 Diabetes
1525-P
Association of Dietary Fiber Intake With Inflammation and Arterial
Stiffness in Youth With Type 1 Diabetes
LINDSAY M. JAACKS, JAMIE L. CRANDELL, ANGELA D. LIESE, ARCHANA P.
LAMICHHANE, RONNY A. BELL, DANA DABELEA, RALPH B. D’AGOSTINO, JR.,
LAWRENCE M. DOLAN, SANTICA M. MARCOVINA, KRISTI REYNOLDS, AMY S.
SHAH, ELAINE M. URBINA, PAUL WADWA, ELIZABETH J. MAYER-DAVIS, Chapel
Hill, NC, Columbia, SC, Winston-Salem, NC, Denver, CO, Cincinnati, OH, Seattle, WA,
Pasadena, CA
Table 1. Cox regression analysis of incidence of stroke and intake of total,
soluble and insoluble dietary fibre and vegetables and fruits
Q2 v.s. Q1
Q3 v.s. Q1
Q4 v.s. Q1
HR 95%CI p
HR 95%CI
p
HR 95%CI p
Total dietary fibre
0.44 (0.20–0.95) 0.04 0.37 (0.15–0.91) 0.03 0.39 (0.12–1.29) 0.12
Soluble dietary fibre 0.45 (0.21–0.96) 0.04 0.37 (0.15–0.89) 0.03 0.32 (0.10–1.02) 0.05
Insoluble dietary fibre 0.55 (0.26–1.16) 0.11 0.36 (0.15–0.89) 0.03 0.44 (0.14–1.40) 0.16
A high-fiber diet may be protective against the development of atherosclerosis and subsequent vascular disease. We characterized the association
of fiber intake with inflammation and arterial stiffness using cross-sectional
data from youth ≥ 10 years old with clinically diagnosed type 1 diabetes
(T1D) for ≥ 3 months and ≥ 1 positive autoantibody in the SEARCH for
Diabetes in Youth Study. Dietary fiber and energy intake were assessed by
food frequency questionnaire with measurement error (ME) accounted for by
a structural sub-model derived using additional 24-hour dietary recall data in
a calibration sample. Markers of inflammation included IL-6 and CRP (n=1308)
and fibrinogen (n=1244); markers of arterial stiffness available in a subset of
participants included pulse wave velocity (PWV; n=183), augmentation index
(AIx; n=179) and brachial distensibility (BrachD; n=176). Mean (SD) diabetes
duration was 51.1 (43.5) months; 12.5% of participants were obese. Mean
(SD) predicted fiber and energy intake from the ME model were 14.6 (2.8) g/
day and 2064 (380) kcal/day, respectively. Fiber intake was not significantly
associated with inflammation or arterial stiffness (Table). In conclusion,
among youth with T1D of relatively short duration, fiber intake is not
associated with measures of systemic inflammation or vascular stiffness.
Whether fiber intake is associated with these outcomes in patients with T1D
of greater duration requires further study.
Vegetables and fruits 0.72 (0.36–1.44) 0.35 0.45 (0.19–1.04) 0.06 0.35 (0.13–0.96) 0.04
HR: hazard ratio, CI: confidence interval *Adjusted for age, sex, body mass
index, HbA1C, diabetes duration, diabetic retinopathy, treatment by insulin,
treatment by oral hypoglycaemic agents, systolic blood pressure, LDL cholesterol, HDL cholesterol, triglycerides, current smoker, physical activity, alcohol
intake, proportions of total fat, saturated fatty acids, n-6 fatty acids and n-6
fatty acids, dietary cholesterol and sodium intake and total energy intake.
Supported by: Ministry of Health, Labour and Welfare (Japan)
&
For author disclosure information, see page 829.
A398
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—NUTRITION
hyperandrogenism in lean women with PCOS. Sixty lean women with PCOS
were randomized to one of two 1800 kcal isocaloric diets with different meal
timing:
1) High Calorie Breakfast Diet (BREdiet): 700 Kcal breakfast with
%carbohydrate;protein;fat: 50:30:20%; lunch (600 Kcal,20:45: 25 %), and
small dinner (200 Kcal, 13:40:47 %). 2) High Calorie Dinner Diet (DINdiet:
200 Kcal breakfast 13:40:47 %), lunch (600 Kcal,20:45:25 %), and large
dinner (700 Kcal,50:30: 20 %). Ovarian P450c17 alpha activity, fasting serum
steroids, and insulin resistance by oral glucose tolerance were assessed.
Subjects were 29.4 ± 6.5 yrs of age with BMI 23.0 ± 0.64 kg/m2. No change
in BMI occurred over 90 days. Area under the curve (AUC) glucose and AUC
insulin did not change in the DINdiet. In the BREdiet group, AUC glucose and
insulin decreased significantly; basal serum 17 alpha-hydroxyprogesterone
decreased from 128 ± 21 to 66 ± 18 ng/dL (P = 0.05); serum sex hormonebinding globulin (SHBG) increased from 2.5 ± 0.4 to 4.9 ± 0.8 µg/dL (P = 0.003).
Isocaloric diets with different meal timing influence glucose metabolism and
free testosterone plasma levels in women with PCOS. The BREdiet may
facilitate the therapeutic management of women with PCOS.
1527-P
White Rice Consumption and Incident Risk for Type 2 Diabetes Mellitus in Japanese Men and Women
MASARU SAKURAI, KOSHI NAKAMURA, KATSUYUKI MIURA, TOSHINARI TAKAMURA, KATSUSHI YOSHITA, SHIN-YA NAGASAWA, YUKO MORIKAWA, MASAO
ISHIZAKI, TERUHIKO KIDO, YUCHI NARUSE, HIDEAKI NAKAGAWA, Uchinada,
Japan, Otsu, Japan, Kanazawa, Japan, Osaka, Japan, Toyama, Japan
We have reported the association between dietary glycemic index (GI)
and the incidence of diabetes in Japanese men (Metabolism, 2012). Rice,
especially white rice, is the major contributor to dietary GI for Japanese.
However, there are only a few studies which have evaluated the association
between white rice intake and the incidence of diabetes from Japan. We
examined the relationship between white rice intake and 7-year incidence
risk of diabetes in Japanese men and women. Participants were 3,515
employees (2,035 men and 1,480 women) of a metal products factory in
Japan. We measured consumption of white rice using a self-administered
diet history questionnaire. The incidence of diabetes was determined in
annual medical examination over a 7-year period. Hazard ratios (HRs) with
95% confidence intervals for diabetes were estimated, with adjustment for
age, sex, body mass index (BMI), family history of diabetes, dietary and other
lifestyle factors. The mean participant age at baseline was 46.2 years and
the mean BMI was 23.0 kg/m2. Mean (SD) consumption of white rice was
183 (86) g/1,000 kcal. During the study, 273 participants developed diabetes
(12.2 / 1,000 person-years). Adjusted HRs (95% confidence interval) for
diabetes across the quartile of white rice consumption were 1.00 (reference),
1.26 (0.87-1.83), 1.36 (0.95-1.96), and 1.40 (0.96-2.04), and significant linear
association was observed between white rice consumption and incidence
of diabetes (P for trend = 0.016). No interaction was observed between
sex and rice consumption with regard to the association with incidence of
diabetes. White rice consumption was significantly associated with the risk
for diabetes in Japanese men and women.
MOLLY M. LAMB, MILISSA MILLER, MIRANDA KROEHL, MARIAN J. REWERS,
JILL M. NORRIS, Aurora, CO, Toronto, ON, Canada
Dairy exposure has been inconsistently associated with IA and Type 1
Diabetes (T1D) development. We examined interactions between dairy
introduction in infancy, childhood dairy consumption, and HLA genotype in
IA development. DAISY has followed children at increased T1D risk for IA
development (presence of autoantibodies to insulin, GAD65 or IA-2 twice
in succession) and T1D development. We examined 1,828 DAISY children
with available dietary data, 135 of whom developed IA, and 36 of whom
subsequently developed T1D. Childhood diet was collected prospectively via
parent- and self-reported food frequency questionnaires (FFQ). HLA genotype
was defined as high risk: HLA-DR3/4,DQB1*0302; and low/moderate risk:
all other genotypes. In a survival model adjusted for total calories, FFQ
type, family history of T1D, and ethnicity, childhood lactose consumption
was associated with IA development. Children with low/moderate risk
HLA genotypes (n = 1414) had an increased risk for IA development (Hazard
Ratio: 1.32, 95% Confidence Interval: 1.04-1.68). In children with high risk
HLA genotype (n = 414), childhood lactose consumption was associated with
decreased IA risk for those introduced to dairy later in infancy (Figure). Similar
results were seen for childhood dairy protein consumption. Childhood dairy
consumption may modify the effect of HLA genes and infant dairy exposure
on IA development.
1528-P
High-Calorie Breakfast Improves Weight Loss and Metabolism vs.
Isocaloric Meal at Dinner in Obese Women With Metabolic Syndrome
DANIELA JAKUBOWICZ, JULIO WAINSTEIN, OREN FROY, Holon, Israel, Rehovot,
Israel
The effect of meal timing on weight loss and metabolic syndrome is
unknown. The present study was designed to compare two isocaloric weight
loss diets with calorie loading at breakfast vs. dinner. Subjects included 93
obese women (BMI 32.4 ± 1.8 kg/m2) with metabolic syndrome who were
randomized into two isocaloric (~1400 kcal) weight loss diets, a breakfast
(BF) diet (700 kcal breakfast, 500 kcal lunch, 200 kcal dinner) or a dinner
(D) diet (200 kcal breakfast, 500 kcal lunch, 700 kcal dinner) for 12 weeks.
Anthropometric measurements, oral glucose tolerance test (OGTT) and meal
tests were performed. After 12 weeks, the BF group showed greater weight
loss (-8.7±1.4 vs. -3.6±1.5 kg) and reduction in waist circumference (-8.5±1.9
vs. -3.9±1.4 cm) compared with the D group. Although fasting glucose,
insulin, ghrelin levels as well as HOMA-IR, and HOME-B were reduced in
both groups, fasting glucose, insulin and HOMA-IR decreased significantly
to a greater extent in the BF group. In addition, mean triglyceride levels
decreased by 33.6% in the BF group, but increased by 14.6% in the D group.
Total cholesterol slightly decreased only in the BF group. After OGTT, the
extent of reduction of AUCglucose and AUCinsulin was significantly greater in the
BF (-22% and -58%, respectively) compared with the D group. In response
to a meal challenge, the overall daily AUCglucose AUCinsulin, AUCghrelin and
mean hunger scores were significantly lower, whereas mean satiety scores
were significantly higher in the BF group. An Isocaloric diet with switched
caloric intake during breakfast and dinner differentially influences weight
loss, waist circumference, appetite and ghrelin and lipid levels. High-calorie
breakfast with reduced intake at dinner might be a useful alternative for the
management of obesity and metabolic syndrome.
&
1530-P
&
1529-P
1531-P
The Influence of Meal Timing on Glucose Metabolism and Hyperandrogenism in Lean Women With Polycystic Ovary Syndrome
Association between Detetary Sodium Intake and Cardiovascular
Complications in a French Cohort of Type 2 Diabetes Patients
DANIELA JAKUBOWICZ, YOSEFA BAR DAYAN, JULIO WAINSTEIN, Holon, Israel
PIERRE-JEAN SAULNIER, RONAN ROUSSEL, RICHARD MARECHAUD, PHILIPPE
SOSNER, STEPHANIE RAGOT, SAMY HADJADJ, Poitiers, France, Paris, France
Weight loss improves insulin resistance and hyperandrogenism in
obese women with PCOS but is unnecessary in lean women with PCOS;
however, meal timing and composition may influence glucose metabolism
and hyperandrogenism. The study was designed to investigate the effects
of two isocaloric diets with different meal timing on insulin resistance and
ADA-Funded Research
&
In type 1 diabetes and in the general population, epidemiological data
suggest that sodium intake is associated with cardiovascular outcomes
with a J-shape curve. However no data examined the association of sodium
intake and cardiovascular or renal complications in type 2 diabetes patients.
For author disclosure information, see page 829.
Guided Audio Tour poster
A399
POSTERS
&
&
Dairy Introduction in Infancy, Childhood Dairy Consumption and
HLA Interact to Affect Risk of Islet Autoimmunity (IA): The Diabetes
Autoimmunity Study in the Young (DAISY)
Epidemiology/
Genetics
&
EPIDEMIOLOGY—NUTRITION
We performed an observational evaluation in an inception cohort of 1486
type 2 diabetes patients.
Baseline daily urinary sodium excretion (UNa) was calculated by Tanaka’s
formula from spot urine. We used Cox proportional hazard model to estimate
associations between predictors and complication outcome.
Median follow-up was 56 months during which 193 cardiovascular
deaths occurred. The mean value of UNa was 161±48 mmol/day. UNa
was significantly and nonlinearly associated with cardiovascular mortality
(p=0.0455) (Figure 1). This association persisted after adjustment on age,
sex, diabetes duration, estimated glomerular filtration rate, urinary albumin
excretion, prior history of myocardial infarction and systolic blood pressure.
We also found a non linear J-shaped significant association between
UNa and risk of cardio-renal composite outcome (cardiovascular death,
myocardial infarction, stroke, hospitalization for heart failure and end stage
renal disease) after multiple adjustment (p=0.0452)
In type 2 diabetes patients, a nadir of UNa approximating 180 mmol/day
was associated with a least risk for severe complications.
1533-P
High Caloric Intake Is Associated With Longitudinal Deterioration
of Insulin Sensitivity and Beta-Cell Function in Women after Gestational Diabetes Mellitus
Short-term dietary restriction can improve insulin sensitivity and beta-cell
function. Few studied the impact of chronic dietary intake. We examined
the relationship between dietary intake under free-living conditions and
the longitudinal trajectory of metabolic traits. Subjects were 62 Hispanic
women with gestational diabetes mellitus (GDM) without T2D at 15-month
postpartum who underwent follow-up every 12-15 months for up to 12
years postpartum. Self-reported food frequency and physical activity (PA)
questionnaires, bioelectrical impedance to assess percent body fat (%BF),
oral (oGTT) and intravenous (ivGTT) glucose tolerance tests were performed
at baseline and every follow-up visit. Mixed effects models were used for
data analyses. Subjects characteristics at baseline were (mean±SD) age:
32±6 years, BMI: 30.4±4.9 kg/m2, total caloric intake: 2111±1116 kcal/day.
68% of the cohort reported zero mins/wk of moderate and vigorous activities.
Dietary intake did not change significantly during follow-up (p>0.24). After
adjustment for baseline age, BMI, PA, baseline values of each outcome, and
change in BMI, high baseline caloric intake was significantly associated with
greater decline of insulin sensitivity (SI) and beta-cell function (DI) over time
(p=0.012 and 0.0003, respectively). The adjusted mean rates of change were
-0.14 vs. -0.02 units/yr for SI, and -371.4 vs. -155.6 units/yr for DI comparing
women with baseline caloric intake above vs. below the cohort median.
Analysis of macronutrients indicated that baseline fat density was positively
associated with rates of change in BMI (p=0.005) and %BF (p=0.04). High fat
density was significantly associated with faster increase of fasting glucose
(FSG; p=0.033) adjusted for baseline FSG and change in BMI. Our findings
indicate that a diet rich in calories and fat accelerates the deterioration of
insulin sensitivity and beta-cell function in women after GDM.
POSTERS
Epidemiology/
Genetics
ZANGHUA CHEN, RICHARD M. WATANABE, DANIEL O. STRAM, THOMAS A. BUCHANAN, ANNY H. XIANG, Los Angeles, CA, Pasadena, CA
Supported by: PHRC interrégional; AFD Recherche (2003); ALFEDIAM (2009);
GEM
1534-P
Role of G308A Variant of Tumor Necrosis Factor Alpha Gene on
Weight Loss and Insulin Resistance after Two Diets
1532-P
DANIEL DE LUIS, ROCIO ALLER, OLATZ IZAOLA, ENRIQUE ROMERO, Simancas,
Spain
WITHDRAWN
The aim of our study was to investigate the influence of G-308A promoter
variant of the TNF alpha gene on metabolic changes and weight loss
secondary to a high monounsaturated fat vs a high polyunsaturated fat
hypocaloric diets in obese subjects. A sample of 261 obese subjects was
enrolled in a prospective way. In the basal visit, patients were randomly
allocated during 3 months to; Diet M (high monounsaturated fat hypocaloric
diet) and Diet P (high polyunsaturated fat hypocaloric diet). One hundred
and ninety seven patients (73.2%) had the genotype G-308G and 64 (26.8%)
patients had the genotype G-308A. There were no significant differences
between the effects (on weight, BMI, waist circumference, fat mass) in
either genotype group with both diets. With the diet type P and in genotype
G-308G, glucose levels (-6.7+22.1 mg/dl vs -3.7+2.2 mg/dl:p<0.05), HOMA-R
(-0.6+2.1 units vs -0.26+3.1 units:p<0.05), insulin levels (-1.7+6.6 UI/L vs
-0.6+7.1 UI/L:p<0.05), total cholesterol levels (-15.3+31.1 mg/dl vs -8.4+22.1
&
For author disclosure information, see page 829.
A400
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—NUTRITION
mg/dl:p<0.05), LDL cholesterol levels (-10.7+28.1 mg/dl vs -3.8+21.1 mg/
dl:p<0.05) and triglycerides (-12.1+52.1 mg/dl vs -6.6+43.1 mg/dl:p<0.05)
decreased.
In conclusion, carriers of G-308G promoter variant of TNFalpha gene have
a better metabolic response than A-308 obese with a high polyunsaturated
fat hypocaloric diet.
1537-P
Macronutrient Composition in Weight Loss Diets: A Meta-Analysis
MONA BOAZ, DANIELA JAKUBOWICZ, JULIO WAINSTEIN, Holon, Israel
Despite their poor long term performance, dietary interventions for
weight loss remain the first line treatment for obesity. This meta-analysis
was designed to compare low fat to low carbohydrate diets in terms of
weight loss or maintenance of weight loss. Studies were included in this
meta-analysis if they were 1) well-designed randomized clinical trials
comparing low fat to low carbohydrate diets; 2) included healthy overweight
and obese adults; 3) measured body weight as the primary endpoint; 4) were
published in 2009 or later. Four studies meeting all inclusion criteria were
identified. Together, these studies included 1878 subjects, 941 of whom
were exposed to low carbohydrate diets and 937 to low fat diets. Two of
the studies targeted weight loss as the primary endpoint, and two focused
on maintenance of weight lost using meal replacement products. Overall
compliance was poor and attrition was high across studies. In a random
effects model, no significant advantage to either diet strategy could be
identified - standardized differnece in means -0.07, 95% CI -0.3-0.4, p=0.7.
Manipulation of macronutrient composition of weight loss diets does not
appear to be associated with significantly different weight loss outcomes.
Both types of macronutrient-centered weight loss diets appear to be
associated with poor adherence and high attrition rates. Novel weight loss
strategies must be investigated.
1535-P
Association of 25(OH)D With Insulin Resistance and Beta Cell Function in an Aboriginal Canadian Community
SHEENA KAYANIYIL, ALAA BADAWI, STEWART B. HARRIS, BERNARD ZINMAN,
ANTHONY J. HANLEY, Toronto, ON, Canada, London, ON, Canada
Aboriginal Canadian populations living in northern environments are at
increased risk of both type 2 diabetes (T2DM) and vitamin D deficiency.
Emerging evidence suggests a role for low vitamin D in the etiology of
T2DM, but data examining this association in Aboriginal groups in Canada
are limited. Our objective was to determine the cross-sectional association
of vitamin D [25-hydroxyvitamin D, 25(OH)D] with risk of T2DM and related
traits, specifically insulin resistance (IR) and beta (β)-cell dysfunction in 445
Aboriginal Canadian participants in a community-wide survey in 2003-05.
Participants’ mean age and BMI were 34y and 29.8 kg/m2, respectively,
and 59% were female. Serum 25(OH)D was measured using a competitive
chemiluminescence immunoassay. Fasting blood samples were collected,
and 75g oral glucose tolerance tests (OGTT) were administered. Insulin
sensitivity was measured using the Matsuda index (ISOGTT) and HOMA-IR.
β-cell function was determined using both the insulinogenic index divided
by HOMA-IR (IGI/IR) and the Insulin Secretion Sensitivity Index-2 (ISSI-2).
Multivariate regression models adjusted for age, sex, season, PTH, vitamin
D supplement use, and % body fat.
The mean 25(OH)D concentration was 23.2 ± 9.6 nmol/L; 98.4% had insufficient 25(OH)D levels (<50 nmol/L). Linear regression analyses indicated
significant associations of 25(OH)D with both ISOGTT and HOMA-IR [β=0.015
(95% CI 0.007, 0.002) and β=-0.013 (-0.02, -0.004), respectively], as well as
with both IGI/IR and ISSI-2 [β=0.017 (0.002, 0.03) and β=0.011 (0.004, 0.02),
respectively]. Logistic regression analyses indicated a significantly reduced risk
of OGTT-detected T2DM [OR=0.45 (0.22, 0.91)] per SD increase in 25(OH)D.
In conclusion, low 25(OH)D levels were significantly associated with poor
insulin sensitivity and β-cell function, as well as an increased risk of type
2 diabetes in an Aboriginal Canadian population with a high prevalence of
vitamin D insufficiency.
1538-P
In people with diabetes, recent observational studies have found an
association between low baseline 24h urinary sodium excretion (24hUNa)
and the subsequent risk for increased mortality. The aim of this study was
to determine whether a similar relationship exists between serial 24hUNa
measurements and mortality. We studied patients with type 2 diabetes
(n=638) attending a single diabetes clinic. Baseline characteristics were
determined in 2001 and follow up was completed in 2010. Serial 24hUNa was
measured at 6-12 month intervals. A joint model was developed comprising a
longitudinal Linear Mixed Model and a Weibull Parametric Survival model to
take into account the association between both the longitudinal 24hUNa and
eGFR measurements and total mortality. Significant independent predictors
of the longitudinal Linear Mixed Model were: time, 24hUNa as a continuous
variable over the observational period, baseline eGFR, AER, age and BMI.
Significant independent predictors of the survival component of the joint
model were: 24h UNa over time, baseline eGFR, eGFR over the observational
period, presence of CHF and/or AF, duration of diabetes, baseline HDL and
diastolic blood pressure. The model showed that low 24hUNa over time
was independently associated with increased mortality in type 2 diabetes
(FIGURE). These data call for interventional studies to determine if dietary
sodium intake has a causative role in determining adverse outcomes in
patients with type 2 diabetes.
Supported by: CIHR
1536-P
Chewing Areca Nut and Risk of Metabolic Diseases, Cardiovascular Disease, and All-Cause Mortality: A Meta-Analysis
TOMOHIDE YAMADA, KAZUO HARA, TAKASHI KADOWAKI, Tokyo, Japan
Areca nut (AN) (Betel nut) is a fruit of the Areca catechu tree.
Approximately 600 million individuals chew AN regularly worldwide and it is
a known risk factor for oral cancer. Several studies have shown that chewing
AN influences the risk of systemic diseases. We performed a meta-analysis
to assess the influence of chewing AN on metabolic diseases, cardiovascular
disease, and all-cause mortality.
We searched Medline and the Cochrane Library for pertinent articles
(including their references) published between 1951 and 2012. Only English
language reports of original observational studies were included. Data were
extracted independently by two reviewers. The adjusted relative risk (RR)
and 95% confidence interval (95% CI) were calculated using the random
effect model. Sex was used as an independent category for comparison.
Of 569 potentially relevant studies, 16 studies (8 cohort studies and 8
case-control studies) covering 385,933 subjects (range: 1,049 to 97,244)
conformed to the selection criteria of 21 comparison categories. All of these
studies were performed in Asia. Pooled analysis showed that the adjusted
RR for AN use compared with nonuse was 1.56 (95% CI: 1.2-2.03; p=0.001)
for metabolic syndrome (N=5), 1.36 (95% CI: 1.05-1.76; p=0.02) for obesity
(N=6), 1.47 (95% CI: 1.2-1.81; p<0.001) for diabetes (N=2), 1.45 (95% CI:
0.98-2.15; p=0.06) for hypertension (N=4), 1.2 (95% CI: 1.03-1.4;p=0.02) for
cardiovascular disease (N=6), and 1.22 (95% CI: 1.03-1.44; p=0.02) for allcause mortality (N=5). The funnel plot, Begg’s test, and Egger’s test did not
show any evidence of publication bias (all P≥0.05).
In conclusion, chewing AN is associated with an increased risk of
several metabolic diseases, as well as cardiovascular disease and all-cause
mortality. Stopping AN use could be valuable in terms of preventing metabolic
diseases, especially considering the rapid increase in the prevalence of such
diseases in South-East Asia and the Western Pacific.
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A401
POSTERS
ELIF I. EKINCI, JOHN MORAN, KAREY CHEONG, MERLIN THOMAS, SOPHIE
CLARKE, AMANDA LEONG, ANGELA CHEN, MATTHEW DOBSON, RICHARD J.
MACISAAC, GEORGE JERUMS, Melbourne, Australia, Adelaide, Australia
Epidemiology/
Genetics
Relationship between Serial 24h Urinary Sodium Excretion and
Mortality in Type 2 Diabetes
EPIDEMIOLOGY—OTHER
EPIDEMIOLOGY—OTHER
1541-P
Exploration of Efficient Case Ascertainment Methods for Surveillance of Childhood Diabetes Using Electronic Health Data: The
SEARCH for Diabetes in Youth Study, Carolina Site
1539-P
Dietary Glycemic Index during Pregnancy Is Associated With Biomarkers of the Metabolic Syndrome in Offspring at Age 20 Years
WENZE ZHONG, EMILY R. PFAFF, JOAN THOMAS, LINDSAY M. JAACKS, TIMOTHY S. CAREY, DANIEL P. BEAVERS, SHARON H. SAYDAH, JEAN M. LAWRENCE,
RICHARD F. HAMMAN, DANA DABELEA, CATHERINE PIHOKER, ELIZABETH J.
MAYER-DAVIS, Chapel Hill, NC, Winston-Salem, NC, Atlanta, GA, Pasadena, CA,
Aurora, CO, Seattle, WA
POSTERS
Epidemiology/
Genetics
INGE DANIELSEN, CHARLOTTA GRANSTRÖM, THORHALLUR HALDORSSON,
DORTE RYTTER, BODIL HAMMER BECH, TINE BRINK HENRIKSEN, ALLAN VAAG,
SJURDUR OLSEN, Copenhagen, Denmark, Reykjavik, Iceland, Aarhus, Denmark
Growing evidence indicates that MS is rooted in fetal life with a potential
key role of nutrition during pregnancy. The objective of the project was to
assess the possible associations between the dietary glycemic index (GI)
and glycemic load (GL) during pregnancy and biomarkers of the metabolic
syndrome (MS) in young adult offspring.
Dietary GI and GL were assessed by questionnaires and interviews in
gestation week 30 and offspring were clinically examined at the age of 20
years. Analyses based on 439 mother-offspring dyads were adjusted for
maternal smoking during pregnancy, height, pre-pregnancy body mass index
(BMI), education, energy intake, and the offspring’s ambient level of physical
activity. In addition, possible confounding by gestational diabetes mellitus
was taken into account.
Main outcome measures: Waist circumference, blood pressure, HOMA
insulin resistance (HOMA-IR) and plasma levels of fasting glucose,
triglycerides, HDL cholesterol, LDL cholesterol, total cholesterol, insulin, and
leptin were measured in the offspring.
Significant associations were found between dietary GI in pregnancy and
HOMA-IR (the relative increase in HOMA-IR per 10 units’ GI increase was
1.08 [95% CI: 1.01, 1.16], p=0.02), insulin (1.08 [95% CI: 1.01, 1.16], p=0.02)
and leptin (1.21 [95% CI: 1.07, 1.38], p=0.004) in the offspring; whereas no
associations were detected for GL. Exclusion of 11 women diagnosed with
gestational diabetes mellitus did not change the results.
Our data suggests that high dietary GI in pregnancy may affect MS marker
levels in young adult offspring in a potentially harmful direction.
We used electronic health data from the University of North Carolina
Health Care System’s Data Warehouse to explore approaches for efficient
childhood diabetes (DM) case ascertainment. 57,767 children aged 0-19
years who were seen by a health care provider for any reason in 2011 were
identified. From these, 1348 presumed DM cases were selected who met
≥ 1 of the following criteria using data back to July 1st 2008: 1) HbA1c ≥
6.0%; 2) ≥ 1 fasting glucose ≥ 126mg/dl or ≥ 2 random glucose ≥ 200mg/
dl on different days; 3) ≥ 1 DM-related ICD-9 codes on problem list ; 4) ≥
1 DM-related ICD-9 billing codes; 5) any DM medications. Children who
didn’t meet any of the listed criteria were assumed non-diabetic. Medical
record review of 1348 presumed cases yielded 537 true DM cases. Among
the criteria, billing codes had the best performance with a high sensitivity
(97.0%) and a moderate positive predictive value (PPV) (82.2%) (Table).
Although by design, meeting ≥1 criteria had a sensitivity of 100%, the PPV
was low (39.8%). When ≥ 2 criteria were met, the PPV improved to 77.2%,
but the sensitivity decreased to 91.6%. When ≥3 or ≥4 or 5 criteria were
met, sensitivity dropped greatly (81.8% -37.6%). While further analyses will
consider combinations of number and type of criteria by DM type, use of
billing data may provide the most efficient approach to initial surveillance,
with little gain from use of more complex data sources.
Table. Validation of single and multiple criteria in identifying childhood diabetes cases in the University of North Carolina Health Care System’s Data
Warehouse (source population n=57,767; total presumed cases n=1348; true
cases n=537)
Supported by: Danish Council for Strategic Research
criteria met
False
Sensitivity Specificity Positive Negative
positive n
(%)
(%)
predictive predictive
(%)
value (%) value (%)
HbA1c
486 99(20.4)
72.1
99.8
79.6
99.7
Fasting/random glucose 857 464(54.1)
73.2
99.2
45.9
99.7
Diabetes related ICD-9 266 8(3.0)
48.0
99.9
97.0
99.5
codes* on problem list
Diabetes related ICD-9 634 113(17.8)
97.0
99.8
82.2
99.9
billing codes
Diabetes medications¶ 782 299(38.2)
89.9
99.5
61.8
99.9
# of criteria met
At least 1
1348 811(60.2)
100.0
98.6
39.8
100.0
At least 2
637 145(22.8)
91.6
99.7
77.2
99.9
At least 3
458 19(4.1)
81.8
99.9
95.9
99.8
At least 4
378 6(1.6)
69.3
99.9
98.4
99.7
5
204 2(1.0)
37.6
99.9
99.0
99.4
*Diabetes related ICD-9 codes included: 250.xx (diabetes); 775.1 (neonatal
diabetes); 648.0x (diabetes in pregnancy, non-gestational); 357.2 (diabetic
retinopathy); 362.0x (diabetic retinopathy); 366.4 (diabetic cataract)
¶ Diabetes medications included: insulin, metformin, GLP-1, glucagon, sulfonylureas, Thiazolidnediones, and other hypoglycemic agents such as acarbose
and nateglinide.
1540-P
Is Genetic Ancestry Associated With Incident Type 2 Diabetes?
REBECCA PICCOLO, JOHN B. MCKINLAY, JAMES B. MEIGS, RICHARD GRANT,
LISA D. MARCEAU, Watertown, MA, Boston, MA, Oakland, CA
Type 2 Diabetes (T2D) is more prevalent among Black and Hispanic minority
populations in the US relative to Whites. Genetic ancestry (as measured by
Ancestry Informative Markers, AIMs) is associated T2D, HbA1c and insulin
resistance in recent studies. However, the association between ancestry
and T2D appears to be almost totally confounded by socioeconomic factors.
In order to further quantify the association between genetic ancestry,
socioeconomic factors, and T2D we used data from the longitudinal Boston
Area Community (BACH) Survey.
The BACH Survey is a racially/ethnically diverse, longitudinal, epidemiologic
study of community-dwelling residents of Boston. A panel of 63 AIMs designed to
discriminate African, Native American, and European ancestry were collected
from 2,732 non-diabetic participants, along with a breadth of measures
including: sociodemographics, health care access/utilization, lifestyle/
behavior, health status, physical measures, and biochemical parameters.
We examined the relationship between % African and % Native
American ancestry on incident T2D (average follow-up = 7.2 years). In ageand gender-adjusted models, the odds of developing T2D were 14% higher
(OR= 1.14, 95% CI [1.07-1.22]) for every 10% increase in African ancestry
(relative to European ancestry). Results were similar for Native American
ancestry although not statistically significant (OR=1.14 [ 0.97,1.33]). As in
previous studies, these results were attenuated with further adjustment
for socioeconomic factors (African ancestry: OR=1.07, [0.99-1.15]; Native
American ancestry: OR=0.99, [0.83-1.18]). Further, genetic ancestry only
accounted for 0.3% of the variation in T2D incidence (by comparison, income,
education, and occupation accounted for 1.4% and BMI 1.6%).
We conclude that while African and Native American genetic ancestry are
associated with incidence of T2D in minimally adjusted models, the effect of
genetic ancestry on T2D is likely explained by differences in socioeconomic
position.
n
Supported by: CDC
1542-P
Extent of Increase Over Time in U.S. Diabetes Prevalence Explained
by Race-Ethnicity, Aging, and Obesity Trends
ANDY MENKE, KEITH F. RUST, YILING J. CHENG, CATHERINE C. COWIE, Silver
Spring, MD, Rockville, MD, Atlanta, GA, Bethesda, MD
The prevalence of diabetes has been increasing over the past few
decades. This has coincided with an increase in certain risk factors for
diabetes, such as a changing race-ethnicity distribution, an aging population,
and an increase in obesity prevalence. It is unclear how much the increased
prevalence of diabetes is due to an increase in these known risk factors
and how much is due to other factors. We used data from participants ages
20-74 years (for consistency across survey years) in the National Health and
Nutrition Examination Survey (NHANES) II (1976-1980; N=4570), NHANES
Supported by: NIH/NIDDK (U01DK056842), (R01DK080786)
&
For author disclosure information, see page 829.
A402
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—OTHER
III (1988-1994; N=7278), NHANES 1999-2002 (N=4118), NHANES 2003-2006
(N=3961), and NHANES 2007-2010 (N=5109), all nationally representative
samples of the U.S. population. Diabetes, defined as a self-reported diagnosis
or fasting plasma glucose ≥126 mg/dL (common measures for all surveys),
increased among men from 4.8% in 1976-1980 to 11.3% in 2007-2010, and
among women from 5.7% in 1976-1980 to 8.6% in 2007-2010 (both p-trends
<0.001). Using logistic regression, adjustment for age, race-ethnicity, and
body mass index decreased the diabetes slope over time by 47% among
men and 110% among women. Changes over time in the distribution of age,
race-ethnicity, and body mass index explains about half of the increase in
diabetes prevalence in men and the entire increase in diabetes prevalence in
women in the U.S. population between 1976-1980 and 2007-2010.
1544-P
Depressive Symptoms and Incidence of Diabetes
Percent of diabetes slope over time explained by differences in the distribution of race-ethnicity, age, and body mass index
Logit (SE) of diabetes Percent explained
per 1 year increase
by covariate
Men
Unadjusted
0.0310 (0.0035)
—
Age
0.0311 (0.0037)
-0.3
Race-ethnicity
0.0306 (0.0036)
1.3
Body mass index, kg/m2
0.0184 (0.0038)
40.6
All 3 combined
0.0163 (0.0042)
47.4
Residual
—
52.6
Women
Unadjusted
0.0154 (0.0034)
Age
0.0140 (0.0036)
9.1
Race-ethnicity
0.0138 (0.0035)
10.4
Body mass index, kg/m2
-0.0011 (0.0035)
107.1*
All 3 combined
-0.0015 (0.0039)
109.7*
Residual
—
—
*Values >100% indicate a decrease in diabetes prevalence over time after
adjustment
1545-P
Supported by: NIDDK (GS10F0381L)
Sex Steroid and Sex Hormone Binding Globulin Changes in Premenopausal Women in the Diabetes Prevention Program (DPP)
1543-P
CATHERINE KIM, F. XAVIER PI-SUNYER, ELIZABETH L. BARRETT-CONNOR,
FRANKIE B. STENTZ, MARY BETH MURPHY, SHENGCHUN KONG, BIN NAN, ABBAS E. KITABCHI, FOR THE DIABETES PREVENTION PROGRAM, Ann Arbor, MI,
New York, NY, San Diego, CA, Memphis, TN
Paternal Diabetes Is Associated With Lower Birth Weight in the UK
Biobank Study of 500,000 Individuals
JESSICA S. TYRRELL, HANIEH YAGHOOTKAR, RACHEL M. FREATHY, ANDREW
T. HATTERSLEY, TIMOTHY M. FRAYLING, Truro, United Kingdom, Exeter, United
Kingdom
Our objective was to examine associations between intensive lifestyle
modification (ILS) and metformin and changes in SHBG and sex steroids
(estradiol, testosterone, dehydroepiandrosterone, androstenedione [A4]) in
premenopausal women.
The DPP was a randomized trial designed to assess the impact of ILS and
metformin upon diabetes incidence in overweight, glucose-intolerant adults.
We examined a subgroup of participants who were premenopausal women;
non-Hispanic white (NHW), African-American (AA), or Hispanic (H) race/
ethnicity; and who did not use estrogen (n=301). Main outcome measures
were changes in sex hormones between baseline and 1-year by study arm
and race/ethnicity.
ILS, but not metformin, increased median SHBG by 3.1 nmol/l (about
11%) compared to decreases of 1.1 nmol/l in the placebo arm (p<0.05), with
differences persisting after adjustment for age, race/ethnicity, and changes
in waist circumference. Neither intervention changed any sex steroids
compared to placebo. SHBG changes were not associated with fasting
glucose or post-challenge glucose changes. Racial/ethnic comparisons
were not significant. The exception was that median baseline A4 was lower
in Hs compared to NHWs (5.7 nmol/l vs. 6.5 nmol/l, p<0.05), and median
increases in A4 were also greater in Hs compared to NHWs (3.0 nmol/ vs.
1.2 nmol/l, p<0.05). These differences persisted after adjustment for waist
circumference.
Among premenopausal glucose intolerant women, ILS increased SHBG,
but this was not associated with reductions in fasting or 2-hour glucose. Sex
steroids were similar by race/ethnicity, with the possible exception of lower
A4 and greater increases in A4 in Hs vs. NHWs
Low birth weight is associated with an increased risk of type 2 diabetes
but the mechanisms behind this association are poorly understood. We
aimed to investigate the association between birth weight and parental
diabetes in the UK Biobank population study of 500,000 individuals.
We used linear regression to test associations between reported
parental type 2 diabetes and birth weight in individuals of European descent
(n=257,715). We used logistic regression to investigate the association
between participants’ birth weight and subsequent risk of developing type
2 diabetes.
Of 257,715 individuals born as singletons and providing birth weight data,
6,872 were defined as having type 2 diabetes, 20,968 individuals reported
a history of maternal diabetes (but no paternal history), 20,521 individuals
reported a history of paternal diabetes (but no maternal history) and 2,754
participants reported both parents as having diabetes.
Type 2 diabetes was associated with lower birth weight. A one standard
deviation increase in birth weight (~500g give exact SD) was associated
with a reduced risk of type 2 diabetes (Odds ratio: 0.75 [95%CI: 0.72, 0.77];
P=1x10-55). Paternal diabetes was associated with reduced birth weight
(32g reduction [95%CI: 25, 32g]; P=1.6x10-23) relative to individuals with no
parental diabetes. Maternal diabetes was associated with increased birth
weight (38g increase [95%CI: 32, 44]; P=6.2x10-36).
In summary, data from the UK Biobank provides the strongest evidence by
far that paternal diabetes is associated with lower birth weight. Our findings
are consistent with a role of genetic factors in determining both fetal growth
and adult diabetes and cast doubt on the likely success of interventions
aiming to reduce the prevalence of type 2 diabetes by improving intrauterine nutrition.
Supported by: NIDDK (U01DK048489), (R01DK083297), (R01DK53061), (GCRCRR00211), (K23DK071552)
Supported by: Diabetes UK
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A403
POSTERS
Using data from the Coronary Artery Risk Development in Young Adults
study (1995, 2000, and 2005), we examined the association between
depressive symptoms, measured by the Centers for Epidemiologic Studies
Depression (CES-D) Scale score, and incident diabetes (DM) and possible
variation by race.
The 3580 study participants (mean age 34.9, standard deviation 3.6
years) were free of DM in 1995. We defined incident DM by a self-reported
physician diagnosis of DM, use of DM drugs, or fasting plasma glucose
values ≥ 126 mg/dL. We used Cox regression models to determine the hazard
ratio (HR) of DM by CES-D score ( <16 and ≥ 16) at baseline, adjusted for
race, age, systolic and diastolic blood pressure, total cholesterol, HDL, LDL,
triglycerides, and CES-D score*race interaction. Other potential covariates,
such as body mass index, sex, and education, were not considered because
they were highly correlated with depression, and depression was the focus
of our study
During the 10-year period, the cumulative incidence of DM was 4.9% among
participants with CES-D score < 16 and 7.3% among those with score ≥16 (p=
0.01). The interaction term between CES-D score and race was statistically
significant (p=0.02), indicating that the response to depression differed
between whites and blacks. Among blacks, the cumulative incidence of DM
was 7.9% and 7.6%, respectively, among those with CES-D score ≥16/<16
(p=0.84). In whites, 6.0%/2.7% of those with CES-D ≥16/<16, respectively,
developed DM (p<0.01). In the un-adjusted model, among whites, the hazard
ratio of DM for participants with CES-D score ≥16 was 2.29 [95% confidence
interval: 1.30-4.03], compared to those with CES-D score <16. Among blacks,
the HR was 0.98 [0.65-1.46]. After adjustment, the HR in whites and blacks
was 2.17[1.82-2.60] and 1.15[0.78-1.71], respectively.
In CARDIA participants, the effect of depressive symptoms on incident
DM differs by race; depressive symptomatology was a significant predictor
of incident DM only among whites.
Epidemiology/
Genetics
XUANPING ZHANG, GIUSEPPINA IMPERATORE, LAWRENCE E. BARKER, GLORIA
L. BECKLES, DESMOND E. WILLIAMS, ANN L. ALBRIGHT, KAI MCKEEVER BULLARD, EDWARD GREGG, Atlanta, GA
POSTERS
Epidemiology/
Genetics
EPIDEMIOLOGY—OTHER
1546-P
1548-P
Potassium and Glucose Metabolism in Older Adults: The Cardiovascular Health Study Cohort
The Impact of Past Severe Hypoglycemic Events on the Risk of Future Events in the United States
RANEE CHATTERJEE, MARY LOU BIGGS, IAN DEBOER, LAURA SVETKEY, FREDERICK BRANCATI, JOSHUA BARZILAY, LUC DJOUSSE, JOACHIM IX, JORGE KIZER, DARIUSH MOZAFFARIAN, DAVID SISCOVICK, DAVID EDELMAN, KENNETH
MUKAMAL, Durham, NC, Seattle, WA, Baltimore, MD, Tucker, GA, Boston, MA, San
Diego, CA, Bronx, NY
MICHAEL L. GANZ, QIAN LI, NEIL S. WINTFELD, YUAN-CHI LEE, VERONICA ALAS,
JOANNA C. HUANG, Lexington, MA, Princeton, NJ
History of severe hypoglycemia (SH) is a known risk factor for future
events. To estimate the real-world impact of past SH events, we analyzed a
sample of 7,271 adults (mean age: 61) with type 2 diabetes initiating basal
insulin in 2008-2011 using a major electronic health records (EHR) database.
Because we used medical records data, we defined SH events based on
diagnosis codes and blood glucose measurements ≤40 mg/dL. We assumed
a 16-week titration period that started upon basal insulin initiation; all
analyses focused on the post-titration period. We used logistic regression
to estimate the association of SH during the first 3 months on the risk of SH
in the next 9 months. To account for the temporal ordering of SH events and
the impact of patients’ time-varying SH histories, we also used repeated
measures logistic regression to estimate the dynamic association of SH
during any 3-month period on the risk of SH in the subsequent 3 months. All
results were adjusted for patient demographic and clinical characteristics,
including use of OADs during the year before insulin initiation. Based on
the first logistic model, we found that patients who had SH during the first
3 post-titration months were more likely to have ≥ 1 SH event during the
next 9 months than those who did not (probability: 45% vs. 6%; odds ratio
[OR]: 13.7, p<0.01). We also found a significant dynamic association. Patients
who had SH during any (post-titration) 3-month period were more likely to
have ≥ 1 SH event during the subsequent 3 months than those who did not
(probability: 15% vs. 1%; OR: 14.7, p<0.01). These results suggest that the
impact of past SH events on the risk of future SH may not be minor as well as
the potential value of preventing SH among high-risk patients. For example,
using previously estimated quarterly costs for patients with and without
SH events ($3,613 and $484), our repeated measures results imply that
preventing one SH event may be associated with 2.2 fewer annual events
and with annual costs savings of $6,733.
In middle-aged cohorts, low levels of serum and dietary potassium (K)
have been associated with increased diabetes risk, but their impact on
other populations and on glucose metabolism is unknown. We examined
associations of serum and dietary K with measures of insulin sensitivity
and risk of incident diabetes among 4754 participants in the Cardiovascular
Health Study, a community-based cohort of older American adults aged ≥
65 years.
We calculated the Matsuda insulin sensitivity index (ISI) using oral glucose
tolerance test data from the baseline exam. Diabetes was defined as a
fasting glucose ≥ 126 mg/dL, nonfasting glucose >=200, or use of diabetes
medications. We used linear regression to assess the relationship of baseline
K and ISI, and Cox regression to evaluate the association between baseline
K and incident diabetes. All models were adjusted for age, race, sex, clinic
site, BMI, waist circumference, physical activity, smoking status, alcohol
use, systolic blood pressure, ACE-inhibitor and diuretic use; dietary K models
were additionally adjusted for diet score and total energy intake.
Participants with a serum K <4.0 mEq/L had an adjusted mean difference
in Matsuda ISI of -0.22 (-0.43, -0.01) compared to those with a serum K ≥4.5.
Participants in the lowest quartile of dietary K intake had a corresponding
adjusted mean difference in Matsuda ISI of -0.61 (-0.94, -0.29) compared
to the highest quartile. A total of 445 cases of incident diabetes occurred
over a median follow-up of 12 years. In multivariate models, neither serum
nor dietary K was associated with diabetes risk, with a HR (95% CI) of 1.00
(0.74-1.35) for serum K <4.0 mEq/L compared to ≥4.5.
Among older adults, low-normal serum and low dietary K were associated
with decreased insulin sensitivity, but not with diabetes risk. Additional
study in older adults is needed to clarify the associations between low
serum and dietary K with insulin resistance and diabetes risk.
1549-P
Age-Specific Changes in Diabetes Incidence and Mortality among
U.S. Adults, 1990–1994 to 2000–2004
1547-P
YILING J. CHENG, TED THOMPSON, XIAOHUI ZHUO, GUISSEPINA IMPERATORE,
LAWRENCE BARKER, LINDA S. GEISS, EDWARD GREGG, Atlanta, GA
OGTT Modeled β-Cell Function Measures Predict the Development
of Type 2 Diabetes in Japanese Americans
The increase in diabetes (DM) prevalence depends on the magnitude of
increase in DM incidence in the general population and the magnitude of
decrease in mortality in the diabetes population. We used National Health
Interview Survey data to compare changes from 1990-1994 to 2000-2004
in the age-specific incidence of DM among adults aged 20 to 84 years and
mortality in those with DM. Incident DM was defined as a self-report of DM
diagnosed in previous 12 months. Logistic regression with a cubic term for
age was used to model age-specific incidence and prevalence. Piecewise
exponential regression with a quadratic age term was used to model agespecific mortality. During the 10-year interval between two survey periods,
the age-sex-race/ethnicity adjusted prevalence increased 61.4% (from 4.1%
to 6.9%), the adjusted annual incidence increased 68.2% (from 0.44% to
0.74%) and the adjusted annual mortality among the diabetic population
decreased 11.1% (from 1.8% to 1.6%). The figure below shows the magnitude
of changes in incidence and mortality when expressed in terms relevant to
their impact on prevalence. These findings suggest that for most of the age
spectrum, increases in incidence affected increases in prevalence more
than decreases in mortality. Therefore, although mortality rates will likely
continue to affect DM prevalence, especially among the oldest segment of
the population, reducing incidence through preventive intervention is crucial
to reducing prevalence.
KRISTINA M. UTZSCHNEIDER, ANNA LARGAJOLLI, ALESSANDRA BERTOLDO,
DONNA L. LEONETTI, MARGUERITE J. MCNEELY, WILFRED Y. FUJIMOTO, CLAUDIO COBELLI, STEVEN E. KAHN, EDWARD J. BOYKO, Seattle, WA, Padova, Italy
Decreased β-cell function is a key feature of type 2 diabetes (T2DM).
C-peptide modeling of OGTT data is being used to estimate β-cell function.
We sought to determine if modeled measures of β-cell function can predict
the development of T2DM and how they compare with already established
measures. OGTTs (time points: 0, 30, 60 and 120 min) were performed on 658
Japanese-American subjects (136 with T2DM) at baseline. Those without
T2DM at baseline were followed for up to 10 years for development of
incident diabetes. Modeling was successfully performed on 461 subjects.
After excluding outliers and those with missing or negative values, baseline
data from 426 subjects (n=180 NGT, n=179 IFG/IGT and n=67 T2DM)
(318M/108F; age mean±SD: 50.5±11.7 y) were analyzed. β-cell function
measures included the insulinogenic index (ΔI/ΔG from 0-30 min) and
model-derived β-cell responsivity indices (Φstatic, Φdynamic, Φtotal). The
ability of each measure to predict incident T2DM was estimated in logistic
regression models adjusted for age, sex, BMI, family history of T2DM, and
insulin sensitivity (using a model derived measure for the Φ measures and
the Matsuda Index for ΔI/ΔG).
At baseline all β-cell function measures were significantly higher in NGT,
intermediate in IFG/IGT and lower in T2DM. Of the 359 subjects without
T2DM at baseline, 62 developed diabetes over 10 years. In adjusted logistic
regression models, only Φ dynamic and ΔI/ΔG predicted T2DM at 10 yrs (odds
ratio per 1 unit change [95% CI]: ln Φ dynamic 0.29 [0.13-0.64] p=0.002; lnΔI/
ΔG 0.24 [0.13-0.46] p<0.001,), but Φ static and Φ total did not. Area under
ROC curves did not differ for Φ dynamic (0.83) and ΔI/ΔG (0.83) in the ability
to predict T2DM.
We conclude that of modeled β-cell function measures from a standard
OGTT, only Φ dynamic predicts diabetes development and was equivalent
to the insulinogenic index in this regard. Modeling of β-cell function may
perform better with inclusion of more early time points than those collected
in this study.
&
For author disclosure information, see page 829.
A404
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—OTHER
1550-P
1552-P
Fasting Insulin Levels Predict Incidence of Diabetes among American Young Adults: The CARDIA Study
Maintained Fitness May Especially Benefi t Young Adults With High
BMI & Insulin Resistance: The CARDIA Study
PENGCHENG XUN, KIANG LIU, WENHONG CAO, MARTHA DAVIGLUS, CATHERINE LORIA, MICHAEL STEFFES, DAVID R. JACOBS, KA HE, Bloomington, IN,
Chicago, IL, Chapel Hill, NC, Bethesda, MD, Minneapolis, MN
LISA S. CHOW, DAVID R. JACOBS, MERCEDES CARNETHON, BARBARA STERNFELD, LYNN E. EBERLY, ERIN AUSTIN, NA ZHU, STEPHEN SIDNEY, CLAUDE
BOUCHARD, PAMELA J. SCHREINER, Minneapolis, MN, Chicago, IL, Oakland, CA,
Baton Rouge, LA
Background: Experimental studies in animals have shown that hyperinsulinemia is necessary for diet-induced obesity and insulin resistance, a
precursor of type 2 diabetes mellitus. However human studies are lacking.
Research design and methods: A cohort of 3,429 American young adults,
aged 18-30 years, free of diabetes in 1985-86 (baseline), was enrolled in
CARDIA and attended up to 7 follow-up examinations through 2010-11 (Year
25). Fasting glucose were assessed by a hexokinase method. Fasting insulin
was assessed by several methods, each calibrated to an isotope dilutionliquid chromatography/tandem mass spectrometry method that used
purified recombinant insulin as its standard. Incident diabetes was identified
by plasma glucose levels, oral glucose tolerance tests, hemoglobin A1C
levels and/or anti-diabetic medications.
Results: Medians of cumulative average insulin levels were 5.95, 7.55,
8.84, 10.79 and 15.25 µU/mL across five groups (fasting insulin: <7 µU/mL
(about 1/3 of the sample); quartiles for insulin ≥7). During the 25-year followup, 394 incident cases were identified. Covariates were age, sex, race, study
center, education, smoking, alcohol consumption, physical activity, family
history of diabetes, BMI, LDL/TC, HDL/TC, systolic blood pressure and
baseline glucose concentration. Insulin grouping and covariates were time
dependent. Hazard ratios (95% confidence intervals) for incident diabetes
from the lowest to highest groups of insulin levels were 1.00, 1.26 (0.68,
2.34), 1.86 (1.06, 3.25), 3.67 (2.17, 6.21) and 7.05 (4.13, 12.04); Ptrend<0.001.
The positive association persisted in each gender/ethnicity/weight status
subgroup.
Conclusions: Fasting insulin levels or hyperinsulinemia was positively
associated with incidence of diabetes for men and women, African
Americans and Caucasians, and normal weight or overweight. Early fasting
insulin ascertainment may help clinicians identify those at high risk of
diabetes later in life.
1551-P
Mortality among Veterans With Type 2 Diabetes Initiating Metformin, Sulfonylurea, or Rosiglitazone Monotherapy
Supported by: N01-HC95095, N01-HC48047,N01-HC48048, N01-HC48049, N01HC48050
EDWARD J. BOYKO, STEPHANIE WHEELER, KATHRYN MOORE, CHRISTOPHER W.
FORSBERG, KEVIN RILEY, JAMES S. FLOYD, NICHOLAS L. SMITH, Seattle, WA
Aims/hypotheses: Oral hypoglycemic medications are the most commonly
used type 2 diabetes pharmacologic treatments. Despite their frequent use,
existing research is limited on their comparative safety and in particular their
effects on overall mortality. We compared mortality risk with monotherapy
initiation of four oral hypoglycemic medications in a nationwide cohort of
U.S. veterans with type 2 diabetes.
Methods: We identified new monotherapy oral diabetes medication users
between 2004-2009 who received care for at least one year from the Veterans
Health Administration. Patients were followed until initial monotherapy
discontinuation, addition of another diabetes pharmacotherapy, death, or
end of follow-up (December 31, 2009). Mortality hazards ratios (HR) were
estimated using Cox regression adjusted for potential confounding factors.
Results: New users of metformin, sulfonylureas, and rosiglitazone
numbered 193,172 (mean age 63.4 yrs, 95.9% male), of whom 4,256 (2.2%)
died during the study period. Metformin was prescribed most frequently
(68%), followed by glipizide (15%), glyburide (15%), and rosiglitazone (2%).
Mean duration of use for each medication was 1.4-1.7 years. Adjusted HR
for sulfonylurea or rosiglitazone monotherapy compared with metformin
monotherapy were as follows: glyburide (HR 1.38, 95% CI, 1.27-1.49);
glipizide (HR 1.58, 95% CI, 1.46-1.70); and rosiglitazone (HR 1.26, 95% CI,
1.02-1.56). Glipizide monotherapy was associated with a higher risk of
mortality compared to rosiglitazone (HR 1.25, 95% CI 1.01-1.56) or glyburide
monotherapy (HR 1.15, 95% CI 1.05-1.25). Risk of mortality did not significantly
differ between glyburide compared to rosiglitazone monotherapy (HR 1.09,
95% CI 0.88-1.36).
Conclusions/interpretations: Significantly higher mortality was associated
with the use of glyburide, glipizide, or rosiglitazone compared to metformin,
and with the use of glipizide compared with rosiglitazone or glyburide.
ADA-Funded Research
&
1553-P
Diabetes as a Predictor of Survival in Metastatic Nasopharyngeal
Carcinoma
XIAO YE, YING JIN, YUBO XING, YINGXIANG SONG, LIJUN WANG, LIZHONG SU,
YIPING ZHANG, YANYIN HUA, Hangzhou, China
Epidemiologic and clinical evidence suggests that diabetes may associate
with the occurrence and prognosis of many types of cancer. However, the
relationship between diabetes and metastatic nasopharyngeal carcinoma
(NPC) is still unknown. The aim of this study is to explore the role of diabetes
on metastatic NPC patients. 405 patients with metastatic NPC referred
to two teaching hospitals in China were retrospectively analyzed. The
Kaplan-Meier method was used to compare survival curves for patients
with and without diabetes. Univariate and multivariable analyses were
performed using the Cox proportion hazard model to estimate hazard ratio
for prognostic factors. Factors analyzed included general characteristics
(age, sex and performance status), LDH level, presence of metastasis at
presentation, specific metastatic sites, DFI, anemia and diabetes status. The
overall survival (OS) in patients with diabetes was lower than those without
diabetes (median OS is 20 months for diabetes and 15.5 months for nondiabetes,P <0.001 ). Independently prognostic factors included performance
status, LDH level and the presence of diabetes. After adjusted by other
prognostic factors, patients with diabetes had 34% excess risk (P = 0.006)
of all-cause mortality compared to those non-diabetes patients. We found
diabetes is an indicator of poor outcome for patients with metastatic NPC.
Prevention and treatment of diabetes may contribute to the improvement of
prognosis for these patients.
For author disclosure information, see page 829.
Guided Audio Tour poster
A405
POSTERS
Epidemiology/
Genetics
Decreased fitness is associated with higher weight & waist girth; whether
this association is influenced by body mass index (BMI) & insulin resistance
(IR) remains unknown.
Participants from the Coronary Artery Risk Development in Young Adults
(CARDIA) study without year (Y) 0 diabetes [n=2048, 43.4% men, Y0 (1985)
age 18-30] who had fitness measured longitudinally (Y0,Y20) by treadmill
were classified by Y0 BMI [normal: nBMI < 25 vs high: hBMI≥25] & Y0 HOMAIR [Insulin Sensitive (IS): HOMA-IR <1.84 (75%tile) vs Insulin Resistant (IR):
HOMA-IR≥1.84] into nBMI/IS, hBMI/IS, nBMI/IR, hBMI/IR. Fitness change
was classified by change in sex-specific treadmill time (Y20-Y0): Maintained
Fitness [increase or decline ≤20%tile] or Decreased Fitness [decline
>20%tile]. Association of fitness change with each of weight & waist girth
(Y20 & Y25) was assessed by multiple linear regression.
Within each Y0 BMI/IR group, those who maintained fitness had lower
weight & waist girth at Y20 & Y25 compared with those who decreased
fitness (Table 1). The overall interaction between Y0 BMI/IR & fitness change
was significant for: Y20 weight (p<0.01), Y20 waist girth (p <0.01) & Y25
weight (p <0.01); the hBMI/IR group had the largest differences in weight &
waist girth between fitness categories.
Young adults, particularly those with high BMI & IR, who maintained
fitness had less middle age weight gain & waist girth compared with young
adults who decreased fitness.
EPIDEMIOLOGY—OTHER
1555-P
Urinary Bisphenol A Concentrations and Glucose Metabolism in
Adolescents
ELLEN M. WELLS, LEILA W. JACKSON, MICHAELA B. KOONTZ, Cleveland, OH
Bisphenol A (BPA) is a ubiquitous endocrine-disrupting chemical which has
been associated with adverse metabolic outcomes including diabetes and
insulin resistance in adults. Our objective was to examine the association
between urinary BPA concentrations and measures of glucose homeostasis
and insulin resistance in children using National Health and Nutrition
Examination Survey 2003-2010 data. The main outcomes were fasting
glucose, hemoglobin A1C (HbA1C), and fasting insulin. The outcomes and BPA
were not normally distributed and were thus log-transformed or described
using quartiles. Complete data were available for 1,759 individuals aged
12-18 years, including 822 who had fasting laboratory data; laboratory
measures were not obtained in individuals younger than 12 years of age. In
models adjusted for urinary creatinine, age, sex, race/ethnicity, education,
and smoking status, no significant associations were found between BPA
concentrations and any of the outcome measures (Table). In conclusion,
there were no significant associations between BPA exposure and measures
of glucose metabolism or insulin resistance in this cross-sectional analysis
of adolescents, which is in contrast with recent epidemiologic studies in
adults. This may indicate that BPA-related disruption of glucose-insulin
homeostasis develops over time or is influenced by life stage. Longitudinal
studies are needed to further examine this relationship.
Adjusted percent change (95% confidence interval) for glucose metabolism
markers with increasing BPA
BPA quartile
Glucose (N=822) HbA1C (N=159)
Insulin (N=813)
Quartile 1 (<LOD to 1.4 ng/mL BPA)
Referent
Referent
Referent
Quartile 2 (1.5 to 2.7 ng/mL BPA)
-1.01 (-4.16, 2.25) -0.60 (-1.81, 0.63) 3.53 (-12.81, 22.94)
Quartile 3 (2.8 to 5.3 ng/mL BPA)
0.63 (-2.77, 4.14) -0.94 (-2.13, 0.27) -2.04 (-17.05, 15.67)
Quartile 4 (5.4 to 193 ng/mL BPA)
0.85 (-3.10, 4.95) 0.53 (-0.84, 1.92) -4.97 (-18.98, 11.47)
1554-P
POSTERS
Epidemiology/
Genetics
Association of Differential White Blood Cell Count With Insulin Resistance and β-Cell Dysfunction—The PROMISE Cohort
CHRISTINE C. LEE, STEWART B. HARRIS, RAVI RETNAKARAN, HERTZEL C. GERSTEIN, BRUCE A. PERKINS, BERNARD ZINMAN, ANTHONY J. HANLEY, Toronto,
ON, Canada, London, ON, Canada, Hamilton, ON, Canada
Higher white blood cell count (WBC) is associated with incident type
2 diabetes (T2DM), but little is known on the role of differential WBC in
insulin resistance and β-cell dysfunction. We examined the cross-sectional
associations of granulocytes, lymphocytes and monocytes with insulin
resistance and β-cell dysfunction in 712 non-diabetic participants in
the PROMISE (Prospective Metabolism and Islet Cell Evaluation) cohort.
Differential WBCs were measured in fasting samples with granulocytes
consisting of basophils, neutrophils and eosinophils. Insulin resistance was
measured by Matsuda’s insulin sensitivity index (ISOGTT) and homeostasis
model assessment of insulin resistance (HOMA-IR), while β-cell dysfunction
was measured by insulinogenic index (IGI) divided by HOMA-IR (IGI/IR) and
Insulin Secretion Sensitivity Index-2 (ISSI-2). We used multiple regression
models to examine the association of each WBC subtypes with outcome
measures, adjusting for demographics, smoking, family history of diabetes
and BMI. All WBC subtypes were inversely associated with ISOGTT (β= -0.12
[-0.15, -0.080] for granulocytes, β= -0.24 [-0.32, -0.16] for lymphocytes, β=
-0.67 [-0.99, -0.34] for monocytes), and positively associated with HOMA-IR
(β= 0.11 [0.070, 0.14] for granulocytes, β= 0.22 [0.14, 0.30] for lymphocytes,
β= 0.66 [0.33, 0.99] for monocytes, all p<0.001). Granulocytes and
lymphocytes were inversely associated with ISSI-2 (β= -31.3 [-51.3, -11.3], β=
-84.4 [-128, -40.5] respectively, all p<0.001). An initial significant association
of monocytes with ISSI-2 was no longer significant after adjusting for BMI
(β= -20.1 [-199, 159]). WBC subtypes were not associated with IGI/IR. In
conclusion, granulocytes and lymphocytes were independently associated
with insulin resistance, but association with β-cell dysfunction could not
be confirmed. Our data is consistent with the literature on the link between
inflammation and metabolic disorders for T2DM.
Supported by: Case Western Reserve University (to M.B.K.); NIH (U01-HL-103622
to M.B.K.)
1556-P
Cognitive Function and the Risk for Diabetes among Young Men
GILAD TWIG, ISRAEL GLUZMAN, AMIR TIROSH, GAL YANIV, ARNON AFEK, ARI
SHAMISS, ESTELA DERAZNE, DORIT TZUR, BARAK GORDON, EYAL FRUCHTER,
TALI CUKIERMAN-YAFFE, Ramat Gan, Israel, Boston, MA, Tel Hashomer, Israel, Tel
Aviv, Israel
Objective: The association between cognitive function within normal
range and the risk for diabetes among young men is unknown. Research
Design & Methods: General Intelligence Score (GIS) was assessed by a
9-point scale among men that were part of the MELANY cohort of the Israeli
Defense Forces between January 1st 1995 and December 31th 2010. GIS was
assessed at the age of 17.4 years and was based on language ability and
intellectual performance (>80% correlation with the Wechsler IQ scale).
Excluded were participants with a history of diabetes or those with a follow
up shorter than 2 years, yielding a total of 35,500 men that were included
in final analysis.
Results: During 220,265 person-years of follow-up, 770 new cases of
diabetes were diagnosed. A multivariate model adjusted for age, BMI,
family history of diabetes, physical activity, socioeconomic status, smoking,
education level, birth country, country of origin, triglyceride level and WBC
count revealed a 10.7% increase in incident diabetes for every unit decrement
in GIS (p<0.001). Cox proportional hazard functions for the latter multivariable
model is shown in figure 1a. General linear models showed that the onset of
diabetes was different between the groups; the onset of diabetes among
the highest GIS group was delayed by 2.03 years (95%CI=0.042-4.033 years,
p=0.042) as compared to the lowest GIS (Fig. 1b).
Conclusions: Cognitive function that is well within the normal range is an
independent risk factor for diabetes in young men.
Supported by: CDA
&
For author disclosure information, see page 829.
A406
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—OTHER
1558-P
Association between Colchicine Use and Risk of Incident Diabetes
among Veterans With Gout
Supported by: Talpiot Medical Leadership Program
Supported by: Takeda Pharmaceuticals U.S.A., Inc.
1557-P
1559-P
Rates and Costs of Severe Hypoglycemic Events in Type 2 Diabetes
in the United States: Findings from a Systematic Literature Review
and Electronic Health Records
The Ethiopian Experience With Diabetes after Immigration to Israel
ANAT JAFFE, ANNE E. SUMNER, SHMUEL M. GIVEON, Hadera, Israel, Bethesda,
MD, Tel Aviv, Israel
MICHAEL L. GANZ, YINGXIN XU, NEIL S. WINTFELD, QIAN LI, YUAN-CHI LEE,
MICHAEL J. BYRNES, AJIBADE O. ASHAYE, ELYSE GATT, JOANNA C. HUANG,
Lexington, MA, Princeton, NJ
Mass migration of Jewish Ethiopians to Israel began abruptly in 1984. On
arrival in Israel, undernourishment was common and type 2 diabetes (DM)
occurred in <1% of immigrants. Years after arrival in Israel and with exposure
to urban-industrial lifestyles, DM is now common in Ethiopian Israelis. It is
unknown if the long term consequences of DM differ in Ethiopians vs. other
Israelis. From 2003 to 2012, a prospective study of 223 diabetic Israelis (34%
Ethiopian, 44% male, age 62±13y, mean±SD) receiving health care at the
Clalit Health Services, the largest HMO in Israel, was undertaken. By 2 to
1 non-Ethiopians were matched to Ethiopians by age and sex. Compared
to non-Ethiopian Israelis, Ethiopian Israelis had shorter citizenship period
(15±3 vs. 40±13y, P<0.01), shorter duration of DM (5±4 vs. 10±8y, P<0.01),
lower BMI (24.8±4.0 vs. 30.2± 5.0, P<0.05), lower rate of smoking (3% vs.
52%, P<0.01) and less volitional physical activity (15% vs. 42%, P<0.01). In
addition, at baseline and 10y, compared to non-Ethiopians, Ethiopians had
less hypertension and less dyslipidemia. Furthermore after 10y of follow-up,
Ethiopian diabetic Israelis were more healthy than non-Ethiopian diabetic
Israelis because Ethiopians had less neuropathy, nephropathy, retinopathy,
ischemic heart disease and peripheral vascular disease. In addition, the 10y
death rate was lower in Ethiopians than non-Ethiopians (13% s. 36%, P<0.01).
Determinants of less severe diabetic complications in Ethiopians vs. other
Israelis include: healthier lifestyle prior to immigration, less smoking, lower
BMI, migration selectivity , and possibly a lower genetic risk profile. It is a
key goal in Israel to maintain the best possible health in future generations
of Ethiopians born in Israel.
Severe hypoglycemic (SH) events have frequently been assessed, but
few reports have focused on basal insulin-treated type 2 diabetes (T2D)
patients. To study real-world rates and costs of SH in this population we
conducted two complementary studies: a systematic literature review and
an analysis of adults with T2D initiating basal insulin in 2008-2011 using a
major electronic health records (EHR) database. The EHR included physician
and hospital encounters and laboratory test results. Because we used
medical records data, we defined SH events based on diagnosis codes and
blood glucose measurements ≤40 mg/dL. The systematic review identified
8 studies of the target population (9 patient cohorts) that reported SH
incidence and 9 studies (14 patient cohorts) that reported total SH event
rates. The literature showed median incidence and total SH event rates of
6.5 and 16.5 per 100 patient-years, respectively. These results were similar to
those of the EHR analysis where the incidence and total SH event rates were
5.0 (95% confidence interval [CI]: 4.5-5.3) and 9.3 (95% CI: 8.6-10.0) per 100
patient-years, respectively. Only 3 articles reported SH-related costs, which
ranged from $1,049-$1,678 per event. The average SH event cost derived
from the EHR was similar ($1,891; 95% CI: $1,124-2,657). We also examined
total healthcare costs (SH-related plus all other medical costs) using the
EHR. Due to the variable lengths of follow-up across patients, we analyzed
quarterly, rather than annual costs. Patients with ≥1 SH event had greater
average quarterly healthcare costs, adjusted for patient demographic and
clinical characteristics, including use of metformin, sulfonylureas, and other
OADs, than patients without any SH event ($3,613 [95% CI: $1,196–6,050]
vs. $484 [95% CI: $445–527]; p<0.01). These results suggest that real-world
SH incidence and total event rates and costs among basal insulin-treated
T2D patients are significant.
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A407
POSTERS
This retrospective study aimed to examine the association between
colchicine use and incidence of type 2 diabetes among 27,876 veterans
with gout (ICD-9-CM codes: 274.xx) in Veterans Affairs veterans integrated
services network (VISN 16) with up to 11 years of follow-up. Diabetes
defined by ICD-9-CM codes (250.xx) or any use of anti-diabetic medications
was required to not occur prior to the first recorded gout diagnosis (index
diagnosis). Propensity score (PS) 1:1 matching was employed for 9,965
colchicine users and 17,911 non-colchicine users. The final study sample
was 1,046 pairs of PS matched patients with comparable one-year baseline
variables (all p-values>0.05). Time to the incident diabetes from the index
diagnosis was modeled by Poisson model, Cox Proportional Hazard (PH)
model, and time-varying Cox (PH) model, controlling for one-year baseline
information (e.g., age, gender, race, index year, body mass index, serum
uric acid, anti-gout drug use and healthcare utilization). The duration and
dosage of colchicine were also specified in the models. Among the 1,046
matched pairs, 234 colchicine users and 224 non-colchicine users had
records of incident diabetes (i.e., incidence rates of 38.95 per 1000 patientyears and 39.02 per 1000 patient-years, respectively). In Poisson and Cox
(PH) regressions, the risk of incident diabetes was reduced with increased
duration of colchicine use, but the overall difference across quartiles of
colchicine duration was not statistically significant. In time-varying analysis
with adjustments for confounding factors, the hazard ratio for incident
diabetes among colchicine users was 0.877 (95% confidence interval: 0.6621.163) compared with non-colchicine users. In summary, the trend toward
and moderate reduced risk of diabetes among colchicine users appear to be
associated with an increased duration and dose of colchicine use in patients
with gout. Further studies are warranted to focus on the patients with high
intensity of colchicine exposure.
Epidemiology/
Genetics
LIZHENG SHI, LIYA WANG, YINGNAN ZHAO, QIAN SHI, VIVIAN FONSECA, New
Orleans, LA, Wilmington, DE, Hartford, CT
EPIDEMIOLOGY—OTHER
Physical inactivity is prevalent among middle-aged and older Americans
with diabetes and prediabetes, and this prevalence was decreased by nearly
half in 4 years. Effort to improve and sustain physical activity over time is
urgently needed.
1560-P
Low Eradication Rate of Helicobacter Pylori (HP) in Patients With
Diabetes: A Meta-Analysis
CHIKA HORIKAWA, SATORU KODAMA, SAKIKO YOSHIZAWA, KAZUYA FUJIHARA, RYOKO TAJIMA, YOKO YACHI, AKIKO SUZUKI, OSAMU HANYU, HITOSHI
SHIMANO, HIROHITO SONE, Tsukuba, Japan, Mito, Japan, Niigata, Japan, Tokyo,
Japan
1562-P
The Role of Neighborhood Socioeconomic Status in Racial/Ethnic
Disparities in Type 2 Diabetes
REBECCA S. PICCOLO, ANDRE B. ARAUJO, JOHN B. MCKINLAY, Watertown, MA
Racial/ethnic disparities in type 2 diabetes (T2D) are a major public
health problem with black and Hispanics at a greater risk relative to whites.
The search for contributors to disparities in T2D tends to focus on three
major areas of research: (1) lifestyle and behavioral risk factors, (2) early
biochemical changes, and (3) genetics. We hypothesize two additional,
complementary, contributors to racial/ethnic disparities: (4) individual and
(5) neighborhood level socioeconomic factors.
Participants were drawn from the Boston Area Community Health (BACH)
Survey, a racially/ethnically diverse, longitudinal epidemiologic study of
community-dwelling residents of Boston. Participants’ residential addresses
were geo-coded and merged with neighborhood-level data obtained from
the US Census. Within this cohort, we identified 2732 subjects without
diabetes at baseline who were followed for diabetes incidence. The inperson interview included validated questionnaires on demographics, health
care access/utilization, lifestyles, health status and behaviors, physical
measures, and biochemical parameters.
In age-, gender-, and BMI- adjusted models, black and Hispanic participants were twice as likely to develop T2D over the 7 year study period
(black: OR=2.27, 95% CI [1.30-3.97]; Hispanic: 1.91, [ 1.14-3.18]) versus
white participants. Individual socioeconomic status attenuated these
results considerably (black: OR=1.67, [0.94-2.96], Hispanic: 1.26, [0.73-2.17]).
There were significant differences in the incidence of T2D by neighborhood
(p=0.03) even after adjustment for individual race/ethnicity, age, gender,
BMI and SES.
However, adjustment for neighborhood SES did not attenuate the racial/
ethnic disparities further.
While studies of neighborhood contributions appear promising, their
contribution to disparities remains uncertain. Further, there is a need to identify
specific characteristics of neighborhoods that explain disparities in disease.
POSTERS
Epidemiology/
Genetics
In general, diabetic patients are more resistant to antibiotics than
non-diabetic individuals causing a prolongation of infectious diseases.
However, it is controversial whether diabetes affects the eradication rate
of HP. We conducted a systematic review and meta-analysis to compare the
eradication rate between diabetic and non-diabetic individuals. Electronic
literature searches using Biosis, MEDLINE, Embase, PASCAL, and SciSearch
were conducted for studies on eradication of HP and that presented data
on individuals undergoing eradication treatment for HP and achieving
HP eradication according to the presence of diabetes. The difference in
eradication rate was pooled with a random-effects model. We analyzed
7 eligible studies. The Figure shows the difference in the eradication rate
between those with and without diabetes with the 95% confidence interval
(CI). Overall, patients with diabetes had an 18% lower eradication rate
than non-diabetic individuals (P=0.008). A lower eradication rate was also
observed in 2 studies of type 1 diabetes vs. non-diabetes (-12%, P=0.08) and
4 studies of type 2 diabetes vs. non-diabetes (-25%, P=0.008). Results of this
meta-analysis showed that the eradication rate for HP was lower in diabetic
than in non-diabetic individuals. Therefore, diabetic patients might be at risk
for persistent prolongation of gastrointestinal tract symptoms and at high
risk of gastric cancer, in particular, MALT lymphoma.
Supported by: NIH/NIDDK (U01DK056842), (R01DK080786)
1563-P
Predicting Incident Type 2 Diabetes by Insulin Sensitivity Index using Reclassification
YUKIKO ONISHI, TOMOSHIGE HAYASHI, KYOKO K. SATO, MARGUERITE J. MCNEELY, DONNA L. LEONETTI, STEVEN E. KAHN, WILFRED Y. FUJIMOTO, EDWARD
J. BOYKO, Tokyo, Japan, Osaka, Japan, Seattle, WA
1561-P
Physical Activity in U.S. Adults With Diabetes and Prediabetes,
2006-2010
We sought to determine which insulin sensitivity index best predicted
future type 2 diabetes (T2DM). We followed 398 non-diabetic Japanese
Americans for 10-11 years for the development of T2DM defined by the
American Diabetes Association 1997 criteria using a 75-g oral glucose
tolerance test (OGTT). At baseline we measured the following insulin
sensitivity indices: fasting plasma insulin or C-peptide concentration,
HOMA-IR, QUICKI, fasting insulin/glucose ratio, 2-hr insulin, 2-hour insulin/
glucose ratio, area under the insulin curve for a 2-hr OGTT (AUC insulin),
insulin sensitivity index (ISI) [10000/(fasting glucose x fasting insulin)], 2-hr
ISI [10000/(2-hr glucose x 2-hr insulin)], and indices by Duncan, Stumvoll,
Gutt, Avignon, and Matsuda. We examined which index best improved a
multiple logistic regression model predicting incident T2DM that included
age, gender, family history of T2DM, BMI, and fasting glucose. Improvement
was evaluated by category-free net reclassification improvement (cfNRI)
and integrated discrimination improvement (IDI). There were 84 incident
cases of T2DM. Gutt index (= m/(mean of fasting and 2-hr glucose)/log (mean
of fasting and 2-hr insulin), m = [75,000 + (fasting glucose - 2-hr glucose) x
0.19 x weight]/120) had the highest total cfNIR (0.994), which is the sum
of cfNIR for events (0.548) and cfNIR for nonevents (0.446). Total cfNRI of
the other indices were as follows: 2-hr ISI (0.879), Stumvoll index (0.643),
2-hr insulin (0.607), Avignon index (0.536), fasting C-peptide (0.461), 2-hr
insulin/glucose ratio (0.354), Matsuda index (0.318), AUC insulin (0.259),
fasting insulin (0.253), HOMA IR and Duncan index (0.245), fasting insulin/
glucose ratio(0.229), and ISI and QUICKI (0.20 0). Gutt index also had the
highest IDI (0.135) of all the indices. In conclusion, Gutt index showed the
best risk reclassification and improvement in discrimination of the insulin
sensitivity indices that we evaluated in predicting future T2DM in Japanese
Americans.
PEARL G. LEE, CHRISTINE CIGOLLE, JINKYUNG HA, LILLIAN MIN, CAROLINE S.
BLAUM, WILLIAM H. HERMAN, Ann Arbor, MI
Physical activity (PA) on a regular-basis is essential for diabetes selfmanagement and prevention of diabetes. The objective of this study is to
determine the prevalence of PA and its change over 4 years among adults
with diabetes and prediabetes.
We performed longitudinal analysis of the 2006-2010 waves of the Health
and Retirement Study, a biennial, longitudinal, nationally representative
survey. We limited the analysis to 5,352 respondents aged 53 years and older
who had a measured HbA1c in 2006 and were alive in 2010. All respondents
self-reported the number of days they participated in mild, moderate, and
vigorous levels of physical activities. Mixed effects models were performed
to compare PA changes in 4 years among respondents with normoglycemia
(no diabetes history and HbA1c<5.7%), prediabetes (no diabetes history and
HbA1c 5.7-6.4%), and diabetes (diabetes history or HbA1c ≥ 6.5%).
In 2006. 38% of all the respondents were physically active (at least 150
minutes of moderate level PA per week), including 44%, 38%, and 30% of
respondents with normoglycemia, prediabetes, and diabetes, respectively.
Older age, having less education, and being obese were associated with
being less active. Four years later, the prevalence of all respondents
remaining physically active was decreased by 47%; the prevalence
decreased by 43%, 50%, and 56% for respondents with normoglycemia,
prediabetes, and diabetes, respectively. Respondents with diabetes were
less likely than normoglycemic adults to perform vigorous PA (21% vs. 34%)
but more likely to perform mild level PA (46% vs. 31%). Over 4 years, the odds
of respondents with diabetes performing vigorous or moderate PA was 0.70
times the odds for normoglycemia (p<0.001).
&
For author disclosure information, see page 829.
A408
Guided Audio Tour poster
ADA-Funded Research
1566-P
Sarcopenic Obesity Is Associated With Insulin Resistance and Cardiovascular Risk Factors in Healthy Young Adults
YUNJUAN GU, XUHONG HOU, LEI ZHANG, JIE LI, YUQIAN BAO, WEIPING JIA,
Shanghai, China
HYUN MIN KIM, EUN YOUNG LEE, SUN OK SONG, HANNAH SEOK, JI HYE HUH,
BYUNG-WAN LEE, EUN SEOK KANG, CHUL WOO AHN, HYUN CHUL LEE, BONG
SOO CHA, Seoul, Republic of Korea
The aim of the study was to estimate the risk of cancer and mortality in
Chinese patients with type 2 diabetes mellitus (T2DM).
Based on the Shanghai Diabetes Registry database linking to the
Shanghai Cancer Registry and Surveillance System, a total of 12,276 T2DM
were defined and followed from December 2001 to July 2011. Gender-, and
age-stratified standardized incidence ratio (SIR) and mortality ratio (SMR)
with 95% confidence interval (CI) were calculated using the same regional
population as reference.
The overall cancer risk was found significantly increased with an SIR of
3.14 (2.73-3.56) and 4.29 (3.64-4.94) in both male and female, respectively.
As for site-specific cancers, risks of lung cancer, colorectal cancer, gastric
cancer, liver cancer and pancreatic were significantly elevated with SIRs of
1.74 (1.13-2.34), 3.93 (2.61-5.24), 3.13 (2.06-4.21), 3.86 (2.43-5.29) and 5.46
(2.69-8.22) in male, 5.71 (3.74-7.69), 2.56 (1.30-3.81), 4.19 (2.25-6.13), 3.56
(1.15-5.97) and 9.00 (4.59-13.41) in female, respectively. Risks of prostate
cancer and breast cancer were significantly increased with an SIR of 5.48
(3.01-7.05) in male and 4.60 (2.90-6.31) in female. Overall cancer mortality
was significantly increased with an SMR of 2.27 (1.86-2.68) and 1.86 (1.462.26) in male and female, respectively. Regarding site-specific cancer
mortality, in male T2DM, risks of gastric cancer, liver cancer and pancreatic
cancer were found significantly increased with SMRs of 2.14 (1.06-3.22),
3.28 (1.85-4.71) and 4.35 (1.88-6.82), respectively. In female T2DM, risks of
lung cancer and pancreatic cancer significantly were increased with SMRs
of 4.90 (2.90-6.90) and 7.76 (3.83-11.69), respectively.
The patients with T2DM have excess risks of cancer and mortality.
Additional cancer screening should be performed in the treatment of
patients with T2DM.
Recently, the clinical significance of sarcopenia or sarcopenic obesity
has been emphasized especially in an elderly population, however, not
sufficiently in a younger population.
This study aimed to investigate the association between body composition
and cardiometabolic parameters in healthy young adults aged 18 to 30
years from KHANES IV conducted in 2009. Sarcopenia was defined as an
appendicular skeletal muscle mass (ASM) divided by weight (%) (ASM/Wt) <
1 SD below the sex-specific mean for young adults. Obesity was defined as a
body mass index (BMI) ≥25 kg/m2. The subjects were further classified into
sarcopenic obesity (SO), nonsarcopenic obesity, sarcopenic nonobesity, and
nonsarcopenic nonobesity groups based on both ASM/Wt and BMI.
A total 1001 subjects (460 men and 541 women; mean age 25.1 ± 3.4
years) were analyzed. ASM/Wt was negatively correlated with BMI, waist
circumference, total body fat mass, HOMA-IR, total cholesterol, triglyceride
level, number of components of the metabolic syndrome, and Framingham
risk score in both men and women. The prevalence of SO was 10.4 % in men
and 7.0 % in women. Subjects with SO had a higher blood pressure, a more
atherogenic lipid profile (high triglyceride and low HDL-cholesterol level),
and a greater insulin resistance (high fasting blood glucose, fasting serum
insulin, and HOMA-IR) than any other group. The prevalence of metabolic
syndrome was 28.9 % in SO group which was much higher compared to 1 %
in nonsarcopenic nonobesity group. In contrast to the previous report in an
elderly population, 25-hydroxyvitamin D level was slightly higher in obese
group, however, was not different between subjects with sarcopenia and
those without sarcopenia.
In conclusion, ASM/Wt showed significant negative correlations with
various metabolic parameter and cardiovascular risk factors. And SO group
was more closely associated with insulin resistance and cardiovascular risk
factors even in healthy young adults.
Supported by: National Basic Research Program (2011CB504001)
1565-P
What Fraction of Type 2 Diabetics in the United States Meet the
Recommended Levels of HDL-Cholesterol, One Half or Two Thirds?
1567-P
YITING WANG, ZHONG YUAN, RACHEL WEINSTEIN, PAUL E. STANG, JESSE A.
BERLIN, Titusville, NJ
Prevention of Type 2 Diabetes: A Systematic Review and MetaAnalysis of Different Intervention Strategies
Low HDL cholesterol (HDL-C) and high triglycerides (TG) is the most
prevalent pattern of dyslipidemia in patients with type 2 diabetes (T2D). A
study using the National Health and Nutrition Examination Surveys (NHANES)
reported that 69.0% and 63.9% of diabetics met the recommended levels of
HDL-C (>40 mg/dl in men and >50 mg/dl in women) in the 2005-2006, and
2007-2008 surveys, respectively. However, the study used a complete-case
approach to missing data-restricting analyses only to respondents who had
complete data for all lipids.
We pooled data from the NHANES 2007-2008 and 2009-2010 cycles and
estimated the percent of T2D meeting the recommended levels of HDL-C.
T2D was defined as self-reported diagnosis at age≥ 30 , without initiation of
insulin therapy within 1 year of diagnosis. Missing data for the lipids were
handled in 2 ways: “all-available” approach included all respondents with
data for any individual lipid; and the complete-case approach. Percentage
estimates accounted for the complex sampling design of NHANES, and were
age-adjusted to the US 2000 Census population.
From a total of 20,686 respondents, 1,248 were identified as T2D; 1,114
(89.3%) and 507 (40.6%) were included in the all-available and completecase analysis of HDL-C, respectively. T2D included in complete-case
analyses had significantly (p<0.001) higher HDL-C (mean 50.1, SD 13.3), and
lower TG (mean 143.2, SD 68.1) than those excluded (HDL mean 46.5, SD
14.2; TG mean 395.6, SD 442.6).
When age-adjusted, 46.9% of T2D (95% CI 36.5%-57.2%) met the
recommended levels of HDL-C using the all-available approach compared
with 67.2% (95% CI 52.9-81.5%) using the complete-case approach.
These results suggest a larger therapeutic concern than previously
appreciated. The marked difference was mainly driven by exclusion of
subjects with low HDL-C and high TG levels in the complete-case analysis.
The assumption of data missing at random can substantially impact results
and must be carefully examined.
ALBERTO MORABITO, CLAUDIA MERLOTTI, ANTONIO E. PONTIROLI, Milan, Italy
ADA-Funded Research
&
Different intervention strategies can prevent new cases of type 2 diabetes
(T2DM). Aim of the present systematic review and meta-analysis was to
evaluate the effectiveness of different strategies. Studies were grouped
into 15 different strategies: 1: diet plus physical activity; 2: physical activity;
3-6: anti-diabetic drugs [glitazones, metformin, beta-cell stimulating drugs
(sulphanylureas, glinides), alfa-glucosidase inhibitors]; 7-8: cardiovascular
drugs (ACE-inhibitors*, ARB**, calcium-antagonists); 9-14 [diets, lipidaffecting drugs (orlistat, bezafibrate), vitamins, micronutrients, estrogens,
alcole, coffee]; 15: bariatric surgery. Only controlled studies were included
in the analysis, whether randomized or non-randomized, and whether
intentional interventions or post-hoc analysis (groups 7 and 8). Appropriate
methodology (PRISMA statement) was used. Seventy-one studies (490,813
subjects), published in english language as full papers, were analysed to
identify predictors of new cases of T2DM, and were included in a metaanalysis (random-effects model) to study the effect of different strategies.
Intervention effect (new cases of diabetes) was expressed as odds ratio (OR),
with 95% confidence intervals (CIs). Body mass index was in the overweight
range for 13 groups, obese or morbidly obese in groups 9 and 15. All nonsurgical strategies, except for beta-cell stimulating drugs, estrogens, and
vitamins, were able to prevent T2DM, with different effectiveness from 0.37
(0.26,0.52) to 0.85 (0.77,0.93); Multiple comparisons were not possible, but
bariatric surgery was the most effective strategy [0.16 (0.11,0.24)]. These
data indicate that several, but not all strategies, prevent T2DM; bariatric
surgery was the most effective measure, indicating it as an adequate
strategy for morbidly obese subjects.
*ACE = angiotensin converting enzyme; **ARB = angiotensin receptor
blockers
For author disclosure information, see page 829.
Guided Audio Tour poster
A409
POSTERS
1564-P
Increased Cancer and Mortality in Patients With Type 2 Diabetes: A
10-Years Cohort Study in Shanghai, China
Epidemiology/
Genetics
EPIDEMIOLOGY—OTHER
EPIDEMIOLOGY—OTHER
1568-P
1570-P
Do Sex Steroid Levels Influence Response to Weight Loss Interventions in Postmenopausal Women in the Diabetes Prevention Program (DPP)?
Prevalence and Correlates of Diabetes among South Asians: Results from the MASALA Study
ALKA M. KANAYA, KIANG LIU, SWAPNA DAVE, SHWETA SRIVASTAVA, YASIN
PATEL, FAREEHA QURESHI, NAMRATHA KANDULA, San Francisco, CA, Chicago, IL
POSTERS
Epidemiology/
Genetics
CATHERINE KIM, ELIZABETH L. BARRETT-CONNOR, JOHN F. RANDOLPH,
SHENGCHUN KONG, BIN NAN, KIEREN J. MATHER, SHERITA H. GOLDEN, FOR
THE DIABETES PREVENTION PROGRAM, Ann Arbor, MI, San Diego, CA, Indianapolis, IN, Baltimore, MD
South Asians (SA) are the second fastest growing ethnic group in the US
with approximately 3 million residents. SA have disproportionately high type
2 diabetes prevalence, but few studies have assessed glucose tolerance and
measured sociocultural behaviors.
We conducted a population-based study of SA between ages 40-84
without known cardiovascular disease. We obtained demographic, lifestyle
and cultural information, conducted fasting and 2-hour glucose tolerance
tests, physical examination, carotid ultrasound for intima media thickness
and cardiac CT scan for coronary artery calcium (CAC). We created separate
logistic regression models to examine covariates associated with prediabetes (fasting glucose 100-125 mg/dl and/or 2-hour post-challenge
glucose 140-199 mg/dl) and diabetes (fasting glucose ≥126 mg/dl, 2-hour
glucose ≥200 mg/dl and/or diabetes medication use).
Of 810 (42% women) SA, mean age was 55±9, and 98% were immigrants
living a median 27±11 years in the US. Mean BMI was 26±4 kg/m2; the
prevalence of pre-diabetes was 30% and diabetes was 25%. The table
shows covariates associated with each glycemic state.
Similar metabolic covariates were associated with both pre-diabetes and
diabetes among South Asians. A cultural variable, frequency of fasting, was
associated with increased odds of pre-diabetes. Prospective follow-up of
this cohort will determine whether fasting is predictive of incident diabetes
as this may be a potentially modifiable risk factor.
Prior studies have suggested that estrogen therapy leads to weight
reductions in postmenopausal women. We examined whether estrogen use
potentiates weight loss interventions via sex steroid levels and whether
endogenous sex steroid levels predict response to weight loss interventions
among women who do not use estrogen.
The DPP was a randomized trial of the impact of an intensive life-style
intervention (ILS) or metformin upon diabetes incidence in glucose intolerant
adults. This secondary analysis examines postmenopausal women who did
(n=324) or did not (n=382) use oral estrogen at baseline and 1 year. Main
outcome measures were associations between baseline sex hormones and
changes in weight and waist circumference (WC) by study arm. β-coefficients
(sβ) were standardized by 1 standard deviation for each hormone.
Among women not using estrogen, only higher baseline E2 was associated
with weight loss only in the metformin arm, but not the ILS arm, even after
adjustment for baseline weight, age, and race/ethnicity (sβ =-2.1, p=0.01).
Among estrogen users, lower DHEA, but not E2, was associated with
greater weight loss among women in the ILS arm, but not the metformin
arm, even after adjustment for baseline weight, but this association was
weakened after adjustment for age and race/ethnicity (sβ 1.0, p=0.06). Sex
steroid levels were not associated with reductions in WC among estrogen
users or non-users in the ILS or metformin arms.
Among postmenopausal glucose-intolerant women who used estrogen,
baseline sex steroid levels were not associated with response to weightloss interventions, suggesting that exogenous estrogen does not potentiate
weight loss interventions by altering actual serum levels. In contrast, among
women who did not use estrogen, higher baseline E2 levels were associated
with greater weight loss among metformin users.
Pre-diabetes model
OR (95% CI)
Age, per year
1.02 (1.00 – 1.05)
Sex, reference group: male
0.76 (0.49 – 1.18)
Family history of DM
1.61 (1.09 – 2.37)
Hypertension (≥140/90 mmHg or medication use) 1.61 (1.04 – 2.48)
Waist circumference, per cm
1.03 (1.01 – 1.06)
Total cholesterol, per mg/dl
—
HDL cholesterol, per mg/dl
—
Triglycerides, per mg/dl
1.01 (1.00 – 1.01)
Ln (CAC + 1)
1.14 (1.03 – 1.27)
Fasting practice, reference: never fasts
Fasts 1-3 times/week
1.76 (0.95 – 3.28)
Fasts 1-2 times/month
0.40 (0.17 – 0.92)
Fasts < once per month
0.84 (0.42 – 1.69)
Fasts approximately once per year
0.89 (0.54 – 1.46)
Supported by: U01DK048489; R01DK083297; K23DK071552
1569-P
WITHDRAWN
Diabetes model
OR (95% CI)
1.03 (1.00 - 1.06)
1.02 (0.60 - 1.74)
3.15 (1.96 – 5.07)
3.54 (2.10 – 5.97)
1.04 (1.01 - 1.07)
1.04 (1.02 – 1.07)
0.95 (0.93 – 0.97)
—
1.19 (1.06 – 1.32)
—
Supported by: NIH/NHLBI (5R01HL093009)
1571-P
Lower Blood Volume in the Pulmonary Vasculature Is Associated
With Diabetes
GREGORY L. KINNEY, JENNIFER BLACK-SHINN, SHARON LUTZ, RAUL SAN JOSÉ
ESTÉPAR, GEORGE WASHKO, JOHN E. HOKANSON, Aurora, CO, Boston, MA
Diabetes damages organ systems primarily through increased inflammation
and disrupted glycemic control. The effects of diabetes on the lung have been
of interest for decades but the modest reduction in pulmonary function and its
non-progressive nature have limited investigation into its cause. One of the
primary candidates is reduction in diffusing capacity due to reduced pulmonary
capillary blood volume. This study reports the results of CT measurement of
pulmonary blood volume comparing individuals with and without diabetes.
One hundred four smokers with at least 10 pack years smoking history and
no obstructive lung disease were recruited from the COPDGene study, mean
age 57 ± 10. Ten participants reported diabetes and 94 did not. None of the
participants without diabetes reported use of insulin or insulin sensitizing
agents. Intraparenchymal pulmonary vessels were automatically segmented
and measured from a CT scan of the chest. Total Blood Vessel Volume (TBV)
and the aggregate vessel volume (BV) for all vessels was calculated in
increments of 5mm2 cross section area (CSA) ranging from ≤ 5mm2 through
90mm2. BV at each increment was divided by TBV and expressed as %
TBV and these values were compared by diabetes status. P values were
calculated at each increment using Mann-Whitney U.
Participants with diabetes were older, reported more pack years of
smoking, and did not differ by sex or BMI. They showed reduced pulmonary
function (FEV1 2.5 vs 3.01, p=0.002 and FVC 3.2 vs 3.9, p=0.001) but no
&
For author disclosure information, see page 829.
A410
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—OTHER
NNT of 77 (to eliminate one MACE event over 10 years). The results provide
support that the current ADA standard for SBP treatment in the general
population with T2D would result in significantly lower rates of major CV
events at clinically relevant levels of NNT. Large scale prospective clinical
trials would be required to confirm these findings.
difference in bronchodilator response, total lung capacity or % emphysema.
BV in the smallest vessels (≤5mm2 CSA) was significantly reduced in
participants with diabetes (53% vs 57% p=0.02) and increased in all vessels
> 40mm2 where 4 of 10 comparisons were significant at p <0.05.
To our knowledge this is the first study to show reduced pulmonary blood
volume in vessels < 5mm2 (CSA) with concomitant echo of volume in the
largest vessels. Reduced blood volume may play an important role in the
reduced pulmonary function seen in diabetes.
1574-P
Diabetes, Diabetes Risk Factors and Treatments, and Breast Cancer
Supported by: U01HL089856, U01HL089897
To clarify the potential association between diabetes, related factors,
treatments and breast cancer risk, a series of meta-analyses was carried
out following PRISMA guidelines.
For breast cancer at all ages, the risks obtained from prospective
studies were: diabetes (SRR=1.27, 95% CI (1.16, 1.39); physical activity
(SRR=0.88 (0.85,0.92)); glycaemic load (SRR=1.05, (1.00, 1.10)); glycaemic
index (SRR=1.05,(1.00, 1.09)); fasting glucose (SRR=1.14, (0.94, 1.37));
serum insulin(SRR=1.11, (0.75, 1.85)); c-peptide (SRR=1.00, (0.69, 1.46))
and adiponectin (SRR=1.16, (0.93, 1.46. An increase of 5 units in BMI was
associated with post-menopausal breast cancer (SRR=1.12, 95% CI (1.08,
1.16)) but not at pre-menopausal ages (SRR=0.83, 95% CI (0.72, 0.95)). Serum
insulin and c-peptide were associated with breast cancer at post-menopausal
ages but not at pre-menopausal. For IGF-1, Hodge’s Standardised Mean
Difference (HSMD) was calculated and there was no significant association
with breast cancer (HSMD=0.026, 95% CI (-0.031, 0.084).
The SRR for breast cancer among users of insulin glargine was 1.08 (0.98,
1.20) and was 0.92 (0.32, 2.65) when restricted to randomized trials. Among
new users, the SRR for breast cancer was 1.09 (0.98, 1.21) and there was
no trend of increasing breast cancer risk with increasing duration of use
of glargine (β=0.04)(p=0.52). Risk of breast cancer in a prospective cohort
declined with increasing follow-up, from 1.99 (1.31, 2.03) with two years of
follow-up, to 1.60 (1.10, 2.32) with 3 years, 1.50 (1.10, 2.10) with four years
and 1.18 (0.84, 1.66) with five years of follow-up. There is no reduction in risk
of breast cancer associated with metformin use (SRR=0.96, 95% CI (0.85,
1.08)) even for the longest duration of use (SRR=0.94, 95% CI (0.81, 1.09)).
An association between these two common diseases could have
important implications for public health with common risk factors driving
further increases in both diseases yet holding the tantalizing possibility for
prevention of both.
KIMBERLY G. BRODOVICZ, ZHIWEN LIU, SAMUEL S. ENGEL, CHARLES M. ALEXANDER, CYNTHIA J. GIRMAN, North Wales, PA, Rahway, NJ
Psoriasis affects 1-4% of the adult population and patients with psoriasis
are 20-40% more likely to develop type 2 diabetes (T2DM) than patients
without psoriasis. This study in 3 administrative databases examined the
prevalence of psoriasis in patients with T2DM and without diabetes. Psoriasis
prevalence was estimated using an electronic medical records database from
the UK (Clinical Practice Research Datalink, CPRD, Jan 2003-Oct 2011) and
2 US insurance claims databases (Clinformatics DataMart, OptumInsight™,
Jan 2003-Dec 2011 and Humana Medicare Advantage Plan, Jan 2007Jan 2011). CPRD data included patients aged ≥25 yrs; OptumInsight data
included patients aged 25-64 yrs; Humana data included patients aged ≥65
yrs. Patients with ≥12 months of continuous enrollment were included. The
index date was the date of first record in the study period of a T2DM defining
event (diagnosis code, antihyperglycemic prescription, or laboratory result)
or, for patients without diabetes, the date of the first record in the study
period meeting entry criteria. Psoriasis (by diagnosis code) prevalence in the
year before the index date was estimated. Roughly 1% of the population in
each database had a psoriasis diagnosis (table). Across all 3 databases, the
proportion of patients with T2DM and a psoriasis diagnosis was twice that
of patients without diabetes, with 1.3-2.7% of patients with T2DM having a
psoriasis diagnosis (table). The apparently increased prevalence of psoriasis
in T2DM warrants further investigation.
Total Population
with psoriasis
Patients with T2DM
with psoriasis
Patients without diabetes
with psoriasis
CPRD
4,779,111
63,812 (1.3%)
285,542
7,724 (2.7%)
4,493,569
56,088 (1.2%)
OptumInsight Humana MAPD
4,300,715
1,736,442
46,486 (1.1%) 15,967 (0.9%)
1,406,104
586,483
22,280 (1.6%) 7,456 (1.3%)
2,894,611
1,149,959
24,206 (0.8%) 8,511 (0.7%)
1575-P
Factors Associated With Untreated Diabetes: The Japanese National Health and Nutrition Survey
MAKI GOTO, ATSUSHI GOTO, NAYU IKEDA, HIROYUKI NODA, KENJI SHIBUYA,
MITSUHIKO NODA, Tokyo, Japan, Osaka, Japan
1573-P
Clinical Implications of Changing ADA Guidelines for Systolic Blood
Pressure (SBP) Management: A Modeling Analysis
Currently, a large number of individuals with diabetes do not receive
treatment in Japan. We used data from the Japanese National Health and
Nutrition Survey, 2005-2009, to examine factors associated with untreated
diabetes. Excluding individuals aged less than 20 years and pregnant
women, 40,431 participants were included in the analysis. Diabetes was
defined as a diagnosis of diabetes, HbA1c (NGSP) ≥ 6.5%, fasting plasma
glucose ≥126 mg/dL, or casual glucose ≥ 200 mg/dL. Diabetic participants (n
= 5,043) tended to have a higher age and body mass index (BMI) (kg/m2) than
non-diabetic participants; 2,245 were currently being treated for diabetes,
whereas, 2,798 were not. The untreated participants had lower HbA1c than
the treated participants (6.6% vs 7.3%; P < 0.001). However, in a subgroup
analysis restricted to participants with higher HbA1c (≥ 7.0%), untreated
participants had higher HbA1c than the treated participants (8.6% vs 8.1%; P
< 0.001). We also conducted multiple logistic regression analysis to examine
factors associated with untreated diabetes among diabetic participants. We
included covariates such as sex, age (year), BMI, exercise habits (yes/no),
and smoking history (never, past, or current). We found that age (odds ratio =
0.97 [95% confidence interval = 0.96-0.97]), BMI (0.96 [0.95-0.98]), and
exercise habits (0.76 [0.65-0.87]) were inversely associated with untreated
diabetes. Additionally, in a subgroup analysis restricted to higher HbA1c, sex
(male vs female; 1.34 [1.01-1.79]), age (0.96 [0.95-0.97]), and exercise habits
(0.77 [0.60-0.97]) were associated with untreated diabetes. In conclusion,
our findings indicate that many untreated diabetic participants had poor
glycemic control; further, younger age, male gender, lower BMI, and physical
inactivity may be factors related to untreated diabetes. Promoting an
environment that leads individuals to consult a doctor may be important
especially among younger, lean, or physically inactive population.
BETH D. MITCHELL, SARAH WARD, BRAD CURTIS, DAVID R. NELSON, DAVID M.
KENDALL, Indianapolis, IN
The ADA has provided guidelines recommending a SBP goal of <130 (all
values mmHg) as appropriate for the majority of patients with type 2 diabetes
(T2D). This recommendation has been challenged as the ACCORD trial found
that targeting SBP <120 in T2D patients at high risk for cardiovascular (CV)
events provided no additional benefit in reducing CV risk although resulted
in a significant reduction in the risk of stroke. The aim of this analysis was
to compare the impact of lowering SBP levels from those observed in a
community population with type 2 diabetes (NHANES with mean SBP of
>140), as compared to achieving SBP targets of <120 or <130 on rates of
major CV events. In order to provide a broader perspective than that derived
from the ACCORD trial, we utilized the Archimedes Model to simulate
10,000 virtual patients, performed to estimate rates of major adverse
coronary events (MACE), myocardial infarction (MI), and stroke. Output from
each simulation included the number of CV events (95% CI) for individuals
receiving (1) current care of SBP as observed in NHANES (mean SBP of 151)
(2) achieving SBP targets of <130 or (3) achieving SBP targets of <120. The
simulated population (45% male) had a mean age of 61.0 yrs, and baseline
HbA1c of 7.5 %. As compared to the current SBP achieved in the NHANES
population, lowering mean SBP to < 130 in all patients would result in an
additional 24% relative risk reduction (RRR) in MACE, while lowering to < 120
achieved a 30% RRR. Therefore a strategy aimed at reducing SBP to <130
would require a number needed to treat (NNT) of 21 (to eliminate 1 MACE
event over 10 years), while further lowering SBP from <130 to <120 results in
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A411
POSTERS
1572-P
Prevalence of Psoriasis in Patients With Type 2 Diabetes
Epidemiology/
Genetics
PETER BOYLE, ALICE KOECHLIN, CHRIS ROBERTSON, MARIA BOTA, MATHIEU
BONIOL, DEREK LEROITH, GEREMIA B. BOLLI, JULIO ROSENSTOCK, PHILIPPE AUTIER, Lyon, France, Glasgow, United Kingdom, New York, NY, Perugia, Italy, Dallas, TX
EPIDEMIOLOGY—OTHER
the presence of HP infection worsened glycemic control in patients with
diabetes.
1576-P
Factors Influencing Time to Case Ascertainment in Youth With Type
1 (T1D) and Type 2 Diabetes (T2D) in the SEARCH for Diabetes in
Youth Study
TESSA L. CRUME, RICHARD F. HAMMAN, SCOTT ISOM, JASMIN DIVERS, ELIZABETH MAYER-DAVIS, WENZE ZHONG, SHARON H. SAYDAH, DEBRA A. STANDIFORD, JEAN M. LAWRENCE, CATHERINE PIHOKER, DANA DABELAA, Aurora,
CO, Winston-Salem, NC, Chapel Hill, NC, Atlanta, GA, Cincinnati, OH, Pasadena, CA,
Seattle, WA
1578-P
The Association of Leg Length With Metabolic Abnormalities Underlying Type 2 Diabetes Mellitus: The PROMISE Cohort
LUKE W. JOHNSTON, STEWART B. HARRIS, RAVI RETNAKARAN, HERTZEL C.
GERSTEIN, JILL K. HAMILTON, BERNARD ZINMAN, ANTHONY J. HANLEY, Toronto, ON, Canada, London, ON, Canada, Hamilton, ON, Canada
Although shorter leg length (LL), a marker of early childhood deprivation,
has been linked with increased risk of type 2 diabetes mellitus (DM), there
is limited data regarding LL and the metabolic change underlying DM. Our
aim was to study the association of LL with insulin resistance (IR) and β-cell
dysfunction.
Height and sitting height were measured on 524 non-diabetic subjects in
the PROMISE cohort to calculate LL and leg-to-height ratio (LHR). Glucose
and insulin were measured during an oral glucose tolerance test. IR was
assessed using HOMA-IR and the Matsuda insulin sensitivity index (ISI).
The insulinogenic index over HOMA-IR (IGI/IR) and the Insulin Secretion
Sensitivity Index 2 (ISSI-2) was used to evaluate β-cell function. Linear
regression models were adjusted for age, sex, ethnicity, family history of
diabetes, waist, and weight.
LL and LHR were significantly associated with HOMA-IR (β = -0.03 (SE
0.007), β = -8.97 (2.01), respectively) and ISI (β = 0.027 (0.007), β = 6.77
(2.02), respectively, all p < 0.001) after full adjustment. LHR was significantly
associated with ISSI-2 (β = 2.87 (1.3), p = 0.027), but not with IGI/IR (β = 5.95
(3.1), p = 0.056). Interaction analyses indicated that increased LL significantly
modified the detrimental effect of higher waist size on IR (p < 0.009; Figure).
Shorter legs were associated with greater IR and β-cell dysfunction,
suggesting that early childhood deprivation may increase the risk of
developing DM.
POSTERS
Epidemiology/
Genetics
A sustainable diabetes surveillance system for U.S. youth (age 0-19 years)
requires us to better understand case ascertainment. Using the SEARCH for
Diabetes in Youth registry, we examined the relationship between time from
diabetes diagnosis to case identification/registration and how it differed by
diabetes type (T1D, T2D), demographics (age and race/ethnicity) and type of
diabetes provider. We included all 2002-2007 incident cases of T1D (n=6181)
and T2D (n=1611) among youth aged 0-19 years registered by the SEARCH
study. Plots for time from diagnosis to registration were developed and
differences by core variables were examined using the Wilcoxon test. We
found that it took 2.5 times longer to identify the median number of total
registered T2D cases compared to T1D cases at similar levels of ascertainment
(Figure) (p<0.001). For T1D, a longer time to registration was associated with
older age (15-19 years vs. younger) (p<0.001) and having a primary diabetes
care provider other than an endocrinologist (p<0.001). For T2D, only having a
primary diabetes care provider other than an endocrinologist was associated
with a longer time to case ascertainment (p<0.0001). These patterns likely
reflect US health care delivery’s decentralized nature, the need to identify
multiple providers and hospitals for nearly complete ascertainment, and use
of more specialized care by youth with T1D than those with T2D.
Supported by: CDC
1577-P
Effect of Helicobacter Pylori (HP) Infection on Glycemic Control in
Patients With Diabetes: A Meta-Analysis
SAKIKO YOSHIZAWA, SATORU KODAMA, RYOKO TAJIMA, KAZUYA FUJIHARA,
CHIKA HORIKAWA, YOKO YACHI, AKIKO SUZUKI, OSAMU HANYU, HITOSHI
SHIMANO, HIROHITO SONE, Niigata, Japan, Mito, Japan, Tokyo, Japan, Tsukuba,
Japan
It has been hypothesized in several studies that HP infection worsens
glycemic control in patients with diabetes based on the general finding
that chronic infection causes persistent hyperglycemia. However, results of
studies to prove or disprove that hypothesis have been inconsistent. The aim
of this meta-analysis was to compare glycemic control between diabetic
patients with and without HP infection. We searched for studies reporting
the hemoglobin A1c (A1C) level according to the existence of HP infection
using Biosis, MEDLINE, Embase, PASCAL, and SciSearch. Mean difference
in A1C between diabetic patients with and without HP infection was pooled
with a random-effects model. We analyzed 13 eligible studies. The Figure
is a forest plot of mean differences in A1C in those with HP infection vs.
those with HP non-infection with 95% confidence intervals (CIs). Overall,
compared with diabetic patients without HP, those with HP did not have
significantly higher A1C levels (mean difference [95% CI], 0.2% [-0.1-0.5])
(Figure). In the 11 studies that specified the type of diabetes, there were
modest differences in A1C between patients with and without HP (mean
difference [95% CI]: 0.7% [-0.3-1.7] for type 1 diabetes (5 studies); 0.3% [0.00.6] for type 2 diabetes). In conclusion, there was insufficient evidence that
&
For author disclosure information, see page 829.
A412
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—OTHER
1579-P
1581-P
Recent Trends in Breastfeeding Initiation Rates among Women
With and Without Diabetes during Pregnancy, 2006-2011
Smoking Cessation in Relation to Weight, Glycemic Control, Blood
Pressure, and Lipid Levels in Patients With Type 2 Diabetes: The
Japan Diabetes Outcome Intervention Trial-2-LT Study
REENA OZA-FRANK, Columbus, OH
National data indicate recent increases in rates of breastfeeding initiation.
Whether these increases are consistent among women with diabetes, who
have been shown to have lower rates, is unknown. Ohio birth certificate
data from 2006-2011 were used to determine trends in breastfeeding at
discharge by diabetes status (no diabetes [NDM], gestational diabetes
mellitus [GDM], or prepregnancy diabetes mellitus [PDM]). Logistic models
were built, using year as an ordinal variable and adjusting for mother’s sociodemographic and relevant clinical variables, to determine significant trends
over time. Among 807,466 births in Ohio from 2006-2011, 5.5% of women
had GDM and 0.8% had PDM. Rates of breastfeeding increased among NDM
and PDM, however, rates among PDM were consistently lower than NDM or
GDM (Table). Despite similar rates to NDM prior to 2011, rates among GDM
increased through 2010 and declined in 2011 to a rate lower than NDM or
PDM. Contrary to previous literature, GDM women had breastfeeding rates
as high as or even higher than NDM women in most years, whereas PDM
rates were the lowest. Future studies on breastfeeding should differentiate
between GDM and PDM. Despite increases in Ohio breastfeeding rates
in some subgroups, rates were lower than the national average (77%)
and Healthy People 2020 goals (82%). Additional efforts to increase
breastfeeding initiation rates in Ohio, especially among women with PDM,
are necessary to meet national goals.
Table. Trends in Breastfeeding at Discharge by Diabetes Status, Ohio 20062011
2006 2007 2008 2009 2010 2011
No diabetes**
62.5 63.1 64.2 65.0 67.2 69.1
Gestational diabetes**
63.0 64.0 65.3 65.7 67.4 61.1
Prepregnancy diabetes*
60.0 59.3 60.2 58.2 64.5 62.3
P for trend: *p<0.001; **p<0.0001
1582-P
1580-P
Assessing the Phenotypic Extremes of Type 2 Diabetes in the UK
Biobank Study of 500,000 Individual
Status of Diabetes-Related Preventive Care Practices among U.S.
Adult Caregivers With Diabetes, 2009
JESSICA S. TYRRELL, MICHAEL N. WEEDON, TIMOTHY M. FRAYLING, Truro,
United Kingdom, Exeter, United Kingdom
PYONE CHO, LINDA S. GEISS, ISRAEL HORA, Atlanta, GA
Managing one’s own diabetes and living well with the disease is difficult.
However, the growing prevalence of diabetes in middle-aged and older
adults means that many people with diabetes have to take care of a loved
one with poor health, potentially disturbing their own preventive care
routines. To determine the impact of caregiving on diabetes management,
we analyzed responses from the 2009 Behavioral Risk Factor Surveillance
system diabetes module and assessed the status of preventive care
practices (annual doctor’s visit, A1C testing, dilated eye exam, foot exam,
flu and pneumococcal vaccination; daily blood sugar testing, foot self-exam,
blood pressure medication adherence, and aspirin medication compliance)
among adult respondents aged ≥ 18 years with diabetes and who provided
informal care to others. Of 39,167 adult respondents with diabetes, 17%
were aged ≥ 65 years; 49% were female; 89% had health insurance at the
time of the survey; 19% reported very good or excellent health; 67% were
hypertensive; 55% had attended a diabetes self-management class; and 25%
served as informal caregivers. There was no significant difference between
persons with diabetes who had caregiver responsibility and those who did
not for several routine preventive care practices−annual doctor’s visit (87%),
A1C testing (70%), dilated eye exam (71%), foot exam (72%), flu(61%) and
pneumococcal vaccination (53%); daily blood sugar testing (61%), foot selfexam (73%), and blood pressure medication adherence (90%). While both
caregivers and non-caregivers with diabetes complied poorly with a daily
aspirin regimen (54% and 58%), the caregivers were more likely to have
had diabetes self-management education compared to the non-caregivers
(59% vs. 54%, p<0.0005). Although adults with diabetes generally followed
similar levels of preventive care practices regardless of their caregiver
status, the level of compliance with many care practices could be improved
for both groups.
ADA-Funded Research
&
The UK Biobank study includes 500,000 individuals aged between 40 and
69 years of whom 26,412 had diabetes at baseline. We aimed to identify and
assess diabetes family history in type 2 diabetic and unaffected individuals
at very low and very high risk of the condition based on BMI, age and sex.
Genome-wide or exome-wide sequencing of these individuals is likely to
provide improved power to detect low frequency risk or protective alleles
associated with diabetes compared to the same number of randomly
selected cases and controls.
We used 14,362 individuals defined as having type 2 diabetes (age at
diagnosis >35 years and no insulin within one year of diagnosis) and 446,892
unaffected individuals of British ancestry. We calculated a liability score for
each individual using residuals from a logistic regression model with BMI,
age and sex as risk factors and type 2 diabetes as an outcome.
We identified 4860 affected individuals at low risk compared to 29
expected by chance at >4 standard deviations (SDs) from the liability score
mean (p<0.0001). In contrast there were only two unaffected individuals at
high risk (>4SDs) compared to the 29 expected by chance.
Comparing the 1000 unaffected individuals at most risk with the 1000
unaffected individuals at least risk, there was no difference in parental
history of diabetes (18.9% vs. 17.1%, p=0.40). Comparing the 1000 affected
individuals at least risk to the 1000 affected individuals at most risk, the
low-risk individuals were much more likely to have a parental history of
diabetes (47.9% vs 31.8% p<0.0001).
In summary, using data from 461,254 UK Biobank individuals, a type 2
diabetes liability score identifies an excess of affected individuals at low
risk of the disease with a strong family history of the disease but no excess
of protected unaffected individuals at high risk.
Supported by: Diabetes UK
For author disclosure information, see page 829.
Guided Audio Tour poster
A413
POSTERS
Earlier studies have associated cigarette smoking with a high risk of type
2 diabetes (T2D). Further, smoking cessation has been associated with a high
risk of T2D, possibly mediated by weight gain. However, the associations of
smoking cessation with longitudinal changes in weight, glycemic control,
blood pressure (BP), and lipid levels in patients with T2D remain unclear. To
investigate the associations, we conducted an observational study in the
cluster-randomized controlled trial that examined the effect of a coordinated
intervention on patients’ adherence to regular visits over a 1-year period in
Japanese patients with T2D. Of the 2,200 participants, 1,169 responded to
the smoking questionnaire at both baseline and end of follow-up. Excluding
10 new smokers, we classified 1,159 patients into 3 groups: continuing
smokers (n = 328), quitters (n = 42), and non-smokers (n = 789). To examine
the associations, we used the mixed-effects model adjusting for age, sex,
intervention arm, and baseline weight, physical activity, the Problem Areas in
Diabetes scale, and hypoglycemic medication use. Compared with continuing
smokers, quitters had similar changes in weight (difference in mean changes
per month, 0.00 kg; 95% confidence interval [CI], -0.03-0.04; P = 0.61) and
levels of HbA1c (0.00 %; 95% CI, -0.00-0.02; P = 0.11), LDL (-0.15 mg/dl; 95%
CI, -0.57-0.27; P = 0.48), non-HDL (0.03mg/dl; 95% CI, -0.40-0.46; P = 0.91),
and total cholesterol (0.04 mg/dl; 95% CI, -0.46-0.54; P = 0.87). However,
quitters, compared with continuing smokers, showed greater elevations
in systolic BP (0.36 mmHg; 95% CI, 0.08-0.65; P = 0.01) and diastolic BP
(0.27 mmHg; 95% CI, 0.04-0.50; P = 0.02). Thus, we conclude that although
smoking cessation may not be associated with weight gain, worsening of
glycemic control, or elevations in lipid levels over a 1-year period in patients
with T2D, it may be associated with modest elevations in BP.
Epidemiology/
Genetics
ATSUSHI GOTO, YASUAKI HAYASHINO, KAZUO IZUMI, SHINU HAYASHI, HIKARI
SUZUKI, KATSUYA YAMAZAKI, MITSUHIKO NODA, Tokyo, Japan, Nara, Japan,
Toyama, Japan, Ibaraki, Japan
EPIDEMIOLOGY—OTHER
1583-P
1585-P
A Sibling Analysis of the Relationship between Diabetes during
Pregnancy and Fetal Growth
Sleep Duration and Glycemic Control in Patients With Diabetes
Mellitus: Korea National Health and Nutrition Examination Survey
2007-2010
KELLY J. HUNT, JEFFREY E. KORTE, MULUGETA GEBREGZIABHER, JILL MAULDIN, MARIA E. MAYORGA, Charleston, SC, Clemson, SC
BU KYUNG KIM, JA YOUNG JEON, SO-YEON AN, MIN SUK LEE, YONG JUN CHOI,
SEUNG JIN HAN, YOON-SOK CHUNG, KWAN-WOO LEE, DAE JUNG KIM, Busan,
Republic of Korea, Suwon, Republic of Korea
Short sleep duration has been reported to increase the risk of diabetes.
However, the influence of sleep duration on glycemic control in diabetic
patients has not been clarified. In the present study we evaluated the
association between sleep duration and glycemic control in diabetic
patients. We analyzed the data from the Korea National Health and
Nutrition Examination Survey (KNHANES) 2007-2010. Sleep duration was
self-reported, and classified into five groups: <6, 6, 7, 8, and ≥9 h/day.
Continuous and categorical variables were compared among the five groups
using ANOVA and the χ2 test. To control for socioeconomic and lifestyle
factors and comorbidities, logistic regression was used. The results of
fasting blood glucose and HbA1c according to sleep duration showed a
U-shaped trend, which was stronger in females and younger patients (<65
years). The patients with a sleep duration of 7 h/day had the lowest HbA1c
(7.26%) among the subjects (p=0.026). If the sleep duration was shorter or
longer than 7 h/day, the HbA1c level was elevated. In the older age group
(≥65 years), a sleep duration of 6 h/day was associated with the lowest
HbA1c (7.26%). The adjusted odds ratio (OR) with a 95% confidence interval
(CI) associated with the sleep duration of ≥9 h/day (vs. 7 h/day) was 1.47
(1.03-2.10) for HbA1c. Our results suggest that sleep duration is associated
with glycemic control in diabetic patients. The adequate sleep duration
in Korean adults with diabetes was approximately 7 h/day, and could be
shorter for older patients.
POSTERS
Epidemiology/
Genetics
We conducted a sibling analysis to examine the relationship between
diabetes during pregnancy and fetal growth. Using linked birth certificate,
inpatient hospital and prenatal claims data we examined black and white
women with more than one singleton birth delivered at 34-44 weeks
gestation in South Carolina between 2004 and 2008. Among 29,722 women
with 61,789 infants, 2,203 women had 4,600 infants discordant for in utero
diabetes exposure. We used both conventional generalized estimating
equations (GEE), and fixed-effects models which account for measured and
unmeasured shared familial factors. Results from the GEE analysis in the
61,789 infants indicate that prepregnancy and gestational diabetes are
associated with increased birthweight in both whites and blacks. In contrast,
results from the fixed-effects model indicate that in whites and blacks
neither prepregnancy nor gestational diabetes are significantly associated
with increased birthweight when shared familial factors are accounted for.
When analyses are limited to women with infants discordant for in utero
diabetes exposure, results are attenuated in the GEE model and remain
non-significant in the fixed effects model. Shared family characteristics
(genetic, environmental) appear to explain differences in birthweight among
siblings with discordant in utero diabetes exposure. Hence, between rather
than within family differences may account for the increased fetal growth
associated with diabetes.
1586-P
Global Burden of Diabetes in Women of Childbearing Age: A Review
of Prevalence Estimates
ADOLFO CORREA, JESSICA MARCINKEVAGE, CSABA SIFFEL, PIERPAOLO MASTROIACOVO, LORENZO BOTTO, Jackson, MS, Atlanta, GA, Rome, Italy, Salt Lake
City, UT
Diabetes in pregnancy is one of the most common pregnancy complications,
yet data on the burden of diabetes among women of childbearing age are
limited. To estimate the prevalence of diabetes in women of childbearing
age by global region, we conducted a review of studies with prevalence
data on diabetes in women of childbearing age (15-49) published from
2000 to 2011. We derived prevalence estimates for each type of diabetes
(i.e., diabetes=type 1 or type 2; GDM= gestational diabetes) by country,
region, and development status as defined by the United Nations (UN). We
identified 295 studies with information on diabetes prevalence in women
of childbearing age, representing 65 countries (41 less developed, 24 more
developed). Diagnostic criteria for both diabetes and GDM varied greatly
across studies. For diabetes, the median global prevalence was 3.35%; of
those developed countries with diabetes data (n=15), only 27% of estimates
were above the median, while over half of estimates from less developed
countries with diabetes data (n=34) were above the median. For GDM
population data, we found a median global prevalence of 3.89%, with only
38% of developed countries with GDM population data (n=13) above the
median while 64% of less developed countries with GDM population data
(n=11) were above the median. When applied to UN population estimates for
women aged 15-49, the median prevalence for diabetes corresponds to ~58
million women, of whom >50 million live in less developed countries. The
median estimate for GDM prevalence corresponds to ~11 million women,
of whom 10 million live in less developed countries. This review suggests a
significant number of women of childbearing age are affected by diabetes
worldwide, particularly in less developed countries, highlighting the need
for targeting this group in: a) efforts to conduct diabetes surveillance using
standard diagnostic criteria, and b) examination of current national policies
and interventions for diabetes prevention and proper diabetes control.
Supported by: National Institute on Minority Health and Health Disparities (R01MD004251)
1584-P
WITHDRAWN
&
For author disclosure information, see page 829.
A414
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—OTHER
1587-P
1589-P
Socioeconomic Position and Sensory Impairment Among U.S.
Working-Age Adults With Diabetes
Treatment Utilization Patterns of GLP-1 Agonists and DPP-4 Inhibitors among Type 2 Diabetics in a U.S. Commercially Insured Population: 2005–2011
CHIU-FANG CHOU, GLORIA L.A. BECKLES, YILING J. CHENG, JINAN B. SAADDINE, Decatur, GA, Atlanta, GA
CAROL E. KORO, PANKDEEP CHHABRA, MONIKA STENDER, C. VICTOR SPAIN,
JEFFERY K. ALLEN, HENRY J. KRZYWY, Collegeville, PA, Baltimore, MD, Stockley
Park, United Kingdom, Philadelphia, PA, Research Triangle Park, NC
Socioeconomic position (SEP) is associated with diabetes (DM) and sensory
impairment (SI) among adults. DM, a major cause of SI, has increased among
U.S. adults. Yet, the effect of SEP on SI among working-age adults with DM
has not been studied.
We examined the relationship between SEP and SI among adults aged
25-64 years with DM using 2007-2011 National Health Interview Surveys
(N=7,164). SI was defined by self-reports of visual (VI) or hearing impairment
(HI). SEP indicators were occupation (white-collar (highest SEP), service
group, farm worker, blue-collar, not in labor force), education (<high school,
high school, some college, ≥college), and poverty-income-ratio (<1.00-poor,
1.00-2.99-low, 3.00-3.99-middle, ≥4.00-high income). We conducted logistic
regressions to estimate adjusted prevalence ratios (APRs) for the association
between each SEP indicator and VI and HI, controlling for age, gender, race/
ethnicity, nativity, marital status, insurance coverage, usual source of care,
annual eye doctor visits , smoking, other DM complications, DM medication,
and time since DM diagnosis. We used SAS callable -SUDAAN to account for
the complex survey design. Differences were significant at p<0.05.
Nearly 36% of U.S. working-age adults with DM had SI. Compared with
the highest SEP level for each indicator, APRs for VI were significantly higher
for people with some college (1.2, 95% CI=0.7-2.2), high school (1.3, 95%
CI=0.7-2.2), or <high school (1.5, 95% CI=0.8-2.5) education; for blue-collar
workers (1.2, 95% CI=0.7-2.0); and for those in poor (1.5, 95% CI=0.9-2.5), low
income (1.4, 95% CI=0.8-2.4), or middle income (1.2, 95% CI=0.7-2.1) families.
For HI, APRs were also significantly higher for people with some college or
<high school; farmers, blue-collar workers; and people in poor families.
SEP was independently associated with SI among working-age adults
with DM. Interventions are needed to target adults with DM in low SEP to
increase the effectiveness of risk-reduction efforts.
1588-P
MPR for refill adherence
< 80%
>= 80%
Ethnic Disparities in Conversion from Impaired Fasting Plasma Glucose to Type 2 Diabetes
WANDA ADMIRAAL, FRITS HOLLEMAN, MARIEKE SNIJDER, RON PETERS, LIZZY
BREWSTER, JOOST HOEKSTRA, KARIEN STRONKS, IRENE VAN VALKENGOED,
Amsterdam, Netherlands
Type of Index ADA
Add-on therapy
Despite the ethnic differences in prevalence and incidence of type 2
diabetes (DM), evidence on ethnic disparities in conversion rate from
prediabetes to DM is scarce. We aimed to compare the association of
impaired fasting glucose (IFG), as well as fasting plasma glucose (FPG), with
the 10-year cumulative incidence of DM between South Asians, Africans
and Caucasians.
We analysed data on 90 South Asians, 190 Africans and 176 Caucasians,
who had participated in the population based SUNSET study between 20012003 and participated in a follow up visit between 2011-2012. We excluded
those with a missing FPG at baseline, a missing FPG at follow up, or with DM
at baseline. Baseline IFG was defined as an FPG of 5.7 mmol/L - 6.9 mmol/L.
At follow up, DM was defined as an FPG ≥ 7.0 mmol/L, HbA1c ≥ 48 mmol/mol
(6.5%) or self reported DM.
Of all participants 41.2% were men and the mean age at baseline was
45.6 ± 6.4. The 10-year cumulative incidence of DM was 18.9% in South
Asians, 13.7% in Africans and 4.5% in Caucasians (p<0.05). We found a
much stronger association of both IFG and FPG with the 10-year cumulative
incidence of DM in the South Asians than in the Africans and Caucasians. The
ethnic difference in association, particularly of FPG, remained statistically
significant after adjustment for sex, age, baseline BMI and change in BMI
over 10 years (FPG: odds ratio of 17.9 [3.7-67.8] in South Asians, 6.8 [2.617.8] in Africans, 1.9 [0.5-6.9] in Caucasians per mmol/L increase in FPG. IFG:
odds ratio of 11.1 [3.0-40.8] in South Asians, 5.1 [2.0-13.3] in Africans and 2.2
[0.5-10.2] in Caucasians with IFG at baseline compared to those without IFG
at baseline).
We found a higher 10-year cumulative incidence of DM and a much
stronger association of baseline IFG and FPG with DM among the South
Asians and Africans than among the Caucasians. Our findings do not only
emphasize the high risk of DM in South Asians, but also suggest a more rapid
conversion from IFG to DM in South Asians and, to a lesser extent, those of
African origin than in Caucasians.
ADA-Funded Research
&
New Use therapy
Switch therapy
DPP4
inhibitors,
n (%)
GLP-1
agonists,
n (%)
Other
ADA,
n (%)
GLP vs Other DPP4
ADAs, inhibitors vs
overall chisq Other ADAs,
p-values
chisq
p-values
<.0001
<.0001
11,363 (5.45) 12,195 (9.76) 50,610 (4.26)
197,320
112,730 1,136,892
(94.55)
(90.24)
(95.74)
120,603
(57.79)
31,372
(15.03)
48,022
(23.01)
Treatment Modification
Discontinuation of
143,038
index ADA
(68.54)
Switching of index ADA 42,570
(20.40)
Add-on therapy
37,800
(18.11)
<.0001
<.0001
<.0001
<.0001
<.0001
<.0001
<.0001
<.0001
92,892 49,737 (4.19)
(74.36)
10,157 (8.13) 1,096,225
(92.31)
17,806 38,828 (3.27)
(14.25)
101,509
(81.26)
44,333
(35.49)
13,780
(11.03)
927,050
(78.07)
191,532
(16.13)
151,923
(12.79)
1590-P
Changes in County-Level Disparity in Diagnosed Diabetes Prevalence and Incidence in the Unites States, 2004-2009
SUNDAR S. SHRESTHA, THEODORE J. THOMPSON, KAREN A. KIRTLAND, EDWARD GREGG, GLORIA L. BECKLES, LAWRENCE E. BARKER, LINDA S. GEISS,
Atlanta, GA
County-level disparities in the prevalence/incidence of diabetes exist, but
how these disparities have changed over time is unknown. We examined
the change in county-level diagnosed diabetes prevalence/incidence
among U.S. adults during 2004-2009. We fit unadjusted and adjusted
regressions using percentage point (ppt) change in prevalence/incidence
from 2004 to 2009 as the dependent variable and the level of prevalence/
incidence in 2004 as the independent variable. The adjusted model included
socioeconomic, demographic, and behavioral factors, and accounted for
spatial autocorrelations.
From 2004 to 2009, the county-averaged diabetes prevalence/incidence
increased by 2.1/0.07 ppt, respectively, and rate of increase over time
For author disclosure information, see page 829.
Guided Audio Tour poster
A415
POSTERS
Characteristics
Epidemiology/
Genetics
Purpose: To assess utilization patterns (adherence, type of index
antidiabetic agent (ADA) and treatment modification) of glucagon-like
peptide-1 agonists (GLP-1a) (exenatide, liraglutide), dipeptidyl-peptidase-4
Inhibitors (DPP-4i) (sitagliptin, saxagliptin, linagliptin) and other ADAs
including insulin.
Methods: A retrospective cohort study was conducted in the Thomson
Reuters commercial health insurance database (2005-2011). Adherence, type
of the index ADA (add-on, switch or new therapy), and treatment modification
(discontinuation of index ADA, switching of index ADA, and add-on therapy)
were assessed. Refill adherence was measured by Medication Possession
Ratio (MPR).
Results: We identified 208,683 DPP-4i users, 124,925 GLP-1a users and
1,187,502 other ADA users aged 18-64 years old. The majority of GLP-1a
use was add-on and only 8% was new use. For DPP-4i, 58% were add-on
and 15% were new use. Refill adherence (> 80%) was high for all 3 cohorts.
Discontinuation rate was highest among GLP-1a (81%) and lowest among
DPP-4i (69%). 35% of GLP-1a users switched to another class of medication
compared to 20% of DPP-4i and 16% of other ADA.
Conclusions: GLP-1a and DPP-4i are most commonly used as add-on to
existing therapy. The most common adherence problem was medication
discontinuation, particularly among GLP-1a users, whereas gaps between
medication refills were not a common problem.
EPIDEMIOLOGY—OTHER
decreased. Counties with the greatest prevalence change were mostly in
the South and those with the greatest incidence change were mostly in the
Northeast. For each ppt in 2004 prevalence, the unadjusted annual change
in prevalence increased by 0.04 ppt, implying faster increase in higher
prevalence counties and a widening of prevalence disparity. Prevalence
increases in the South and decreases in the West drove the widening
disparities. However, for each ppt of prevalence in 2004, the adjusted annual
change in prevalence decreased by 0.09 ppt, indicating that socioeconomic,
demographic, and behavioral changes drove the observed change. In
comparison, for each ppt in 2004 incidence, the unadjusted and adjusted
annual changes in county-level incidence decreased, by 0.07 and 0.14 ppt,
respectively, implying a slower rate of increase in high incidence counties
and resulting a narrowing of incidence disparity. This was primarily driven
by incidence decreases in the Northeast, Midwest and South and increases
in the West.
Interventions that target modifiable characteristics, such as education,
obesity, and physical inactivity, could further reduce disparities in incidence
and, over time, in prevalence.
Table 1. Mean Changes in SBP, LDL-c and TG
Baseline HbA1c
Baseline HbA1c
≤ 7%
7.1-9.9%
SBP LDL-c / TG SBP
LDL-c / TG
Pre- Ramadan 131.93 2.69 / 1.48 133.27 2.71 / 1.69
During Ramadan 130.17* 2.67 / 1.34* 130.86* 2.79 / 1.60
Post- Ramadan 132.59* 2.55 / 1.37 133.17* 2.57* / 1.44*
Pre-Ramadan and post-Ramadan were defined as 6 months before and after
Ramadan. The measurements of SBP and LDL-c/TG are in mm Hg and mmol/L,
respectively; *p<0.05.
1593-P
Psychometric Properties of the Hypoglycemia Perspectives Questionnaire (HPQ) in Type 2 Diabetes Mellitus
ARIANE KAWATA, SIEW HWA ONG, CHRISTINA THERAPONTOS, PETROS MAVROGENIS, KAROLY KULICH, WEN-HUNG CHEN, KARIN COYNE, Bethesda, MD,
Basel, Switzerland, Nicosia, Cyprus
1591-P
Ethnic Disparities in Diabetes Risk Irrespective of Degree of Obesity
The Hypoglycemia Perspectives Questionnaire (HPQ) was developed with
clinician and patient input to assess symptoms, behaviors, and impact of
hypoglycemia on diabetic patients.
HPQ was administered to adults with type 2 diabetes mellitus (T2DM) on
antidiabetic treatment as part of a cross-sectional, epidemiological study
evaluating hypoglycemia and health-related quality of life (HRQoL) in Cyprus.
Demographic and clinical data were collected. Patients also completed Audit
of Diabetes Dependent Quality of Life (ADDQoL-19), treatment satisfaction
questionnaire, and EuroQol-5 Dimensions (EQ-5D). The original HPQ
included 45 items rating current status/behavior related to hypoglycemia
on an 11-point numeric rating scale and 7 descriptive hypoglycemia event
frequency items. Analyses examined HPQ item performance, item reduction,
and factor structure. Measurement properties (reliability, construct validity,
known-groups validity) of the final HPQ were evaluated.
500 T2DM patients completed the HPQ; mean age 61±10 years; 32.6%
women. Based on item evaluation, the original HPQ item pool was reduced
to 22 items. Exploratory and confirmatory factor analysis identified 21 items
contributing to 3 hypoglycemia domains (Symptoms [8 items], Compensatory
Behaviors [7 items], Worry [6 items]) and a single-item of global symptom
awareness. HPQ domains had high internal consistency (alpha=0.78-0.92).
Construct validity was demonstrated by significant correlations between
HPQ with HRQoL, treatment satisfaction, and health status. HPQ was also
able to discriminate between known groups. Compensatory behaviors and
symptom awareness were higher for patients with a recent low blood sugar
event (p<0.001) and high symptom awareness corresponded to less concern
about experiencing symptoms of low blood sugar and worry (p<0.05).
These results provide preliminary evidence that HPQ is reliable and
valid for assessing the experience and impact of hypoglycemia on T2DM
patients.
POSTERS
JOSEPH NGUYEN, ANNE HELENE OLSEN, NANA KRAGH, THORKILD SØRENSEN,
Copenhagen, Denmark, Søborg, Denmark, Frederiksberg, Denmark
Epidemiology/
Genetics
Baseline HbA1c
≥ 10%
SBP LDL-c / TG
133.04 3.17 / 2.01
131.28 3.28 / 2.07
132.72 2.78 / 1.64
The prevalence of obesity is increasing around the world and is associated
with a number of co-morbidities including type 2 diabetes (T2D). The risk
of T2D also varies with ethnic group and part of the excess risk appears
to persist after correction for Body Mass Index (BMI). Also, increasing BMI
seems to have a greater effect in some ethnic groups than in others. We
examined the association between BMI group, ethnic group and diabetes
using the 2007-2008 and 2009-2010 NHANES cross-sectional surveys. We
excluded participants who were ≤30 years old at the survey, pregnant,
participated only in the interview, had self-reported diabetes diagnosis at
≤30 years, or were underweight (BMI <18.5 kg/m2). Logistic regression with
the variables age, gender, waist circumference, BMI group and ethnic group
and the endpoint diabetes was used. BMI was split into 5 groups: normal
(18.5-24), overweight (25-29), and obesity class 1 (30-34), 2 (35-39), and 3
(40+). Ethnic groups were Non-Hispanic White, Mexican-American, Other
Hispanic, Non-Hispanic Black, and Other Race. Diabetes was defined by
either HbA1c >6.5%, FPG ≥126 mg/dL, a 2-hour OGTT ≥200 mg/dL, or selfreported diabetes. The OR for having diabetes with normal BMI as baseline
increased from 1.05 (95%CI 0.84-1.31) in the overweight to 2.97 (95%CI 2.263.91) and 4.25 (95%CI 3.16-5.73) in obesity class 2 and 3, respectively. With
non-Hispanic whites as baseline, the OR for having diabetes was around 2
for all other ethnic groups. Increasing BMI seems to have less influence on
diabetes risk among Mexican-Americans than in the other ethnic groups,
probably because Mexican-Americans have a 3 times higher risk than nonHispanic whites even at normal BMI (1.5 times higher in obesity class 2 and
3). It is unclear why there are such great ethnic differences in T2D risk, and
better understanding of this may help preventing T2D in the various ethnic
groups with an elevated risk.
Supported by: Novartis Pharmaceuticals Corporation
Supported by: Novo Nordisk A/S
1594-P
Differences in Predictors of Breastfeeding among Women With and
Without Diabetes during Pregnancy
1592-P
Impact of Ramadan Fasting on Systolic Blood Pressure and Lipid
Profile among Patients With Diabetes in Relation to their HbA1c
Control
REENA OZA-FRANK, RASHMI KACHORIA, Columbus, OH
Women with diabetes during pregnancy exhibit lower breastfeeding
rates, yet predictors of breastfeeding initiation among these women are
limited. Ohio birth certificate data from 2006-2011 were used to build
separate logistic regression models by diabetes status (no diabetes [NDM],
gestational diabetes mellitus [GDM], or prepregnancy diabetes mellitus
[PDM]) to examine predictors of breastfeeding (direct breastfeeding and/
or pumping) at discharge. Among 807,466 births from 2006-2011, 5.5% of
women had GDM and 0.8% had PDM. Across all diabetes groups, women
with less education, Cesarean section, previous live births, enrolled in WIC
or Medicaid, or whose infants were admitted to the neonatal intensive care
unit were less likely to be breastfeeding at discharge. Married women were
more likely to be breastfeeding at discharge as were all race/ethnicities
compared with non-Hispanic Whites. However, there were differences in
breastfeeding by diabetes status by infant gestational age (GA), maternal
age, and adequacy of prenatal care. Among NDM, infants born late
preterm (34-36 weeks) [odds ratio: 0.8; 95% confidence interval: 0.8-0.9]
or moderately preterm (32-33 weeks) [0.9: 0.9-0.9] were less likely to be
breastfed compared with infants born at term (>37 weeks). Among GDM,
infants born late preterm were also less likely to be breastfed [0.9: 0.8-0.9];
MELANIE SIAW, JIELIN TAN, DANIEL CHEW, DARREN SEAH, MATTHIAS TOH,
JOYCE Y. LEE, Singapore, Singapore
Due to the practice of fasting between sunrise and sunset, Ramadan is known
to affect the blood glucose of Muslim patients with diabetes. However, little
is known about its effect on other metabolic parameters such as the systolic
blood pressure (SBP) and lipid profile. In this study, we aimed to elucidate the
impact of Ramadan fasting on SBP, low-density lipoprotein cholesterol (LDL-c)
and triglyceride (TG) in 5,172 Muslim patients from nine primary care facilities
in Singapore in relation to the control of their baseline HbA1c.
The mean age was 60 ± 10.65 years with 61.2% of female and 38.8%
male. Mean SBP improved during Ramadan in all patients with significant
reduction observed in those with baseline HbA1c <10% (p < 0.05). A trend
of improvement in mean TG was also observed in all patients with baseline
HbA1c < 10% while mean LDL worsened in patients with baseline HbA1c
>7% during Ramadan. However, after adjusting for age, gender and HbA1c,
only the changes in mean SBP and mean TG during Ramadan were found to
be significant (Table 1).
&
For author disclosure information, see page 829.
A416
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—OTHER
1.1 [CI: 1.065-1.143], p<0.001) and depression (adjusted OR: 1.1 [CI: 1.0281.178], p=0.006) were the only factors associated with significantly higher
prevalence of SD. Presence of depression in patients with DM may exert
detrimental effects on sexual function. Prompt identification of depressive
symptoms in patients with DM may be of paramount importance for the
detection of underlying SD.
however, infants born moderately preterm were more likely to be breastfed
[1.3:1.0-1.6]. NDM women aged <19 [0.8:0.7-0.8] and 20-24 [0.9:0.9-0.9] were
less likely to breastfeed compared with women aged 25-34. There were no
significant differences in breastfeeding by age among GDM or PDM. Finally,
among NDM [0.8:0.7-0.8] or GDM [0.9:0.7-0.9], inadequate prenatal care
was associated with lower odds of breastfeeding. Among women with PDM,
predictors were mostly similar to women with NDM. However, additional
efforts to increase breastfeeding among women with GDM and NDM based
on infant GA and adequacy of prenatal care may be warranted.
1597-P
Age Dependent Changes of Cadmium Content in Human Islets
MALEK EL MUAYED, KEITH MACRENARIS, WILLIAM L. LOWE, Chicago, IL
1595-P
Experimental evidence by us and others suggest a possible association
between cadmium (Cd) accumulation and beta cell dysfunction and
dysglycemia. Cd is reported to have a long biological half life of up to 20
years, leading to a gradual age dependent accumulation in various organs.
The relationship between age and the concentration of Cd in human islets has
so far not been reported. In the present study we examined the relationship
between age and cadmium levels in human islets from 24 deceased US
donors (gender: 11m, 11f, 2 undocumented, age 42.4, SD 12.0). The average
islet Cd content was 27.6 nmol/gram lysate protein (SD 16.9). There was a
significant linear correlation between age and islet Cd levels with a Pearson
correlation coefficient of 0.51 (95% CI 0.13 to 0.76, P 0.012). For comparison,
no significant correlation between age and other divalent metals including
zinc (Zn), nickel (Ni), and copper (Cu) was found (mean concentrations: Zn
11932.8 +/- 1403.8, Ni 208.7 +/- 35.5, Cu 405.7 +/- 54.4 nmol/g protein).
Accumulation of mercury (Hg) was not evident, except for two samples with
detectable levels (5.05 and 4.68 nmol/g protein, detection limit 4 nmol/g
protein). Given the significant, age dependent accumulation of Cd in islets,
further studies examining a potential link to diabetes are warranted.
Factors Associated With Achieving Target HbA1c Levels in People
With Type 2 Diabetes Beginning Insulin Detemir Treatment: Findings From the A1chieve Study
RACHID MALEK, NABIL K. EL NAGGAR, MOHAMMAD I HASAN, PRADANA SOEWONDO, SEI HYUN BAIK, PHILIP HOME, Sétif, Algeria, Jeddah, Saudi Arabia, Lahore, Pakistan, Jakarta, Indonesia, Seoul, Republic of Korea, Newcastle upon Tyne,
United Kingdom
Epidemiological data can provide information about the factors which
influence attainment of good glycemic control in routine clinical practice.
A1chieve was a non-interventional study in the non-Western world
evaluating the safety and clinical effectiveness of insulin analog therapy in
people with type 2 diabetes (T2DM). This subgroup analysis of 11619 people
examined factors associated with attaining a target HbA1c level of <7.0 %
(53 mmol/mol) 24 wks after starting insulin detemir (detemir) with/without
oral glucose-lowering drugs. An HbA1c <7.0 % was achieved by 3655 people
(32%) at 24 wks, compared with 390 people (3%) at baseline (baseline HbA1c
9.5[1.6] % [88.1[17.4] mmol/mol]). After adjustment for regional differences,
the baseline factors independently associated with achieving target were
HbA1c, PPG levels, and microvascular complications (Table). Baseline age,
duration of diabetes, BMI, fasting plasma glucose, systolic blood pressure
and total serum cholesterol were not predictors of achieving HbA1c target
levels. In conclusion, in a global study in routine clinical practice, attainment
of HbA1c <7.0 % with insulin detemir was related to overall and meal-time
glucose control at baseline, and to microvascular complications. This
emphasizes the importance of defeating clinical inertia in starting insulin
if attainment glucose targets and prevention of complications is to be
improved.
Supported by: Novo Nordisk A/S
Supported by: NIEHS/NIH (1K08ES020880-01 to M.E.M.)
1596-P
The Impact of Depression on Sexual Dysfunction in Patients With
Type 2 Diabetes Mellitus
1598-P
Correlation between Hemoglobin A1c and Meteorological Parameters in Japan
CHRISTOS SAMPANIS, BARBARA NIKOLAIDOU, IOANNA ZOGRAFOU, ELENI
GAVRIILAKI, PANAGIOTA ANYFANTI, GEORGE TRIANTAFYLLOU, ARETI TRIANTAFYLLOU, BETINA HAIDICH, MICHALIS DOUMAS, KONSTANTINOS PETIDIS,
STELLA DOUMA, Thessaloniki, Greece
TAKAYUKI WATANABE, ERI UEDA, MIZUKI SAWAI, MAKIYO MIMURA, KIICHIROU HIRAISHI, Yokohama, Japan
Hemoglobin A1c(A1c) has been reported to change by seasonal variation.
But there is no report about the direct relationship between meteorological
parameters and glycemic control. We studied the correlation between
changes in A1c and meteorological parameters as follows: temperature,
humidity, precipitation, hours of sunshine and atmospheric pressure month
by month. We used 24,255 A1c (NGSP) data measured every visit from 841
patients with diabetes mellitus from January 2006 to September 2012 in
our outpatients office. Meteorological data was gathered from the website
of Yokohama local meteorological observatory in Yokohama, Japan.
We calculated the correlation coefficients between the meteorological
parameters and the difference between A1c and its yearly mean (১A1c).
We also calculated the correlation coefficients between the ১A1c and
meteorological parameters one to three months before because A1c is an
indicator of glycemic control of two to three months. The ১A1c was negatively
correlated with temperature and humidity with r =- 0.496 (p<0.001) and
-0.482 (p<0.001) respectively. The ১A1c was most significantly correlated
with temperature two months before (১A1c = - 0.0143temperature + 0.23,
r =0.715, p<0.001). The ১A1c was positively correlated with atmospheric
pressure three months before with r = 0.632 (p<0.001). The ১A1c was not
correlated with hours of sunshine. The association between ১A1c and
meteorological parameters except temperature and hours of sunshine was
Diabetes mellitus (DM) is a disease of chronic nature severely affecting not
only physical functions including sexual performance, but also psychological
aspects of patients’ health. However, the association of mental health
disorders with sexual dysfunction (SD) in patients with DM has not been
thoroughly investigated. We studied the impact of psychological disorders
(anxiety, depression) on SD in a sample of consecutive patients with type 2
DM attending the Diabetes Centre of the 2nd Propedeutic Department of
Internal Medicine, Aristotle University, Hippocratio Hospital, Thessaloniki,
Greece. The International Index of Erectile Function (IIEF) and the Female
Sexual Dysfunction Index (FSFI) questionnaires were used to detect SD
in male and female patients, respectively. The Hamilton anxiety scale
questionnaire was used to measure anxiety severity, while depressive
symptoms were evaluated with the Zung self-rating depression scale. In
total, 360 patients, 220 females and 140 males, 71±9.6 years old, were
included in the study. SD was detected in 85% of our sample, while anxiety
and depression affected 35.8% and 11.4% of our population, respectively.
SD was significantly associated with anxiety, depression, age, DM duration,
systolic blood pressure, pulse pressure, hypertension, waist circumference,
cardiovascular disease, smoking, glomerular filtration rate, and HbA1c. In the
multiple logistic regression model, it was revealed that age (adjusted OR:
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A417
POSTERS
Epidemiology/
Genetics
Figure: Correlation between age and islet Cd content
EPIDEMIOLOGY—TYPE 1 DIABETES
essentially due to changes in temperature. The results are compatible with
the studies showing that A1c is lowest in summer and highest in winter in
both hemispheres. We conclude the cause of seasonal variation of A1c is not
hours of sunshine but change in temperature.
EPIDEMIOLOGY—TYPE 1 DIABETES
Guided Audio Tour: Type 1 Diabetes Epidemiology (Posters: 1601-P to 1608-P),
see page 17.
POSTERS
Epidemiology/
Genetics
1599-P
&
Association of Napping and Nighttime Sleep With Impaired Glucose
Regulation, Insulin Resistance and Glycated Hemoglobin in Chinese
Middle-Aged Adults Without Diabetes
HbA1c and Mortality in the Pittsburgh Epidemiology of Diabetes
Complications (EDC) Study of Type 1 Diabetes (T1D)
GANG CHEN, HONGJIE CHEN, LIXIANG LIN, JUNPING WEN, Fuzhou, China
RACHEL G. MILLER, TREVOR J. ORCHARD, Pittsburgh, PA
Objective: The purpose of the study was to assess the relationship of
napping and nighttime sleep with impaired glucose regulation (IGR), insulin
resistance and glycated hemoglobin (HbA1c) in Chinese middle-aged adults
without diabetes.
Methods: This cross-sectional study included 7568 adults aged
40-65years in Fujian province, China from June 2011 to January 2012. Selfreported hours of daytime napping and nighttime sleep were obtained by
questionnaire. Anthropometric, laboratory measurements were determined.
The homeostasis model assessment of insulin resistance (HOMA-IR) index
higher than 2.50 was defined insulin resistance. Odds ratios (OR) and 95%
CI (Confidence Interval) were derived from multivariate logistic regression
models.
Results: After adjustment for potential confounders, OR of HbA1c
>6.0% were 1.376(95%CI: 1.179-1.607) for those with ≤1h of napping and
1.361(1.124-1.649) for those with >1h of napping compared with those who
did not nap. Similar associations were found between napping and IGR or
insulin resistance. For nighttime sleep, subjects with shorter sleep had
significantly higher OR of HbA1c and IGR compared with the reference group
(≥8 to <9h), but not insulin resistance.
Conclusions: Napping was associated with higher HbA1c, IGR and insulin
resistance, whilst shorter nighttime sleep was correlated with HbA1c and
IGR. Therefore, a healthy sleep habits may profit glucose metabolism in
middle-aged Chinese adults without diabetes.
Recent type 2 diabetes trials suggest intensive glycemic therapy may
be detrimental. The DCCT/EDIC study demonstrates the value of intensive
therapy starting in short duration T1D, but the impact of HbA1c on mortality
in longer duration T1D is unclear. Thus we assessed all-cause and causespecific mortality by quintiles of both baseline and mean follow-up HbA1c
in a cohort of adults with long-standing T1D. Data are from the EDC study
of childhood-onset T1D (n=658, baseline mean age=27 yrs, T1D duration=19
yrs, 49% female). Deaths were classified by a physician committee after
review of death certificates, hospital, autopsy, and coroner reports over
a 22-yr follow-up into acute T1D complication, renal disease (RD) only,
cardiovascular disease (CVD) only, RD and/or CVD, and “other”. The 22-yr
incidence of all-cause mortality was 24.9%. All-cause mortality increased
linearly across quintile of both baseline (p<.001) and mean (p=0.003) HbA1c.
CVD-only mortality increased linearly across quintiles of mean (p<.001),
but not baseline (p=0.24) HbA1c. Furthermore, for the combined category
of RD and/or CVD deaths, mortality increased linearly across quintiles of
both baseline (p<.001) and mean (p=0.01) HbA1c. No trends were observed
for acute, RD-only, or “other”. These results suggest that, in the EDC study,
mortality increased linearly with increasing HbA1c, with no evidence that
those in the lowest quintile of HbA1c are at an increased risk of mortality.
1601-P
1600-P
Positive Correlations of Liver Enzymes With Serum Glucose Aged
Over 45 Years in Countryside of China
XIE JUN HUI, LIU QIAN, YANG YAN, LIU ZHE LONG, ZHOU XIN RONG, YU XUE
FENG, ZHANG MU XUN, YUAN GANG, HU SHU HONG, Wuhan, China
Objective: To investigate the prevalence of diabetes (DM) and the
association of liver transaminase and serum glucose over 45 years old in
countryside of China.
Methods: A cross-sectional survey of 10800 people aged over 45 years
was undertaken in rural of HuBei province . Participants underwent an oral
glucose-tolerance test(OGTT) . Liver transaminase (ALT,AST, γ-GT),HbA1c,
blood lipid were measured .Meanwhile the participants were invited to
attend a single examination and a standard questionnaire .
Result: 1. The prevalence of IFG (impaired fasting glucose ), IGT(impaired
glucose tolerance), IFG+IGT (impaired fasting glucose combined with
impaired glucose tolerance) and DM were 3.99% , 11.77% , 2.6%, and 9.99%
in the survey, respectively.
2. With the increase of ALT and γ-GT concentrations, OR for glucose
increased gradually. By comparing patients in the highest quartile of γGT
concentration. ALTconcentration with those in the lowest quartile , OR of
GGT for IFG, IGT, IFG+IGT, and DM was 1.34(95%CI 0.96-1.87), 2.14(95%CI
1.75-2.61), 2.08(95%CI 1.37-3.16) , 4.81(95%CI 3.79-6.09); OR of ALT was
2.22(95%CI 1.53-3.22), 1.04(95%CI 0.83-1.32), 2.04(95%CI 1.26-3.28), 2.36
(95%CI 1.84-3.02) respectively .
3. The area under curve forγ-GT was 0.64 and for ALT was 0.57 for
discriminating DM from normal condition. In ROC curve analysis, the optimal
cut-off value for γ-GT to discriminate DM from normal condition was 16.5 IU
with the sensitivity of 71.4% and the specificity of 48.6%.
Conclusion: The prevalence of prediabetes and DM is relatively high over
45 years in countryside of China . Serum γ-GT concentrations were the most
closely related to serum glucose in three liver transaminases and were
independently associated with prediabetes and diabetes.
&
1602-P
Impaired Renal Function Further Increases 6 Year Coronary Artery
Calcification Progression in Type 1 Diabetes
DAVID M. MAAHS, DIANA JALAL, MICHEL CHONCHOL, RICHARD JOHNSON,
MARIAN J. REWERS, JANET K. SNELL-BERGEON, Aurora, CO
Kidney disease increases cardiovascular risk in type 1 diabetes (T1D). We
investigated whether baseline estimated glomerular filtration rate (eGFR)
and albumin-creatinine ratio (ACR) independently predicted coronary artery
calcification progression (CACp) over 6-years in adults with T1D compared
to non-diabetics.
All Coronary Artery Calcification in Type 1 Diabetes Study participants
(n=1,066) with complete data for eGFR at baseline and 6 years were
included. Three CKD-EPI equations (serum creatinine, cystatin C, and both)
were used for eGFR. The association of baseline ACR and eGFR with CACp
was analyzed using multiple logistic regression.
Increasing categorical baseline ACR (<10, 10-30, and >30 µg/mg) predicted
CACp in participants with T1D (Figure, OR=2.15, 95% CI: 1.50-3.09; OR=7.19,
95% CI: 3.90-13.26; OR=18.09, 95% CI: 8.48-38.62, respectively), compared
to non-diabetics. T1D adults with baseline eGFR < 60 ml/min/1.73m2 had 5-7
times higher odds for CACp than non-diabetics with a J-shaped association
for CKD-EPI serum creatinine and a step-wise association for CKD-EPI
cystatin C.
While increasing ACR and/or decreasing eGFR predict CACp, coronary
atherosclerosis progresses faster in people with T1D even in the absence of
Supported by: Chinese Medical Association
&
For author disclosure information, see page 829.
A418
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—TYPE 1 DIABETES
Overall, standard classifications underestimated the proportion of CVD
attributable deaths by 43.7% between 1997-2007, with no significant
change in this over time.
The proportion of deaths attributed to CVD and diabetes among people
with type 1 diabetes has decreased over time. However, we have shown
that we may be underestimating the total burden of CVD mortality if we
use traditional coding and only consider the underlying COD. Accurate
assessment of the total CVD burden in people with diabetes is important
for appropriate health care allocation and requires an approach that fully
recognises the impact of CVD.
diabetic kidney disease. These findings emphasize the interaction between
kidney and cardiovascular disease in T1D and highlight the public health
importance of lowering cardiorenal risk in people with T1D.
Supported by: NHMRC (Australia)
&
Supported by: NIDDK; NHLBI
1603-P
Type 1 diabetes (T1D) is characterized by the loss of pancreatic islet
beta cell function resulting in loss of insulin production. Genetic and
environmental factors may trigger an immune response targeting beta cells
thus generating islet antibodies (IA). Immune response pathways involve
a cascade of events, initiated by cytokines and chemokines, producing
inflammation which can result in tissue damage.
A nested case-control study was performed to identify temporal
changes in cytokine levels in 75 DAISY subjects: 25 developed diabetes
(T1D), 25 developed persistent IA but not T1D (IA), and 25 were controls.
Serum samples were selected at four time points: T1-the earliest available
sample (1-2 yr of age), T2-just prior to IA, T3-just after development of IA,
and T4-prior to diagnosis of T1D or the most recent. Cytokines (Interferon
[IFN]-α2a, interleukin [IL]-6, IL-17, IL-1β, interferon gamma-induced protein
[IP]-10, monocyte chemotactic protein [MCP]-1, IFN-γ, IL-1α, and IL-1ra) were
measured using the Meso Scale Discovery system Human Custom Cytokine
9-Plex assay.
In multivariate mixed models adjusting for HLA risk, first degree
relative status, age, and gender, MCP-1 (p=0.02), IFN- (p=0.008), and IL1β (p=0.0495) were significantly higher at T3 in TID when compared to IA
subjects . At T4, IP-10 was significantly higher in IA subjects than controls
(p=0.034), and IL-17 (p=0.03) and IL-1α (p=0.03) were higher in T1D subjects
than controls.In this repeated measures nested case-control study, we
identified increased inflammatory markers in children with IA who went on
to develop T1D than among children who remained antibody positive but did
not progress to clinical disease, as well as increased inflammation in both
T1D and IA children at the last study time point when compared to control
children. These results suggest that inflammation may be related to both the
development of antibodies and the progression from antibodies to clinical
T1D.
Mortality from type 1 diabetes (T1D) is reported to be three times as
high among Blacks than Whites. Socioeconomic status (SES) and access to
health care may influence these racial differences. We sought to determine
if survival differs between Blacks and White adults with long-standing T1D
and with similarly low SES and access to health care. For a cohort of 391
(299 Blacks, 92 Whites) mostly low income adults aged 40-79 years with
T1D recruited from government funded community health centers in the
Southeast United States, we applied Cox proportional hazards models to
estimate hazard ratios of subsequent all-cause mortality among Blacks
compared with Whites. We also calculated standardized mortality ratios
to compare the mortality experience of the individuals with T1D with the
national and with the general community health center sex-race specific
population norms. Mean age at diabetes diagnosis and baseline age at
cohort entry, respectively, were 21 and 50 years in Blacks and 19 and 51
in Whites. During an average of 6.7 years of follow-up, 29% of the Blacks
and 35% of the White population died. Median age at death was 53.4 years
in Blacks and 53.3 years in Whites. In multivariable analysis adjusted for
diabetes duration, sex, race, BMI, hypertension, high cholesterol, coronary
artery disease, stroke/transient ischemic attack (TIA), a history of smoking,
education, and income, only sex, BMI (U-shaped relationship), and a history
of stroke/TIA predicted mortality. No difference in mortality risk was
observed between Blacks and Whites (p=0.51). Compared to the racespecific U.S. general population, standardized mortality rates were 5.7 times
higher in Blacks and 11.7 times higher in Whites. However, when compared
to the same source population, i.e. the community health center population,
mortality rates were 3.5 and 3.7 times higher in Blacks and Whites,
respectively. Elevated mortality persists in adults with long duration of T1D,
but given similarly low SES and access to health care, mortality rates are
equally high among Blacks and Whites.
Supported by: 2R01DK032493-28
Supported by: NIH (R01CA092447)
&
&
1604-P
Accurate Estimation of CVD Mortality in People With Type 1 Diabetes
TESSA L. CRUME, RICHARD F. HAMMAN, SCOTT ISOM, JASMIN DIVERS, ELIZABETH J. MAYER-DAVIS, WENZE ZHONG, SHARON H. SAYDAH, DEBRA A. STANDIFORD, JEAN M. LAWRENCE, CATHERINE PIHOKER, DANA DABELEA, Aurora,
CO, Winston-Salem, NC, Chapel Hill, NC, Atlanta, GA, Cincinnati, OH, Pasadena, CA,
Seattle, WA
JESSICA L. HARDING, JONATHAN E. SHAW, DIANNA J. MAGLIANO, Melbourne,
Australia
Evidence suggests that cardiovascular disease (CVD) mortality in people
with diabetes is decreasing. However, few national studies have examined
mortality trends in type 1 diabetes. Further, since diabetes can be listed as
the underlying cause of death (COD), when the death certificate indicates
that a CVD event was due to diabetes, there may be classification errors in
the literature. The aim of this study was to examine mortality trends in type
1 diabetes and to explore potential misclassification issues.
The study included 166,177 people with type 1 diabetes registered on
the Australian National Diabetes Service Scheme between 1997 and 2007.
Vital status and COD were collected by linkage to the National Death Index.
Deaths were coded according to ICD-10.
Using standard classifications, the proportion of deaths from CVD
decreased between 1997 and 2007 from 31.0% to 24.6% (ptrend <0.001),
and the proportion due to diabetes decreased from 24.9% to 20.8% (ptrend
<0.001). After recoding CVD deaths previously attributed to diabetes as
CVD deaths, diabetes decreased from 11.6% to 9.4% (ptrend <0.001).
Contrastingly, the proportion of diabetes deaths decreased upon recoding,
but over time still decreased from 11.6% to 9.4% (ptrend <0.001).
ADA-Funded Research
&
1606-P
The Accuracy of Provider-Diagnosed Diabetes Type in Youth: Evidence from the SEARCH Study
One of the main challenges in establishing a sustainable surveillance
system for diabetes in youth is accurate assessment of diabetes type.
The aim of this study was to evaluate the accuracy of provider-diagnosed
diabetes type abstracted from medical records compared to an etiologic
assessment based on two criteria: autoimmunity indicated by the presence
of GAD65 or IA2 diabetes autoantibodies (DA); and insulin sensitivity (IS)
from an equation validated against euglycemic-hyperinsulinemic clamps.
Measures of accuracy for 2349 SEARCH youth < 20 years of age at diagnosis
in 2002-2006 are provided in Table 1. Provider-diagnosed type 1 diabetes
(T1D) was highly sensitive (97%), but less specific (77%), had a positive
predictive value (PPV) of 96% and negative predictive value (NPV) of 80%
compared to an etiologic definition including DA positive, regardless of IS
status, or presence of IS, if DA were not detected. Provider-diagnosed type
2 diabetes (T2D) had lower sensitivity (76%) but high specificity (97%), a
PPV of 83%, and a NPV of 96% compared to the etiologic definition of DA
negative and insulin resistance. In conclusion, provider-diagnosed diabetes
type from medical records is reasonably accurate at identifying T1D but
For author disclosure information, see page 829.
Guided Audio Tour poster
A419
POSTERS
KATHLEEN C. WAUGH, JANET K. SNELL-BERGEON, FRAN DONG, IMAN TAKI,
MICHELLE HOFFMAN, MARIAN J. REWERS, Aurora, CO
BAQIYYAH CONWAY, THOMAS ELASY, MICHAEL E. MAY, WILLIAM J. BLOT, Morgantown, WV, Nashville, TN
Epidemiology/
Genetics
&
Mortality by Race in Type 1 Diabetes
1605-P
Increased Inflammation Is Associated With Islet Autoimmunity and
Type 1 Diabetes in the Diabetes Autoimmunity Study in the Young
(DAISY)
EPIDEMIOLOGY—TYPE 1 DIABETES
insufficient at capturing T2D in youth therefore periodic validation against
etiologic diabetes type will be an important component of a sustainable
surveillance system in the U.S.
Table. Performance of published algorithms for case ascertainment using
electronic health data from the University of North Carolina Health Care System’s Data Warehouse (source population, n=57,767; total presumptive cases
n= 1348; total true cases n=537)
description
N
FP
Se Sp PPV NPV
Algorithm
n(%) (%) (%) (%) (%)
# (Name, location,
age range)
704 201(28.6) 93.7 99.6 71.4 99.9
1 (Klompas,
A1c ≥ 6.5% or FPG ≥ 126 mg/dl or
Massachusetts US, ≥ 2 ICD-9 codes 250.xx or DM
no age limit)
medications¶ at any time
2 (Dart, Manitoba
≥ 1 hospitalizations or ≥ 2 physician
810 309(38.1) 93.3 99.5 61.9 99.9
Canada, 1-18 yr)
claims or ≥ 1 prescription claims in
1 year
3 (NDSS, Canada, start- ≥ 1 hospitalizations or ≥ 2 physician
501 25(5.0) 88.6 99.9 95.0 99.9
ing at 1 yr)
claims in 2 years
4 (Guttmann, Ontario ≥ 2 physician claims in 2 years
493 19(3.9) 88.3 99.9 96.1 99.9
Canada, 0-18 yr)
5 (Guttmann, Ontario ≥ 4 physician claims in 2 years
428 3(0.7) 79.1 99.9 99.3 99.8
Canada, 0-18 yr)
6 (Harris, Ontario
≥ 2 abnormal plasma glucose tests
1348 811(60.2) 100.0 98.6 39.8 100.0
Canada, age not
or A1c ≥ 6.5% or insulin or ≥ 2 oral
specified)
anti-diabetic drugs or diabetes on the
problem list in 2 years
Abbreviations: A1c, HbA1c; DM, diabetes mellitus; FPG, fasting plasma glucose; FP, false positive; Se, sensitivity; Sp, specificity; PPV, positive predictive
value; NPV, negative predictive value.
¶ Klompas algorithm doesn’t include metformin and insulin use during pregnancy.
1. Klompas et al. Diabetes Care. 2012 Nov 27. [Epub ahead of print]
2. Dart AB, et al. Diabetes Care 2011; 34(4): 898-903.
3. NDSS. http://www.phac-aspc.gc.ca/publicat/2009/ndssdic-snsddac-09/
pdf/report-2009-eng.pdf
4&5. Guttmann A et al. Pediatr Diabetes 2010; 11(2): 122-128
6. Harris SB et al. BMC Health Serv Res 2010; 10: 347-352
Table 1. Comparison of provider diagnosed diabetes type compared to etiologic type in SEARCH
Etiologic T1D Total Measures of Accuracy for T1D
+
Sensitivity = 96.5%
Provider diagnosed T1D + 1929
81 2010
Specificity = 76.9%
from medical record
69
270
339
PPV = 95.9%
Total
1998
351 2349
NPV = 79.6%
Provider diagnosed T2D
from medical record
Total
Etiologic T2D
+
+ 266
53
Total Measures of Accuracy for T2D
Sensitivity = 75.8%
319
Specificity = 97.3%
-
2030
2349
85
351
1945
1998
PPV = 83.4%
NPV = 95.8%
Supported by: CDC
POSTERS
Epidemiology/
Genetics
&
1607-P
Testing Childhood Diabetes Case Ascertainment Methods Based
on Published Algorithms: The SEARCH for Diabetes in Youth Study,
Carolina Site
WENZE ZHONG, EMILY R. PFAFF, JOAN THOMAS, LINDSAY M. JAACKS, TIMOTHY S. CAREY, DANIEL P. BEAVERS, SHARON H. SAYDAH, JEAN M. LAWRENCE,
RICHARD F. HAMMAN, DANA DABELEA, CATHERINE PIHOKER, ELIZABETH J.
MAYER-DAVIS, Chapel Hill, NC, Winston-Salem, NC, Atlanta, GA, Pasadena, CA,
Aurora, CO, Seattle, WA
Supported by: CDC
This study compares published case ascertainment methods for childhood
diabetes (DM) surveillance. Using electronic health data from the University
of North Carolina Health Care System’s Data Warehouse, we identified
57,767 children aged 0-19 years who had a physician visit for any reason in
2011. From among this group, we selected 1348 who met ≥ 1 of the following
criteria since July 1st , 2008: 1) HbA1c ≥ 6.0%; 2) ≥ 1 fasting glucose ≥
126mg/dl or ≥ 2 random glucose ≥ 200mg/dl on different days; 3) ≥ 1 DMrelated ICD-9 codes on problem list; 4) ≥ 1 DM-related ICD-9 billing codes;
5) any DM medications. The inclusion criteria ensured a high sensitivity.
Medical record reviews conducted for 1348 presumptive cases yielded 537
true DM cases, with the remaining 57,230 considered to be true negatives.
Using this cohort, we evaluated the performance of 6 published algorithms
(table). For algorithm 6, sensitivity was 100%, but the positive predictive
value (PPV) was only 39.8%. Algorithm 1 and 2 had similar sensitivity but
algorithm 1 had better PPV (71.4% vs 61.9%). Algorithm 3 is used for national
diabetes surveillance in Canada; its performance was good in our system as
well. However, none of the algorithms had both high (>90%) sensitivity and
PPV simultaneously. Results of algorithms may differ based on population
characteristics. Work to refine these approaches and to categorize diabetes
by type is ongoing.
&
1608-P
Age, Glycemic Control and Social Deprivation Independently Predict 10-Year Mortality in a UK Type 1 Diabetes Cohort
DAVID HOPKINS, LAURA YASSA, DANIEL SIMPSON, AMANDA SIMONDS,
STEPHANIE A. AMIEL, STEPHEN M. THOMAS, London, United Kingdom, Crawley,
United Kingdom
To determine the factors influencing poor outcomes in type 1 diabetes
(T1D) we have conducted a retrospective analysis of combined biochemical,
demographic and health resource utilisation data collected over a 10
year period for a cohort of T1D patients (n=1038) attending two inner city
specialist diabetes outpatient clinics. The cohort was defined to include all
patients attending the service in 2002 with sequential HbA1c data available
for each year from 2002 to 2004 and with on-going follow-up within the
clinics until 2010.
Baseline glycemic control was defined as an individual’s mean HbA1c for
the period 2002-2004. Economic status was determined using the index
of multiple deprivation (IMD) a weighted deprivation score derived from a
national dataset based on postcode of residence.
At baseline, mean (+SD) age was 41.6 + 12.3 years and duration of diabetes
16.1 +14.0 years. Mean HbA1c was 8.2 + 1.3. 37 deaths occurred in the cohort
by December 2012 (3.6% total cumulative mortality). Patients who died
were significantly older (50.9 + 9.1 vs 41.2 +12.2 years, p <0.001) and had
higher mean baseline A1c (9.1 + 1.6 vs 8.2 + 1.3, p<0.001) but did not differ
in duration of diabetes (14.8 + 15.7 vs 16.1 + 14.0, p=0.8). For individuals
with baseline HbA1c > 9.0%, cumulative 10-year mortality was significantly
increased at 9.0 % (p< 0.001).
Patients who died were more likely to be socially deprived, 61% of
deceased patients having scores in the upper quintile of the population
range (mean IMD score 32.3 + 11.2 deceased vs 23.6 + 12.3 alive, p=0.001 ).
In a three step regression analysis, baseline HbA1c, age and IMD score were
independent predictors of mortality.
These data indicate the significance of glycemic control and social
deprivation as independent, potentially modifiable risk factors for mortality
in type 1 diabetes.
Supported by: Novo Nordisk, Inc.
&
For author disclosure information, see page 829.
A420
Guided Audio Tour poster
ADA-Funded Research
1611-P
Insulin Resistance and Fasting Plasma Glucose in First Degree Relatives of Patients With Type 1 Diabetes
ANDREA STECK, FRAN DONG, IMAN TAKI, MICHELLE HOFFMAN, MARIAN J.
REWERS, Aurora, CO
KATARZYNA SIEWKO, ANNA POPLAWSKA-KITA, BEATA TELEJKO, AGNIESZKA
NIKOLAJUK, MARIA GORSKA, MALGORZATA SZELACHOWSKA, Bialystok, Poland
Earlier diagnosis and treatment of type 1 diabetes (T1D) may help preserve
endogenous insulin secretion. However, an oral glucose tolerance test
(OGTT) is a cumbersome and poorly reproducible criterion for early diagnosis
of diabetes in high- risk subjects. Continuous glucose monitoring (CGM)
technology offers an opportunity to improve diagnostic criteria.
The Diabetes Autoimmunity Study in the Young (DAISY) follows
prospectively high-risk children for development of T1D. Eleven DAISY children
with persistent multiple islet autoantibodies (IA), but no signs or symptoms
of diabetes, and eight controls used a Dexcom 7 CGM for a minimum of 4
days. Cases and controls had similar demographic characteristics.
Cases showed more impaired glycemia with percent time spent above
140 mg/dl of 18 % compared to 6% in controls (p=0.04). The range of sensor
values was significantly wider in cases versus controls (p = 0.03). The area
under the curve (AUC) overall and during daytime, but not during night, was
significantly greater in cases than in the controls (p ≤ 0.003). Of interest, the
mean HbA1c in the cases was only 5.4%; 5/11 subjects had an OGTT during
CGM: four had normal OGTT while one had impaired glucose tolerance. Two
of the IA cases developed T1D 6 months after their CGM.
Early hyperglycemia can be picked up by CGM and may help with earlier
diagnosis of T1D. Revisions to the current ADA criteria for diagnosis of
diabetes in children at high risk should be considered with more widespread
access to CGM.
CGM
Mean glucose (mg/dl)
SD (mg/dl)
CV (mg/dl)
Range (mg/dl)
% Time > 140 mg/dl
AUC (mg/min/dl)
AUC day (mg/min/dl)
Control
(Mean + SD)
107 + 9
18 + 7
17 + 6
106 + 44
0.06 + 0.06
507028 + 38239
379792 + 27481
Case
(Mean + SD)
117 + 14
26 + 9
22 + 7
154 + 48
0.18 + 0.17
601682 + 68777
459653 + 58657
Background: We analyzed the relationship between fasting plasma
glucose (FPG), the presence of autoantibodies, first phase of insulin secretion
and insulin resistance in the first degree relatives of patients with type 1
diabetes.
Materials and methods: The group studied consisted of 90 healthy
relatives, divided into two groups: “high-normal” FPG group (≥88 mg/dl) and
“low-normal” FPG group (<88/mg/dl). All subjects underwent an intravenous
glucose tolerance test, and the 1st phase insulin response (FPIR) and FPIR-toHOMA-IR-ratio were calculated. Additionally, islet autoantibodies (GADA,
IAA and IA-2A) were determined by radioimmunoassays.
Results: The subjects with “high-normal” FPG were older (p=0.0009),
had higher BMI (p<0.0001) and lower HOMA%B (p=0.0004), FPIR (p=0.006)
and FPIR-to-HOMA-IR-ratio (p=0.004) in comparison with the “low-normal”
FPG group. Autoantibodies were present in 40.9% and in 21,7% of the
subjects with “high-normal” and “low-normal” FPG, respectively. In the
“high-normal” FPG group, FPG correlated positively with GADA (r=0.31,
p=0.04), and HOMA-IR (r=0.19, p=0.02), and negatively with HOMA%B (r
=-0.36, p=0.001), whereas FPIR correlated positively with HOMA%B (r=0.55,
p=0.0001) and BMI (r=0.30, p=0.04). After an adjustment for BMI, the
difference in FPIR between the “high-normal” and “low-normal” FPG groups
remained significant (p=0.025), whereas the difference in FPIR-to-HOMA-IRratio became insignificant.
Conclusions: Our results suggest that taking into account the impact of
age and BMI on insulin sensitivity, it would be expected that the relatives
of patients with type 1 diabetes with “high-normal” glucose levels would
become gradually unable to compensate for increasing insulin resistance.
P
value
0.075
0.062
0.075
0.026
0.04
0.003
<0.001
1612-P
Increase in Weight but no Improvement in Glycaemic Control Over a
Decade in Patients Living With Type 1 Diabetes Mellitus (T1DM)
ANITA BOWES, ALEX HALE, JO HAVILAND, DAVID KERR, Bournemouth, United
Kingdom
Aims: To determine the long-term changes in weight and HbA1c in patients
living with T1DM attending a specialist diabetes centre in the UK.
Methods: Bournemouth Diabetes Centre maintains an electronic
database of patients with T1DM with body weight and HBA1c recorded
at each visit. The Centre offers (a) structured education programme for
patients using multiple daily injections of insulin (EDU), (b) insulin pump
therapy (PUMP) and (c) combination of EDU+PUMP. Non-participants of
EDU, PUMP and ED+PUMP represented the BACKGROUND population. We
compared annual changes in weight and HBA1c for these cohorts between
1999-2012. Longitudinal analyses of yearly observations were carried out
using Generalised Estimating Equations and significance assessed by the
Wald test.
Results: 1503 patients (765 men), age 41 [±17] yrs, (mean[±SD]), diabetes
duration 16 [±13] yrs were identified. Overall, there was a small annual
increase in weight (+0.16 [95% CI +0.05,+0.27] kg/year, p=0.005). The
greatest increase was in the EDU+PUMP group (n=102, +0.80 [95%CI
+0.16,+1.43] kg/year, p=0.014) compared to PUMP (n=311, +0.33 [95%CI
-0.03,+0.69] kg/year, p=0.075), EDU (n=311, +0.12 [95%CI -0.24,+0.49] kg/
year, p=0.504) and BACKGROUND (n=1278 +0.12 [95%CI -0.01, +0.26] kg/
year, p=0.080) groups.
For all groups combined, there was no change in HbA1c over time adjusted
for gender and age (p=0.432). However, the change between the groups in
HbA1c was significant (p=0.035) with a rise in the EDU group (+0.06 [95%CI
0.02, 0.10] %/year, p=0.004) compared to BACKGROUND (+0.04 [95%CI -0.02,
+0.03] %/year, p=0.76), PUMP (-0.01 [95%CI -0.04, +0.02] %/year, p=0.55),
and EDU+PUMP (+0.11 [95%CI --0.07, +0.28] %/year, p=0.23) groups.
Conclusion: For patients living with T1DM there is a small but consistent
increase in weight over time. Glycaemic control does not change markedly
with time and it may be worthwhile considering more intensive inputs to
achieve longer term benefits.
Supported by: NIH (R37DK32493)
1610-P
Longitudinal Analysis of Adiponectin through a 20 Year Type 1 Diabetes Duration
TAMARA J. LECAIRE, MARI PALTA, Madison, WI
Adiponectin (ADPN) has been proposed to be an insulin sensitizer as well as
a marker for inflammation and endothelial function. We examined the pattern
of ADPN in type 1 diabetes with age and duration, and factors predictive of
ADPN across 20 years duration. The Wisconsin Diabetes Registry conducted
clinical exams at 1, 4, 7, 9 and 20 years diabetes duration. Twenty-year
examinees (n=304) participated in (mean) 3.43 total exams yielding 1043
stored plasma samples tested for ADPN. Predictors of ADPN and tracking
in individuals across time were determined by linear mixed regression
models. A cross-sectional linear regression model at 20 years was fit for
comparison. ADPN showed significant tracking (r=0.59) within individuals.
Levels declined during childhood and adolescence. The difference between
genders (females had higher levels) increased with age. Weight (kg) and waist
circumference (cm) were negatively related with ADPN, each accounting for
approximately 4% (95% CI 2.3-5.2% and 1.1-5.8%, respectively) lower ADPN
per 5 unit increase. ADPN was higher by 4% (95% CI 2.4-5.6%) for 1% higher
HbA1c and lower with greater insulin dose and longer duration (p=0.030).
At 20 years duration, 1% change in urine albumin-creatinine ratio (UACR)
was associated with an 8% increase in ADPN (95% CI 5.4-11.7%). Both
levels and trends with duration varied significantly between individuals,
with both positive and negative slopes over time, even after adjustment for
all predictors. Markers for insulin resistance were associated with lower,
and markers for potential microvascular complications with higher ADPN,
supporting both pathways. Associations with HbA1c may represent yet
another pathway. Our results indicate ADPN levels in T1DM may reflect 3
pathways. A positive relationship between ADPN and UACR that became
stronger with duration may make it possible to identify those predisposed to
develop kidney disease earlier in the course of the disease.
Supported by: NIDDK (R01DK36904)
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A421
POSTERS
1609-P
Early Glycemic Changes Detected by CGM in Children at Risk for
Type 1 Diabetes
Epidemiology/
Genetics
EPIDEMIOLOGY—TYPE 1 DIABETES
EPIDEMIOLOGY—TYPE 1 DIABETES
1613-P
Adjusted Odds Ratios for the Achievement of Age-specific Target A1C Levels
Model 1
Model 2
Model 3
(Age < 6)
(Age 6 – 12)
(Age > 12)
n=123
n=453
n=805
Gender
1.00
1.00
1.00
Male
0.64 (0.29-1.41) 1.08 (0.74-1.58) 0.47 (0.29-0.77)*
Female
Age
1.49 (0.83-2.68) 0.94 (0.82-1.09) 1.21 (1.04-1.41)
Distance from London
< 50 km
1.00
1.00
1.00
> 50 km
0.35 (0.16-0.74)* 0.88 (0.60-1.28) 1.09 (0.69-1.74)
Household Income
< $57,000
1.00
1.00
1.00
> $57,000
0.85 (0.36-1.96) 1.18 (0.80-1.73) 1.15 (0.71-1.85)
Diabetes duration
0.85 (0.58-1.24) 1.01 (0.92-1.10) 1.13 (1.06-1.21)*
Body Mass Index
1.10 (0.77-1.59) 1.03 (0.98-1.09) 1.06 (1.01-1.12)*
Attainment of the Previous
Age-Specific Target A1C Level
No
N/A
1.00
1.00
Yes
1.26 (0.84-1.89) 1.95 (1.33-2.86)
Note: Odds Ratio of 1.00 denotes reference category.
95% Confidence Intervals are shown in the brackets.
* Denotes p=0.2 for a stepwise model building entry criteria
A Decade of Temporal Trends in Overweight/Obesity in Youth With
Type 1 Diabetes (T1D) Since the DCCT
CHARU BASKARAN, MONICA M. DIAZ, LISA K. VOLKENING, LORI M. LAFFEL,
Boston, MA
POSTERS
Epidemiology/
Genetics
Youth with T1D are at risk for untoward weight gain due to the combined
influences of the current epidemic of childhood overweight/obesity and
greater use of intensive insulin therapy, which was associated with weight
gain in the DCCT. We assessed use of intensive insulin therapy and weight
status in 4 unique cohorts of T1D youth from 1999-2009. The 537 T1D youth
(48% male) were 8-16 years old and had T1D for 0.5-15 years across all
cohorts. Cohorts differed in age and T1D duration (Table); there were no
significant differences in sex, race, or A1c. Intensive management increased
significantly over time, noted by more frequent daily BG monitoring (p<.0001)
and greater use of intensive insulin therapy, defined as 3+ injections/day
or pump use, which increased from 51% to 96% (p<.0001). Overall, 1/3 of
T1D youth were overweight/obese and zBMI was similar in all cohorts. In
multivariate analysis, higher A1c was related to higher daily insulin dose
(p<.004), less frequent BG monitoring (p<.0001), injection-based insulin
therapy (p<.008), non-white race (p<.0001), and later cohort (p<.001) but A1c
was not related to zBMI. zBMI was not related to intensive insulin therapy
or cohort. Despite near universal intensive insulin therapy, prevalence of
overweight/obesity in T1D youth remained stable over a decade, a pattern
similar to the general pediatric population. However, A1c remains suboptimal
in T1D youth, underscoring the need to reduce risk for future complications.
Participant characteristics according to study cohort
1999
2002
2006
2009
(N=100) (N=153) (N=138) (n=146)
Age (years)
12.1±2.3 12.9±2.3 12.1±1.9 13.5±2.4
T1D duration (years)
2.7±1.5 6.3±3.5
5.6±3.3 6.6±3.5
z-BMI (SDS)
0.7±0.8 0.8±0.7
0.6±0.8 0.7±0.8
Overweight/obesity (%)
18 / 10 25 / 12
26 / 7
22 / 13
BG monitoring (times/day)
3.6±0.7 3.8±1.2
5.2±2.1 5.2±2.2
A1c (%)
8.4±1.1 8.4±1.4
8.3±1.1 8.7±1.4
Regimen (Pump / ≥3 daily injections / 1 / 50 / 49 23 / 62 / 15 41 / 57 / 2 66 / 30 / 4
≤2 daily injections) (%)
1615-P
P value
Trend of Type 1 Diabetes Mellitus Incidence in Children in Beijing
Based on Hospitalization Data During 1995-2010
<.001
<.0001
.66
.5
<.0001
.18
<.0001
CHUN XIU GONG, XI MENG, BING YAN CAO, DI WU, Beijing, China
The incidence of type 1 diabetes mellitus (T1DM) in children younger than
15 years is increasing. Our aim was to assess the trend of T1DM incidence in
Beijing children since 1995 and to predict the number of T1DM in the future.
We collected the newly diagnosed T1DM children younger than 15 years in
Beijing Children’s Hospital in 1995-2010, calculated the incidence of Beijing
children with T1DM, and defined it as the estimated incidence rate.
The standard average estimated incidence was 1.3/100,000 during 19952010, increasing from 0.57/100,000 to 2.25/100,000. The estimated incidence
increased in all age groups compared between 1995-2002 and 2003-2010:
from 0.24/100, 000 to 0.57/100,000 in 0-4 years, from 1.31/100,000 to
2.12/100,000 in 5-9 years, from 1.25/100,000 to 1.86/100,000 in 10-14 years.
The predicted number of new T1DM cases will increase 1.1 times and the
percentage distribution of new cases will be 34.89% (<5 yrs), 37.08% (5-9
yrs) and 28.03% (10-14 yrs) in 2020.
So in conclusion, The T1DM incidence of Beijing children definitely
increased. The age group with greatest increase of estimated incidence was
the younger than 5 years. The predicted new T1DM cases will be more even
distribution across whole age-groups.
Supported by: R01DK046887; Charles H. Hood Foundation
1614-P
Predictors of Glycemic Control in Children and Adolescents With
Type 1 Diabetes in Southwestern Ontario
TAMARA SPAIC, STEWART B. HARRIS, JEFFREY MAHON, London, ON, Canada
Optimal glycemic control in children with type 1 diabetes (T1D) is essential
but often difficult to achieve. There are limited data on factors associated
with suboptimal control under ‘real-world’ conditions.
We performed a population based cohort study from 1998-2008 using
a clinical database (Humabase) at the Children’s Hospital in London, ON.
Over 80% of incident cases of T1D in Southwestern Ontario are followed
in Humabase. Our goal was to identify factors that predicted attainment of
Canadian Diabetes Association age-specific A1C targets (< 8.5% [0-6 years],
<8 % [6-12 years], <7% [>12 years]) in routine clinical practice. Predictors
of interest are listed in the Table. Relationships between these variables
and reaching target A1C levels were assessed by multivariable logistic
regression within each age group.
There were 996 subjects (52 % male) aged 2-20 yrs with T1D for ≥ 1 yr (mean =
9 yrs) in the study. Proportions of subjects with target A1C levels at the last
visit were 63 % < 6 yrs, 44 % 6-12 yrs, and 9.8% > 12 yrs. Results are shown
in the Table. Distance from treatment center predicted target A1C those <6
yrs, while male gender, longer diabetes duration, and higher BMI predicted
target A1C levels among adolescents. This first Canadian study using a
regional pediatric T1D clinical database suggests that attainment of target
A1C levels in routine practice is sub-optimal, particularly in adolescents, and
that a limited number of factors influence glycemic control.
1616-P
Residual C-Peptide in Patients 3-81 Years from Diagnosis of T1D: A
T1D Exchange Study
ASA DAVIS, MICHAEL J. HALLER, KELLEE MILLER, STEPHANIE DUBOSE, CHRISTINA CARPENTER, LINDA DIMEGLIO, DAVID R. LILJENQUIST, ANDREW AHMANN, SANTICA M. MARCOVINA, CARLA GREENBAUM, ROY BECK, Seattle,
WA, Gainesville, FL, Tampa, FL, Indianapolis, IN, Idaho Falls, ID, Portland, OR
While robust data are available to describe the natural history of β-cell
function in T1D immediately following diagnosis, limited data are available
to describe persistence of β-cell function in those diagnosed with T1D for
≥ 3 years.
Eight hundred and eighty eight T1D individuals from 27 T1D Exchange
Clinics were stratified into 10 groups (100/group) by T1D duration and age of
T1D onset (half diagnosed as adults >18 years).
The prevalence of detectable C-peptide (>0.017 nmol/L) varied according
to T1D duration and age at diagnosis (Figure). For most T1D duration groups,
more of those diagnosed as adults had detectable C-peptide. In subjects
diagnosed as children the percentage of individuals still making their own
insulin remained constant (~7%) in 10-19, 20-40 and >40 years duration
groups. Thus, frequency of persistent C-peptide in those >40 years from
diagnosis was approximately equivalent between those diagnosed as
children and those diagnosed as adults.
&
For author disclosure information, see page 829.
A422
Guided Audio Tour poster
ADA-Funded Research
EPIDEMIOLOGY—TYPE 1 DIABETES
Nearly 30 years after the start of the DCCT, the EDIC Study conducted a
4-hour mixed meal tolerance test in 58 patients selected to be most likely
to have residual beta cell function based on a history of near/normal HbA1c
throughout DCCT/EDIC and/or above average stimulated C-peptide at DCCT
baseline. C-peptide was measured by chemiluminescent immunoassay.
Of the 58 patients with an average duration of 27 (25 - 30) years, 10
(17.2%) showed a definite C-peptide response consisting of 2 or more poststimulus values > 0.03 nmol/L (Figure). All responders had a C-peptide >
0.2 nmol/L at DCCT baseline and were assigned to the intensive treatment
group. An additional 4 subjects showed a probable response based on a rise
in c-peptide levels post-stimulus, though the peak was in the range of 0.005
to 0.023 nmol/L.
These results show that a stimulated C-peptide response can be measured,
albeit at low concentrations, in some patients with long-term T1D. Further
investigation of all surviving DCCT/EDIC patients will help relate residual
C-peptide response to history of HbA1c, insulin dose, severe hypoglycemia,
retinopathy, nephropathy and macrovascular disease.
The frequency of residual C-peptide decreases with time from diagnosis
regardless of age at diagnosis. Diagnosis during adulthood is associated
with greater prevalence of C-peptide with the exception of those with
duration of disease >40 years in which ~8-12% have C-peptide regardless
of age at diagnosis. Identification of immunologic and clinical characteristics
associated with retained insulin secretion over time is underway and
will provide critical data for future possible intervention trials in this
population.
Supported by: Leona M. and Harry B. Helmsley Charitable Trust
Epidemiology/
Genetics
JEROME R. BARRERA, ELIZABETH PAZ-PACHECO, CECILIA A. JIMENO, Manila,
Philippines
Insulin resistance (IR) has been proven to increase the risks for cardiovascular complications in type 2 diabetes mellitus. Recently, IR has also been
shown to play a bigger role in the natural history of type 1 diabetes mellitus
(T1DM) disease process than is commonly recognized. The objectives of this
study are to determine the prevalence of IR among Filipino adults with T1DM
and to describe the clinical features of T1DM with IR.
This cross-sectional analytic study recruited 83 adults with established
T1DM in Philippine General Hospital. Mixed-meal stimulated C-peptide
level was done to confirm the diagnosis of T1DM. IR was determined using
estimated glucose disposal rate (eGDR) with the formula of: eGDR= 24.31
- (12.22 x Waist-to-hip ratio) - (3.29 x 1 if with hypertension or on antihypertensive or x 0 if no hypertension) - (0.57 x HbA1c). Subjects with eGDR
of ≤ 7.5 mg/kg/min were considered to have IR.
The prevalence rate of insulin resistance was found to be 53% among
adults with established type 1 diabetes mellitus. Type 1 diabetic subjects
with insulin resistance were significantly older (29.59 vs 25.59, p = 0.007),
with longer duration of diabetes (59.7% vs 40.3 % with duration of diabetes
> 5yr, p = 0.037), with higher waist-to-hip ratio (0.95 vs 0.93, p = 0.005) and
with higher prevalence of hypertension (100% vs 0%, p = 0.00) than those
without insulin resistance. T1DM with insulin resistance tend to have higher
insulin requirement per day, poor glycemic control and higher BMI than those
T1DM with no insulin resistance these were not significantly different.
The result of this study showed a high prevalence rate of insulin
resistance among Filipino adults with long standing type 1 diabetes mellitus.
Hypertension, older age, longer duration of disease and a higher waist-to-hip
ratio are the features more common in type 1 diabetic patients with insulin
resistance than those without insulin resistance.
Supported by: NIH
1619-P
Increasing Prevalence and Younger Age at Onset of Type 1 Diabetes
in Migrant than Italian Children With Type 1 Diabetes: An Emerging
Problem
FRANCESCO CADARIO, GRAZIELLA BRUNO, FRANCO CERUTTI, SILVIA SAVASTIO, STEFANO TUMINI, ITALIAN SOCIETY OF PEDIATRIC ENDOCRINOLOGY AND
DIABETOLOGY STUDY GROUP (SIEDP), Novara, Italy, Turin, Italy, Chieti, Italy
The worldwide increasing incidence of type 1 diabetes (T1DM) is due
to the interaction between environmental determinants and genetic
susceptibility, probably promoting β-cell autoimmunity in early childhood.
Epidemiological studies on people migrated represents a unique opportunity
to test the effect of enviromental modification on incidence of T1DM. In
Italy, a three-fold increase in the number of migrants, particularly in the
youngest age groups occurred in the last two decades. The Italian Society
of Pediatric Endocrinology and Diabetology Study Group (ISPED) performed
a clinic-based, multicentre study including 36 pediatric outpatients clinics,
to examine the burden of the disease in migrated children on our health
care system. Of 4674 children, aged 0-14 years currently cared for T1DM,
720 were from families who migrated to Italy, 33.3% from Morocco,
11.0% Romania, 6.8% Albania, 45.6% from other countries at lower risk
of T1DM (Eastern Europe, Latin America, Asia) and 4.3% only from higher
risk European countries. The prevalence of migrated children with T1DM
has increased five-fold, from 3.4% to 15.4% and most of diabetic children
(71.7%) were born in Italy. Mean age at onset of T1DM was lower in migrated
children born in Italy than in Italian children (5.2 years, IQR 2.3-7.7 vs 9.8
years, 5.9-13.0; p<0.001), whereas it was higher in migrated children who
were born in their original countries (7.8 years, 4.6-10.4). Epidemiological
studies have shown a shift to earlier age of onset of type 1 diabetes in EastCentral Europe and a doubling of incidence in children younger than 5 years
is predicted between 2005 and 2020 in Europe. Although a rise in incidence
in very young children has not been observed in Italy, environmental factors
operating in this age group might be similar. A poor socioeconomic status
with overcrowding may expose to a greater risk of perinatal infection with
diabetogenic microorganisms triggering β-cell autoimmunity.
Supported by: Philippine Society of Endocrinology and Metabolism
1618-P
Residual Beta Cell Function in Patients With Long-Term Type 1 Diabetes
ROSE A. GUBITOSI-KLUG, PAULA MCGEE, MARGARET BAYLESS, MAREN NOWICKI, PATRICIA A. CLEARY, MICHAEL W. STEFFES, JOHN M. LACHIN, JERRY P.
PALMER, DCCT/EDIC RESEARCH GROUP, Cleveland, OH, Rockville, MD, Iowa City,
IA, Minneapolis, MN, Washington, DC, Seattle, WA
The benefits of a stimulated C-peptide response early in T1D include the
ability to achieve optimal glycemic control with less hypoglycemia and to
reduce the development and progression of retinopathy and nephropathy.
However, C-peptide secretion declines over time, and it is not known
whether stimulated C-peptide is common after long-term diabetes.
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A423
POSTERS
1617-P
Insulin Resistance among Adults With Type 1 Diabetes Mellitus at
the Philippine General Hospital
GENETICS—TYPE 1 DIABETES
GENETICS—TYPE 1 DIABETES
&
Guided Audio Tour: Genetics of Type 1 Diabetes and Related Traits (Posters:
1620-P to 1627-P), see page 17.
&
GARETH J. MCKAY, DAVID H. KAVANAGH, DAVID A. SAVAGE, CHRISTOPHER C.
PATTERSON, AMY J. MCKNIGHT, JOHN K. CREAN, JOSE C. FLOREZ, ALEXANDER P. MAXWELL, THE WARREN 3/UK GOKIND STUDY GROUP, Belfast, United
Kingdom, Dublin, Ireland, Boston, MA
1620-P
Non-Synonymous Single Nucleotide Polymorphisms in the IA-2
Gene Improve Prediction of Type 1 Diabetes
Both glomerular sclerosis and renal interstitial fibrosis are characteristic
of diabetic nephropathy (DN) with several studies implicating members of
the WNT signalling pathways in these pathological processes. Our study
sought to comprehensively study common genetic variants in the WNT
pathway for association with DN.
More than 65 genes have been implicated in the WNT pathways.
Genes were selected for analysis on the basis of nominal significance and
consistent direction of effect within each of the 3 independent cohorts used
in the GENIE genome-wide association study (GWAS) meta-analysis dataset.
Common SNPs and inferred haplotypes not available from the GWAS data
were examined within selected genes in a white population with type
1 diabetes, discordant for DN (cases: n=718; controls: n=749). SNPs were
genotyped using Sequenom or Taqman assays. Association analyses were
performed using PLINK, to compare allele and haplotype frequencies in
cases and controls. Correction for multiple testing was performed by either
permutation testing or using false discovery rate.
A logistic regression model including collection center, duration of
diabetes, and average HbA1c as covariates highlighted three SNPs in GSK3B
(rs17810235, rs17471, rs334543), two in DAAM1 (rs1253192, rs1252906) and
one in NFAT5 (rs17297207) as being significantly (P<0.05) associated with
DN, although these SNPs did not remain significant following correction
for multiple testing. Logistic regression analysis of haplotypes with ESRD
and pairwise interaction analyses failed to identify significant association
following correction for multiple testing.
Our results suggest that both common SNPs and haplotypes of WNT
signalling pathway genes are not strongly associated with DN. Nonetheless,
this does not completely exclude these or indeed the WNT pathways from
association with DN, as unidentified rare genetic or copy number variants
could potentially contribute to the genetic architecture of this diabetic
complication.
POSTERS
Epidemiology/
Genetics
MICHAEL P. MORRAN, SANTIAGO SCHNELL, YING-JIAN ZHANG, LIPING YU,
DOROTHY J. BECKER, MASSIMO PIETROPAOLO, Ann Arbor, MI, Aurora, CO, Pittsburgh, PA
The neuroendocrine tyrosine phosphatase-like protein IA-2 is a
transmembrane glycoprotein localized in the secretory granules of β-cells
and a major autoantigen in type 1 diabetes (T1D). Autoantibodies (Ab) to
IA-2 are utilized to identify subjects at risk of developing T1D for enrollment
in prevention trials. Our full length IA-2 nucleotide sequence contains three
validated non-synonymous SNPs (listed in SNP Consortium and Celera
databases) (SNP-IA-2; aa residues 27, 608, and 671). Protein sequence
and folding analysis indicates that the IA-2 variants influence the overall
folding of SNP-IA-2 and create potential new Ab-protein interaction sites
compared to native IA-2. Serum samples were evaluated in 333 relatives of
T1D patients (102 of whom were initially normoglycemic prediabetics before
they progressed to T1D; follow-up range 0.1-20.8 yr; median follow-up 6.1
yr) and 87 newly diagnosed T1D patients. SNP-IA-2 (and conventional IA2ic, ICA512bdc constructs), GAD65 and insulin Ab were assayed in these
subjects. The cutoff point for the SNP-IA-2 Ab assay was established as
the 99th percentile of 308 healthy control values. The prevalence of Ab to
SNP-IA-2 was 60% in new onset T1D and 36.2% in prediabetics respectively.
Kaplan and Meier analysis revealed that a subgroup subjects with no
detectable Ab against the conventional constructs (IA-2ic or ICA512bdc)
exhibited Ab responses toward SNP-IA-2 (Log rank, P = 0.008). This effect
was also observed in relatives positive for GAD65 (Log rank, P = 0.026) or
at least 2 non-IA-2 related autoantigen constructs (Log rank, P = 0.022). This
subgroup of subjects with Ab to SNPs-IA-2 exhibited a very high risk as well
as rapid progression to T1D onset. This finding may provide a mechanistic
link in the search for new pathogenic IA-2 epitopes associated with disease
progression. Identification of sequence variants of IA-2 may lead to advances
in peptide-based immunotherapies targeted to prevent T1D at its preclinical
stage.
Supported by: Northern Ireland Kidney Research Fund
&
Supported by: NIDDK/NIH
&
1622-P
Genetic Association Analysis of WNT Signalling Pathway Genes in
Diabetic Nephropathy
1623-P
Impairment of DNA Repair Pathway as a Novel Mechanism Underlying Diabetic Complications in Patients With Longstanding Type 1
Diabetes
1621-P
The RBP-Jk Type 1 Diabetes Susceptibility Allele Is Associated
With an Alteration in Memory CD4+ T Cells
SHWETA BHATT, RACHAEL MARTINEZ, TOMOZUMI TAKATANI, MARINA A.
GRITSENKO, WEI-JUN QIAN, BRIDGET K. WAGNER, CHONG WEE LIEW, HILLARY
KEENAN, GEORGE L. KING, AMY J. WAGERS, ROHIT N. KULKARNI, Boston, MA,
Richland, WA, Cambridge, MA
WASSIM ELYAMAN, WILL ORENT, RIBAL BASSIL, PHILIP DE JAGER, SAMIA
KHOURY, ELIZABETH BRADSHAW, Boston, MA
Recent genome-wide association studies (GWAS) identified a susceptibility
locus, rs10517086AA that implicates the recombinant binding protein for
immunoglobin kappa J region (RBP-Jκ) gene as a risk factor for type 1 diabetes
(T1D) (combined P value of genome-wide association studies and replication =
4.6x10-10) and rheumatoid arthritis. We have shown that RBP-Jκ, a
downstream transcription effector of Notch signaling, is a positive regulator of
interleukin (IL)-9 transcription, therefore we examined the biologic phenotypes
of healthy subjects selected from the PhenoGenetic cohort at Brigham and
Women’s Hospital, based on homozygousity for the risk or protective allele.
We found that healthy subjects homozygous for the rs10517086AA risk
allele have increase mRNA expression of RBP-Jκ in CD4+CD45RO+ memory
cells (n=8/genotype, p=0.02) but not CD4+CD45RO- naïve T cells relative
to control subjects homozygous for the rs10517086GG protective allele.
As a consequence, the cytokine profile of TCR-stimulated memory T cells
carrying the rs10517086AA risk allele was marked by a specific increase in
IL-9 production as measured by flow cytometry (n=14/group, p=0.01). We also
found an increase in proliferation by the 3H-thymidine incorporation method.
Interestingly, we did not detect any changes in other inflammatory cytokines
including IL-4, IL-10, IL-17 and IFN-gamma. These findings are in agreement
with our recent study demonstrating high levels of IL-9 in memory T-cells from
T1D subjects polarized under Th17 cell conditions (Beriou et al, 2010).
Our results point towards a correlation between rs10517086 and RBP-JK
expression, T-cell activation and IL-9 production in CD4+CD45RO+ memory
T-cells. These studies provide a rational approach for the dissection of the
role of Notch signaling in T1D and may yield novel insights and targets that
can be leveraged for the development of therapeutics for pre-symptomatic
T1D.
Type 1 diabetes (T1D) is associated with micro- and macro-vascular complications whose underlying molecular mechanisms remain elusive due to lack
of cellular models that mimic in vivo disease phenotype. To circumvent this,
we derived induced pluripotent stem cells (iPSCs) by reprogramming skin
fibroblasts obtained from patients with ≥50 years of T1D with (+C) or without
(-C) complications or healthy controls (n=6). Reprogramming efficiency was
compromised in T1D+C (0.002%) compared to T1D-C (0.01%) or controls (0.02%)
[p<0.001]. Furthermore, iPSCs from T1D+C demonstrated impaired in vitro and
in vivo (post transplantation into mice) differentiation potential (10%), unlike
controls (90%) or T1D-C (70%) [p<0.001] suggesting impaired regeneration/
cellular differentiation. To explore the molecular basis, we subjected the iPSCs
to microarray gene expression and quantitative mass-spectrometry proteomics
analyses. Intriguingly, phospho-histone2AX (pH2AX), a surrogate for DNA
double strand breaks (DSBs), was up-regulated in T1D+C. Components of the
DSB repair machinery were down-regulated and phosphorylation-dependent
activation of downstream effectors, Chk1 and Chk2 was impaired (p<0.001).
Further investigations revealed an increased expression of miR200 family of
micro-RNAs in T1D+C (p<0.001). Indeed, over-expression of miR200a and/
or miR200b/c down-regulated ATM/ATR proteins, reduced pChk1 and pChk2
expression, increased pH2AX and cellular apoptosis. These changes were
reversed by restoration of endogenous ATM/ATR proteins. This phenomenon
was consistent in patient fibroblasts and in cell lines representing target cells
in T1D complications (e.g. beta cells, kidney cells) suggesting clinical relevance.
Our work highlights the regulation of DNA DSB repair pathway by miR200 as a
novel mechanism underlying diabetic complications, alterations in which may
enable better therapeutics to reduce the burden of T1D.
Supported by: JDRF; NIH
&
For author disclosure information, see page 829.
A424
Guided Audio Tour poster
ADA-Funded Research
GENETICS—TYPE 1 DIABETES
&
1624-P
1626-P
FOXP3 Mutations Causing Neonatal Diabetes Without Classic Features of IPEX Syndrome
ANGELA M. HENSCHEL, SHUANG JIA, MARY KALDUNSKI, SCOTT PAVLETICH,
JOHN CORBETT, MARTIN J. HESSNER, Milwaukee, WI
JESSICA L. HWANG, HONGGANG YE, VERONICA P. PAZ, ASHLEY PASTORE, XIAOMING LIU, CRAIG L. HANIS, LOUIS H. PHILIPSON, SIRI ATMA W. GREELEY,
Chicago, IL, Houston, TX
Spontaneous T1D in lymphopenic BB DRlyp/lyp rats depends on Iddm1
(MHC class-II, RT1u/u) and Iddm2 (Gimap5-/-, resulting in regulatory T-cell
(TREG) deficiency). BB DR+/+ littermates, wild-type for Gimap5, are not
lymphopenic nor spontaneously diabetic but develop T1D upon TREGdepletion. Introgression of Iddm1 and Iddm2 onto the F344 rat genome is
insufficient for T1D, supporting that BB rats possess additional susceptibility
that is absent in the F344 strain. Unlike other rat strains, BB rat β-cells show
evidence of duress by expressing the chemokine eotaxin after weaning but
before insulitis. To identify genes/pathways that may contribute to isletspecific BB rat T1D susceptibility we used global gene expression profiling
to longitudinally examine the islet transcriptome of DRlyp/lyp, DR+/+ and
nondiabetic Iddm1/Iddm2 congenic F344 control rats during the DRlyp/lyp
pre-onset period: days 20 (weaning), 30 (prior to histological detection of
eotaxin expression), 40 (prior to insulitis) and 50 (early insulitis) (n= 6-10 rats/
cohort). Pathway analysis of transcripts longitudinally regulated in the DRlyp/
lyp and DR+/+ rats but not in the F344 control rats identified an increase in
positive regulation of immune response and chemokine activity, consistent
with a response to lipopolysaccharide and reports of gut hyperpermeability
in BB rats. Upstream regulator analysis based on time-wise comparisons
(| log2 ratio | > 0.5 for BB vs F344 control) identified increased transcript
abundances related to NFkB activation (CXCL10, CXCL2, IRF1, HSPA9 and
VCAM1) by day 40 in the DR+/+ (z-score 3.283; overlap p-value 1.62E-06).
Upstream regulator analyses also showed several activated NFkB regulators
(z-score > 2.0; p < 0.005) in day 30 DRlyp/lyp and day 40 DR+/+ islets including
TNF, IL1 and CHUK. These data support the hypothesis that both BB sub
strains possess an underlying islet-level susceptibility that, in the absence
of immune regulation, results in progression to T1D.
0132SB01
0075JW01
c.1040G>A
c.340C>T
R347H
R114W
Previous reports
Multiple
None
reports-variable
phenotype
Current age (yr)
19
31
Gestational age (wk)
42
40
Birth weight (gm)
3900
3930
Diabetes dx age (wk)
1.5
26.1
Diabetes treatment
Insulin pump Glargine/lispro
Last HbA1c (%)
9.3
7.8
Autoimmune/
Result not
+ anti-thyroid
antibodies
available
FOXP3 mutation
Supported by: NIH
&
1625-P
Encephalomyocarditis (EMC)-D Virus-Induced Diabetes in Tyk2
Gene Knockout Mice
KEIICHIRO MINE, MIHO TESHIMA, YUJI KAI, KATSUYA KAI, KEN-ICHI IZUMI,
HIRONORI KURISAKI, HITOSHI KATSUTA, SEIHO NAGAFUCHI, Fukuoka, Japan,
Saga, Japan
Type 1 diabetes mellitus results form the progressive loss of pancreatic β
cells. The virus, as one of environmental factors, has long been considered
to play a role in the development of type 1 DM. The D variant of encephalomyocarditis (EMC-D) virus induced susceptible strain of mice to induce type
1 diabetes, serving as an excellent animal model of virus-induced diabetes.
We have already reported that innate immunity may play an important role
in protection against EMC-D virus-induced diabetes. In the present study,
we focused on tyrosine kinase 2 (Tyk2) gene which is an interferon receptor
associated signaling molecule. We analyzed the role of Tyk2 gene in the
pathogenic mechanism of EMC-D virus-induced diabetes by using Tyk2 gene
knockout (KO) mice. Tyk2 gene KO C57BL/6J mice developed diabetes. These
mice presented extensive destruction of pancreatic βcells and infiltrations of
mononuclear leukocyte into pancreatic βcells were also observed. In order
to examine whether Tyk2 gene expression was important in parenchymal or
immune cells to protect against EMC-D virus-induced diabetes, we developed
splenic chimera mice: lethally irradiated mice receiving spleen cells. Here,
we have shown that Tyk2 gene expression was important in parenchymal
cells, but not in spleen cells, to resist against EMC-D virus-induced diabetes.
Furthermore, to evaluate Tyk2 gene expression in pancreatic βcells, we
developed mice that Tyk2 gene was specifically expressed in pancreatic β
cells: mouse-insulin-promoter-Tyk2 (MIP-Tyk2) transgenic mice. Consistently,
Tyk2 KO mice crossed with Tyk2 transgenic mice that express Tyk2 gene
specifically in pancreatic beta cells, prevented EMC-D virus-induced
diabetes, without destruction of pancreatic β cells nor infiltrations of
mononuclear leukocyte into pancreatic islets. These observations suggest
that Tyk2 gene expressed in pancreatic β cells plays an important role to
protect against EMC-D virus-induced diabetes in mice.
Gastrointestinal
No enteropathy
Skin
Other medical
problems
Mild eczema
Short stature;
frequent nighttime hypoglycemia associated
with seizures
Immunosuppression
Never
0078NC01
c.1044+5G>A
0078NC04
c.1044+5G>A
One report with classic IPEX
9
41
3520
104.5 (2.1 yrs)
Insulin pump
7.9
+ anti-islet cell
- anti-thyroid
- anti-adrenal
- anti-enterocyte
- TTG/endomysial
7
37.5
3400
26.7
Insulin pump
8.4
+ anti-insulin
+ anti-parietal cell
- anti-thyroid
- anti-adrenal
- anti-enterocyte
- TTG
Mild chronic Extreme FTT, weight at <
No
discomfort
5th percentile; EGD enteropathy
result: inactive peptic
duodenitis and inactive
chronic gastritis; no
apparent enteropathy
Mild eczema Severe eczema, vitiligo Mild eczema
Hypothyroidism Paralyzed diaphragm Vitamin B12
with temporary tracheo- deficiency
stomy; multiple pneumonias and pump site
infections, one time
pyelonephritis
Never
Never
Never
Supported by: UC DRTC (P60 DK020595); JDRF (9-2008-177); NIH (UL1RR024999)
Supported by: Ministry of Health, Labor and Welfare (Japan)
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A425
POSTERS
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked
(IPEX) syndrome is a rare autoimmune disorder caused by mutations in
FOXP3, a gene encoding a forkhead box transcription factor required for
the function of CD4 + CD25 + regulatory T cells which regulate immunologic
tolerance. In addition to neonatal diabetes (NDM), classic IPEX includes
severe autoimmune enteropathy and eczema. Even with aggressive
immunosuppressive treatment or stem cell transplant, death often occurs
by 24 months of age from failure to thrive or sepsis. We describe the variable
phenotypes of subjects unexpectedly found to have FOXP3 mutations within
our Neonatal Diabetes Registry (https://monogenicdiabetes.uchicago.edu/
neonatal-registry/). Exome sequencing of 19 probands without a known
cause for NDM revealed 3 different FOXP3 mutations in 4 male subjects
in 3 families. One mutation is novel (R114W). Clinical information is shown
in the table (0078NC01 and 0078NC04 are brothers). We conclude that
mutations in FOXP3 are not uncommon in patients with NDM even when
they lack other features of IPEX syndrome. Our prevalence is comparable to
a previous report of FOXP3 mutations found in 6.7% of confirmed monogenic
cases. The four cases we describe have only mild inconsistent IPEX-like
features, are currently 7 to 31 years old and have never been treated with
immunosuppressives. Mutations in FOXP3 should be considered in male
patients with early onset diabetes with or without other features.
Epidemiology/
Genetics
&
Biobreeding (BB) Rat Islets Exhibit Underlying Islet Dysfunction Independent of Insulitis and T1D Onset
GENETICS—TYPE 1 DIABETES
&
1629-P
1627-P
Evidence of Stage- and Age-Related Heterogeneity With Non-HLA
Single Nucleotide Polymorphisms (SNPs) and Risk of Islet Autoimmunity (IA) and Type 1 Diabetes (T1D)—The Diabetes Autoimmunity
Study in the Young (DAISY)
Evidence of a Preserved CRP Response to Acute Inflammation in
HNF1A-MODY
SAIMA A. MUGHAL, TIM J. JAMES, SUSAN BEATTY, MARK I. MCCARTHY,
KATHARINE R. OWEN, Oxford, United Kingdom
BRITTNI N. FREDERIKSEN, ANDREA K. STECK, MIRANDA KROEHL, MOLLY M.
LAMB, RANDALL WONG, MARIAN J. REWERS, JILL M. NORRIS, Aurora, CO
Previously, we had examined over 30 non-HLA SNPs in DAISY, and
found SNPs in PTPN22, UBASH3A, INS and IFIHI to be associated with IA
development and/or progression to T1D, two stages in T1D development.
We now investigate 15 additional non-HLA T1D candidate SNPs. Of 1,622
non-Hispanic white DAISY children genotyped, 130 developed IA (defined as
positive for GAD, insulin or IA-2 autoantibodies on two or more consecutive
visits), and 44 IA positive children progressed to T1D. We conducted Cox
regression analyses to examine risk of IA, and progression to T1D in IA
positive children, and whether risk varies by age. C1QTNF6 (rs229541)
predicted increased IA risk, and PRKCQ (rs947474) predicted decreased risk
of progression to T1D in IA positive children. SNP (rs10517086) appears to
exhibit an age-related effect on risk of IA, with increased risk in younger
ages but not older ages (Age*SNP interaction p=0.003). SNP (rs10517086)
was also associated with increased risk of progression to T1D in IA positive
children. SNPs (rs2825932, rs9388489, rs1465788, rs2069762, rs4505848,
rs12722563, rs7804356, rs7221109, rs2104286, rs6897932, rs3788013,
and rs5979785) were not associated with IA or T1D development. This
prospective investigation of T1D loci shows that some SNPs may exhibit
stage- and age-related heterogeneity in the natural history of T1D.
Association between non-HLA SNPs and risk of IA and progression to T1D in
IA positive children
SNP
Minor MAF Risk of IA HR P value Progression to T1D HR P
allele
(95% CI)
(95% CI)
value
rs229541 (C1QTNF6)
A 0.44 1.52 (1.16, 1.98) 0.002
0.37 (0.17, 0.80)
0.01
rs947474 (PRKCQ)
G 0.17 1.30 (0.88, 1.91) 0.19
0.37 (0.17, 0.80)
0.01
rs2104286 (IL2RA)
C 0.27 0.85 (0.63, 1.16) 0.30
1.37 (0.80, 2.33)
0.25
rs6897932 (IL7R)
T 0.28 0.89 (0.65, 1.21) 0.45
0.79 (0.52, 1.21)
0.28
rs3788013 (UBASH3A) A 0.44 1.24 (0.93, 1.66) 0.14
1.18 (0.78, 1.78)
0.43
rs10517086
A 0.30 1.00 (0.73, 1.35) 0.97
1.69 (1.03, 2.76)
0.04
*All SNPs adjusted for HLA-DR3/4,DQB1*0302 genotype and first degree relative with T1D and analyzed additively except PRKCQ, which was dichotomized for at least 1 minor allele. Table limited to SNP analysis models with
p<0.30.
POSTERS
Epidemiology/
Genetics
HNF1A regulates hepatic C-reactive protein (CRP) production and we
reported that European subjects with HNF1A mutations (HNF1A-MODY)
have low baseline levels of CRP. As HNF1A is part of the transcriptional
complex involved in interleukin-6 stimulated CRP production during acute
inflammation, we hypothesised that they would also have an attenuated
CRP rise during an acute inflammatory stimulus. This could lead to impaired
complement activation and macrophage function in HNF1A-MODY.
HNF1A-MODY subjects with diabetes (n=7) and normoglycaemic BMI
and gender-matched controls (n=9), received intravenous endotoxin (E.
coli lipopolysaccharide: 2ng/kg). Serum CRP, white cell count (WCC) and
erythrocyte sedimentation rate (ESR) were measured at baseline and 2, 4, 6,
24 hours and 8 days after endotoxin administration.
CRP and WCC rose as expected in response to endotoxin in both groups
(Figure 1) while no consistent response was seen with ESR. We found no
difference in either the CRP levels or the WCC at any time point during the
acute inflammatory response in subjects with HNF1A-MODY compared to
controls (p=0.42 and 0.15 respectively by repeated measure analysis of
variance). Peak mean CRP (HNF1A-MODY vs. controls) was 28.1 vs. 31.7 mg/L
at 24hrs (p=0.45) and peak mean WCC was 11.2 vs. 9.5 at 6 hours (p=0.31).
In conclusion, we demonstrate that HNF1A haploinsufficiency does not
appear to impair CRP production during the response to a moderate acute
inflammatory stimulus.
Supported by: Oxfordshire Health Services Research Committee
1628-P
Supported by: NIH (R01DK49654), (R01DK32493), (P30DK57516), (UL1RR025780)
Confirmation that Dominant Inheritance of a GATA6 Mutation
Causes Cardiac Defects, Dorsal Pancreatic Agenesis and Diabetes
With Variable Expression
1630-P
DAVID P. MACFARLANE, DAVID GOUDIE, JONATHAN BERG, ANDREW J. CASSIDY, JOANNE RAMSAY, ANNA M. CHOY, ALASDAIR MACKIE, EWAN R. PEARSON, Dundee, United Kingdom
Longitudinal Change in Regional Brain Volumes in Early Wolfram
Syndrome: A Preliminary Report
De novo mutations in the transcription factor encoding GATA6 gene have
recently been described as the commonest cause of pancreatic agenesis
with insulin treated neonatal diabetes, and are commonly associated with
congenital cardiac defects. More recently a Japanese family was found to
have a dominantly inherited GATA6 mutation with variable expression of
the clinical phenotype. Here we describe the case of an affected proband
with a confirmed GATA6 mutation, with a number of family members
displaying variable features of the GATA6 mutation syndrome. Following
an atrial-septal defect (ASD) repair aged 35, our proband had 2 successful
pregnancies complicated by gestational diabetes, and developed diabetes
aged 42, rapidly progressing to insulin therapy. Both daughters (now aged 16
& 18) had congenital heart disease, both with a patent ductus arteriosus and
ASDs, but have no signs of pancreatic endocrine or exocrine insufficiency.
Imaging confirmed pancreatic hypoplasia (absent body and tail) in the
proband and 1 daughter, with rotational abnormalities of the proximal
small bowel also seen in the proband. DNA sequencing in the proband, and
daughters revealed a GATA6 c.1620+5G>A mutation located in intron 6,
predicted to reduce efficiency of the splice donor site. The proband’s parents
have no similar clinical features, but a paternal aunt had suspected type 1
diabetes and 1 of the proband’s 5 siblings was diagnosed with suspected
type 1 diabetes in his third decade. He has 4 live children, 2 with congenital
cardiac abnormalities (pulmonary stenosis and VSD), suggesting that he
may also have inherited the GATA6 mutation, although genetic studies
are outstanding. In summary, we have described a new kindred with a
dominantly inherited suspected pathogenic mutation in the GATA6 gene
causing variable clinical features of congenital cardiac disease, pancreatic
hypoplasia and diabetes presenting later in life.
HEATHER M. LUGAR, JERREL RUTLIN, JONATHAN M. KOLLER, JOSHUA SHIMONY, TAMARA HERSHEY, THE WASHINGTON UNIVERSITY WOLFRAM STUDY
GROUP, St. Louis, MO
Wolfram syndrome (WFS) is a rare autosomal recessive disease with
childhood onset insulin dependent diabetes, optic nerve atrophy, hearing
loss, diabetes insipidus and neurodegeneration that results in death by
middle adulthood. We previously determined that WFS is associated with
reduced brainstem and cerebellar volumes even in the youngest patients
with the mildest symptoms. However, little is known about the course of
neurodegeneration in WFS, particularly at the early stages of the disease.
We acquired structural magnetic resonance imaging on 14 relatively young
WFS patients. Mean age at entry was 13.7 years (SD=5.6, range=5.9 to 25.8).
Ten of these patients were scanned twice and 7 were scanned 3 times, at
1 year intervals. Brainstem, cerebellar gray and cerebellar white matter
were measured using Freesurfer. No volumetric changes were seen after
only 1 year, but a significant decrease in volume was seen over 2 years in
cerebellar gray matter (p=.04), with marginal decreases in brainstem (p=.06)
and cerebellar white matter (p=.09). Examination of a cross-sectional,
convenience sample of healthy controls (n=53) and type 1 diabetics (n=26)
suggested that a decrease in cerebellar gray matter volume is expected
over this age range (r=-.40, p<.001). In contrast, brainstem and cerebellar
white matter volumes tend to increase over this age range in non-WFS
groups (both r=.22, p=.05), suggesting that the WFS patients diverge from a
typical developmental trajectory in these regions. There was also a negative
correlation between age at entry and percent change in brainstem volume
over 2 years (rs=-.43, p=.05), indicating accelerated loss of brainstem volume
&
For author disclosure information, see page 829.
A426
Guided Audio Tour poster
ADA-Funded Research
GENETICS—TYPE 2 DIABETES
wide significance. The common lead SNPs are specific to one ancestry group,
or are polymorphic across ethnicities with predominantly homogenous
effects on T2D susceptibility. Whole exome sequencing of these individuals
will allow evaluation of the role of rare genetic variation on T2D susceptibility
within and between major ancestry groups.
with age. Longitudinal follow-up of a larger WFS cohort and control groups
is ongoing and will be critical for drawing stronger conclusions. However,
preliminary results indicate that structural neuroimaging metrics have
promise as potential biomarkers of neurodegeneration in early WFS.
Supported by: Snow MIR; NIH (DK01674639), (DK064832); NCRR (10RR02298401A),
(UL1RR024992), (HD070855)
&
1631-P
1633-P
Multiethnic Whole Exome Sequencing Identifies Low Frequency
and Rare Coding Variants Associated With Glycemic Traits: Results
from T2D-GENES
Influence of Endogenous IL-27 on Human Monocytes
ELIZABETH M. BRADSHAW, WASSIM ELYAMAN, MICHAEL FRANGIEH, ANNA
TANG, ANGELINA BERNEIR, NIR HACOHEN, VIJAY K. KUCHROO, Boston, MA
Supported by: BADERC; JDRF
Supported by: NIDDK; NHGRI; NIH
GENETICS—TYPE 2 DIABETES
&
Guided Audio Tour: Genetics of Type 2 Diabetes and Related Traits (Posters:
1632-P to 1639-P), see page 17.
&
VASILIKI LAGOU, REEDIK MAGI, LETIZIA MARULLO, KRISTA FISCHER, GUDMAR
THORLEIFSSON, BEBEN BENYAMIN, MIKAEL AKERLUND, SYMEN LIGTHART,
HARMEN H.M. DRAISMA, IDA SURAKKA, SARA HÄGG, JULIE DUMONT, ALINE
MEIRHAEGHE, MARIKA KAAKINEN, MASSIMO MANGINO, JANINA S. RIED,
ANUBHA MAHAJAN, MOMOKO HORIKOSHI, KONSTANTIN STRAUCH, SAMULI
RIPATTI, ANDREW P. MORRIS, VALERIYA LYSSENKO, INGA PROKOPENKO, Oxford,
United Kingdom, Tartu, Estonia, Reykjavik, Iceland, Queensland, Australia, Malmö,
Sweden, Rotterdam, Netherlands, Amsterdam, Netherlands, Helsinki, Finland,
Stockholm, Sweden, Lille, France, Oulu, Finland, London, United Kingdom, Neuherberg, Germany
1632-P
Genome-Wide Association Study of 10,947 Type 2 Diabetes Cases
and Controls from Five Ancestry Groups Provides Novel Insights
into the Genetic Architecture of the Disease
ANDREW P. MORRIS, XUELING SIM, PIERRE FONTANILLAS, T2D-GENES CONSORTIUM, Oxford, United Kingdom, Ann Arbor, MI, Cambridge, MA
We undertook a genome-wide association study (GWAS) of type 2
diabetes (T2D) from five ancestry groups: African American (AA), East Asian
(EA), European, Hispanic American and South Asian. We performed transethnic meta-analysis (MANTRA) of 5,464 T2D cases and 5,483 controls,
imputed at up to 32.3 million variants from the 1000 Genomes Project
(Phase I), providing near complete coverage of variation with minor allele
frequency (MAF) ≥1% in each ancestry group. With these data, we aimed
to: (i) identify novel T2D susceptibility loci; and (ii) provide insights into the
genetic architecture of the disease.
We identified 3 novel susceptibility loci at genome-wide significance,
defined by log10 Bayes’ factor (BF) > 6, near PDGFRL (log10BF=6.43), CLDN10
(log10BF=6.37) and LEP (log10BF=6.36). The lead variant near PDGFRL is
common (MAF≥5%) in all ancestry groups and demonstrates consistent
odds ratios (OR) across ethnicities (fixed-effects OR=1.20 [1.13-1.28]). The
lead variant near LEP is also common in all ancestry groups, but the allelic
effect is heterogeneous between ethnicities (log10BF=5.07), and is specific
to EA populations (MAF=10.5%, OR=1.85 [1.50-2.27]). At CLDN10, the lead
variant is rare (MAF<1%) in EA, EU, HA and SA populations, so that the effect
is AA-specific (MAF=8.7%, OR=1.98 [1.58-2.49]).
Our results highlight the benefits of trans-ethnic GWAS meta-analysis for
discovery and characterisation of T2D susceptibility loci. We identified no
low-frequency variants (MAF<5%) at novel or established loci at genomeADA-Funded Research
&
1634-P
Large-Scale Multi-Phenotype Meta-Analysis Evaluates Pleiotropic
Effects on Cardiometabolic Factors and Risk for Type 2 Diabetes
(T2D) at FTO, FADS1 and GIPR Loci
Cardiometabolic risk factors and T2D are correlated epidemiologically and
share common genetic predisposition, as confirmed by single-trait genomewide association studies. Therefore, a large-scale multi-trait analysis can
be a valuable tool to dissect independence of effects of a genetic variant on
metabolic traits and disease risk, e.g. pleiotropy. We aimed to a) evaluate
the multi-trait analysis method using FTO variant known to exert its action
via body mass index (BMI) and b) explore multi-trait effects at FADS1 and
GIPR. We implemented a method that utilizes multiple logistic regression
with a genetic marker as the outcome and traits as explanatory variables.
Multi-phenotype sets were analysed based on their differential availability
in participating cohorts. Model selection was based on Bayesian Information
Criterion scores summed across studies from derived model likelihoods.
Analysis was performed in up to 167,984 European individuals from 25 studies
within the ENGAGE consortium. Consistent with previous reports, the multitrait meta-analysis confirmed BMI as driving associations with other traits
at FTO, suggesting absence of pleiotropy. Variants at FADS1 have an effect
on lipids, fasting glucose and resting heart rate among others. At FADS1, the
best models within multi-phenotype sets underscored independent effects
for triglycerides and total cholesterol (TG/TC, PLRT =1.6x10 -78). Variants at GIPR
For author disclosure information, see page 829.
Guided Audio Tour poster
A427
POSTERS
Type 2 diabetes (T2D) is a worldwide health concern with a complex
genetic basis. Common genetic variants (MAF>5%) in over 50 loci are
associated with variation in levels of fasting glucose (FG) and insulin (FI).
We tested the hypothesis that rare (MAF<0.5%) and low frequency (LF
0.5%<MAF<5%) variants contribute to variation in FG, FI, and A1C.
Within T2D-GENES consortium, we analyzed whole exome sequences for
1943 subjects used as controls in studies on type 2 diabetes (T2D) of East
Asian (EA, 547 from Korea, 450 from Singapore), South East Asian (SA, 577
Singapore), and European (EU, 369 Finland) origins. We performed singlevariant analysis using all cohorts combined and also each cohort separately.
We also performed gene level burden tests, which aggregate evidence for
association across rare and LF variants within each gene.
We identified 1.8 million variants, 91% of which were rare, 5% were LF,
and 4% were common. We found a genome-wide significant LF-rare variant
associated with A1C in the G6PD gene from the combined sample analysis
(rs72554665, p=1.8x10 -10, MAF 1.7% and 0.1% among EA and SA from
Singapore, monomorphic for Korean EA and EU). Suggestive association
was found between G6PD and FG (p=0.03). Burden tests on FG showed
association with two novel genes POLR1B (p=8.1x10 -7) and IRF9 (p=1.8x10 -6).
Whole exome sequencing identified rare and LF coding SNPs associated
with A1C and FG in a large multiethnic sample. The variant rs72554665 is
a mutation that causes G6PD deficiency and severe hemolytic anemia. Its
association with A1C is likely to be secondary to altered red blood cell life
span, but suggestive association with FG suggests involvement in glucose
homeostasis. Variation at rs72554665 in G6PD is population specific. IRF9
is reported to be a key JAK-STAT pathway factor in eliciting the antiproliferative activity of IFN-alpha, but the mechanism linking it with glucose
homeostasis remains to be elucidated.
Epidemiology/
Genetics
HAE KYUNG IM, T2D-GENES CONSORTIUM, Chicago, IL
IL27 was recently identified as a genetic risk locus for type 1 diabetes,
however how this locus influences susceptibility to type 1 diabetes is
unknown. IL-27 is a pleiotropic cytokine that initially was described as
being pro-inflammatory and an inducer of Th1 cells. More recently it has
been described as an anti-inflammatory cytokine in that it suppresses proinflammatory T helper (Th)17 cells and induces anti-inflammatory T regulatory
(Tr)1 cells. While the majority of studies are focused on the effects of IL-27
on T cells, antigen-presenting cells appear to express high levels of the IL27 receptor ex vivo, as well as be the major producers of it. We have found
that monocytes, negatively isolated by MACS beads from healthy subjects,
in the resting state are repressed by endogenous IL-27, in that the addition
of a neutralizing antibody increases the production of pro-inflammatory
cytokines (IL-6, IL-1b, TNF-a). We are pursuing a systems biology approach
to determine which pathways are repressed by endogenous IL-27. While LPS
activated monocytes produce more IL-27 than resting-state monocytes, they
no longer respond to endogenous IL-27, presumably due to their rapid loss
of surface IL-27 receptor upon activation. Interestingly, ex vivo monocytes
from type 1 diabetic subjects produce more IL-27, consistent with the
studies demonstrating that monocytes from type 1 diabetic subjects are in
an activated state. We also observed that neutralizing endogenous IL-27 in
monocyte-CD4+T cell co-cultures leads to the predicted increase in T cell IL17 production and decrease in IL-10 and IL-21 production. Interestingly, IL10
and IL21 are also in genetic loci associated with type 1 diabetes. IL-27 plays
many roles in the immune system and understanding its primary contribution
to type 1 diabetes susceptibility could lead to potential early intervention
treatments.
GENETICS—TYPE 2 DIABETES
allele of the rs2074196 SNP, and stimulated the transcriptional activity of
the artificial promoter including the rs2074196 SNP in allele-specific manner.
These results suggested that the rs2074196 SNP modulate the affinity of the
locus for KSBF5-7 and induce the subsequent change in gene expression,
which would provide important clues for how the type 2 diabetes-associated
SNPs within KCNQ1 gene promote the disease risk.
are associated with BMI, T2D and 2 hour post load glucose and insulin. We
were not able to detect pleiotropy at GIPR; however we could not rule it out
due to a smaller number of individuals with 2-hour glucose measurements in
the current study. The multi-trait method for dissecting genetic associations
on cardiometabolic risk factors and T2D demonstrated that variants at
FTO confirm BMI-mediated effects, while those at FADS1 exert pleiotropic
effects influencing lipid metabolism, specifically TG and TC.
&
Supported by: European Network for Genetic and Genomic Epidemiology
&
1635-P
Silencing of the Type 2 Diabetes-Associated Gene ADCY5 Impairs
Glucose-Stimulated Insulin Secretion from Human Islets
ERIC R. GAMAZON, NANCY J. COX, SWAPAN K. DAS, Chicago, IL, Winston-Salem,
NC
POSTERS
GUY A. RUTTER, RYAN MITCHELL, MARCO BUGLIANI, PIERO MARCHETTI, DOMENICO BOSCO, PAUL R. JOHNSON, STEPHEN HUGHES, WEN-HONG LI, DALIANG LI, DAVID J. HODSON, London, United Kingdom, Pisa, Italy, Geneva, Switzerland, Oxford, United Kingdom, Dallas, TX
Epidemiology/
Genetics
1637-P
Adipose eQTLs Identify Genetic Basis of Metabolic Traits and Insulin Sensitivity Associated SNPs With Predictive Effect on β Cell
Function
Genome wide association studies (GWAS) have identified single
nucleotide polymorphisms (SNPs) associated with obesity, type 2 diabetes
(T2D) and related metabolic traits (MT). Here, we analyzed genome-wide
adipose expression data (Illumina Human HT-12 V4 chip) from a cohort of 136
metabolically well-characterized non-diabetic subjects (age 19-59 yrs, BMI
19-42, SI 0.66-13.02, and Caucasian/African American 99/37). We found that
physiological variables and hidden confounders have significant effects on
gene expression and conditioning on them substantially improves power to
identify expression quantitative trait loci (eQTLs). We conducted an eQTL
study of SNPs (n=487, Illumina-HumanExome-12v1.1 chip) reproducibly
associated with BMI, T2D, and MT from the comprehensive NHGRI catalogue
of GWAS findings. BMI, T2D, and MT showed trait-specific enrichment for
adipose eQTLs relative to genomic background whereas no adipose eQTL
enrichment was observed among (as control) the subset of SNPs associated
with neurodegenerative disorders (schizophrenia and bipolar). We identified
hundreds of eQTLs among the MT associated SNPs, including cis-eQTLs for
ATP13A1 (triglyceride associated SNP rs17216525, p = 1.16X10 -14), CPEB4
(WHR associated SNP rs6861681, p = 3.27 X10 -11) and ADIPOQ (adiponectin
associated SNP rs17366568, p= 8.17X 10 -11). Using MAGIC consortium data,
we observed a significant excess (p<0.001) of β cell function (HOMA-B)
associated SNPs among top insulin resistance (IR, using HOMA-IR)
associated SNPs (p<1X10 -4). Remarkably, IR associated eQTLs showed a
more dramatic enrichment for SNPs predictive of β cell function relative to
other IR associated SNPs. These findings suggest that eQTL mapping using
detailed physiological phenotypes substantially enhances power to identify
the genetic basis of metabolic traits as well as IR associated SNPs, in a
peripheral tissue, with significant predictive effect on β cell function.
Genome-wide association studies have recently identified a single
nucleotide polymorphism (SNP), rs2877716, which increases the risk of
elevated fasting blood glucose and type 2 diabetes. The SNP is located on
chromosome 3 in intron 1 of the ADCY5 gene, encoding the cAMP-generating
enzyme adenyl cyclase 5. Parallel sequencing has shown that ADCY5 mRNA
levels occupy the top quintile in purified human islets, whilst lower levels are
expressed in mouse islets. We therefore sought to investigate the impact of
silencing this gene on beta cell function using human islets.
To monitor the cell dynamics underlying insulin secretion within intact
human islets, intracellular free Ca2+ ([Ca2+]i) was imaged using fluo2 whilst
the cell surface-bound Zn2+ probe, ZIMIR, monitored hormone release. Genesilencing was achieved using lentivirus particles harbouring shRNA against
ADCY5 or scrambled control (Con). Incubation with lentivirus for 72 h was
sufficient to silence ADCY5 mRNA expression by ~90% in dissociated islets
and ~30% in intact islets. ADCY5 silencing dramatically (63.7 ± 3.0%; P<0.01)
suppressed glucose- (11 vs 3 mM) stimulated rises in [Ca2+]i and mildly
(26.4 ± 2.7%) reduced coordinated cell activity (P<0.05, n = 9 recordings).
Apparent insulin release in the continued presence of the sugar was also
lowered by ADCY5 silencing (64.2 ± 1.7%; P<0.01) (n = 5 recordings). These
actions were not due to cAMP-independent effects on ATP-sensitive K+- or
voltage-gated Ca2+-channels, as silencing did not alter Ca2+ rises induced
by KCl. Paradoxically, ADCY5 knockdown subtly but significantly enhanced
the amplitude and AUC of GLP-1-evoked increases in [Ca2+]i (P<0.01).
In summary, ADCY5 potentiates glucose- but may restrain incretinstimulated insulin secretion. These results are consistent with the
observation that carriers of the rs2877716 variant of ADCY5 present with
elevated fasting glucose, but a normal insulinogenic index 2 hr post-oral
glucose load.
Supported by: NIH (DK039311)
&
1638-P
Parent-of-Origin Effect of GRB10 Variant on Glucose Metabolism
and Islet Function in Man
Supported by: Diabetes UK; Wellcome Trust (MRCEUFP7); The Royal Society
MASAKI HIRAMOTO, HARUHIDE UDAGAWA, ATSUSHI WATANABE, MIHO
KAWAGUCHI, WATARU NISHIMURA, TAKAO NAMMO, KAZUKI YASUDA, Tokyo,
Japan, Obu, Japan
WENNY POON, INGA PROKOPENKO, REEDIK MAGI, ALBERT SALEHI, PETER
ALMGREN, RASHMI PRASAD, B. PETER OSMARK, NILS WIERUP, NABILA
BOUATIA-NAJI, CHARLOTTE LING, PETER KOVACS, ERIK INGELSSON, MARK
MCCARTHY, ALAN SHULDINER, KRISTI SILVER, MARKKU LAAKSO, LEIF GROOP,
VALERIYA LYSSENKO, MAGIC INVESTIGATORS, Malmö, Sweden, London, United
Kingdom, Oxford, United Kingdom, Paris, France, Leipzig, Germany, Uppsala, Sweden,
Baltimore, MD, Kuopio, Finland
Genome-wide association studies have identified a lot of SNPs that are
associated with type 2 diabetes. However, because the most of these SNPs
are located in non-coding regions of the genome, the mechanism by which
they promote disease risk have remained elusive. Type 2 diabetes-associated
SNPs identified in KCNQ1 gene are also located in intron 15 of KCNQ1, a gene
that encodes the alpha-subunit of the voltage-gated potassium channel. In
this study, we tried to identify the proteins that bind this locus in allelespecific manner, and to verify the relationship between the functions of
these proteins and the risk of type 2 diabetes.
We first prepared 2 types of beads, that is, risk allele beads and non-risk
allele beads by immobilizing each allelic DNA onto magnetic nanobeads.
Using these beads, we purified DNA-binding proteins from nuclear extract
of INS-1 pancreatic beta-cell line and analyzed the proteins by SDS-PAGE.
Comparing the bound proteins between using 2 types of beads, we picked
up the differentially bound proteins (KSBFs) and identified the proteins using
mass spectrometry analysis. We next confirmed the DNA-binding activities
of KSBFs in vitro using recombinant proteins and in cell lines using chromatin
immunoprecipitation assay. We further examined the transcriptional
activities of KSBFs using luciferase reporter assay.
We found that the affinities of several proteins for the examined SNPs
(rs2074196, rs2237892, rs2237895, and rs2237897) within KCNQ1 gene
were different between the alleles. KSBF5-7 specifically bound the non-risk
Despite that many identified type 2 diabetes-associated genetic variants
seem to influence β-cell function, no large-scale studies to date have
evaluated the extent to which common genetic variants influence dynamic
measures of insulin secretion. In the Meta-Analyses for Glucose- and
Insulin-related traits Consortium (MAGIC), we conducted a GWAS metaanalysis for dynamic measures of insulin response to glucose during OGTT.
The combined discovery and replication analyses in up to 26,037 nondiabetic individuals identified a variant in the growth factor receptor-bound
protein 10 (GRB10) gene (rs933360) to be associated with reduced glucosestimulated insulin secretion (GSIS) at 30 min at genome-wide significance
level (β=-0.051, p=3.14×10 -09). Paradoxically, the insulin-reducing A-allele
was also associated with reduced fasting glucose levels (N=23,208, β=0.016, p=0.007). GRB10 is imprinted in a parent-of-origin manner in different
tissues. We examined the effect of rs933360 on GSIS in 2,000 non-diabetic
unique individuals from 2,289 parents-offspring trios from Finland, Sweden
and USA. We observed that maternally transmitted A-allele was associated
with reduced GSIS (5 out of 8 indices: β=-0.127--0.095, p=0.005-0.016). No
effect was observed for paternally transmitted A-allele on insulin secretion.
Surprisingly, maternally transmitted A-allele was associated with reduced
glucose levels (β=-0.139, p=0.001). In contrast, paternally transmitted
A-allele was associated with elevated glucose levels (β=0.102, p=0.002).
Disruption of GRB10 through knock-down (KD) in human pancreatic islets
&
1636-P
Type 2 Diabetes-Associated SNPs Within KCNQ1 Gene Modulate
the Affinity of the Locus for DNA-Binding Factors
&
For author disclosure information, see page 829.
A428
Guided Audio Tour poster
ADA-Funded Research
GENETICS—TYPE 2 DIABETES
resulted in reduced glucagon secretion. The strong effect of GRB10 KD may
explain the paradoxical reduction of glucose values despite a decrease
in insulin secretion. Taken together, these data provide new insights into
the mechanisms by which GRB10 influences glucose metabolism, and the
potential targeting of GRB10 as a mean to lower glucose without influencing
insulin secretion.
&
1639-P
1641-P
Variation in MODY Genes Observed in Whole Exome Sequence Data
from 10,000 Individuals: T2D-GENES Consortium
Genome-Wide Association Analysis Identifies Variants Associated
With Non-Alcoholic Fatty Liver Disease in Koreans
HEATHER M. HIGHLAND, PIERRE FONTANILLAS, GRAEME I. BELL, NANCY J.
COX, CRAIG L. HANIS, T2D-GENES CONSORTIUM, Houston, TX, Cambridge, MA,
Chicago, IL
JAE HEE AHN, JI HEE YU, CHAI RYOUNG EUN, SEUNG KU LEE, HO CHEOL HONG,
HAE YOON CHOI, YOON JUNG KIM, NAM HOON KIM, HYE JIN YOO, JI A. SEO,
SIN GON KIM, KYUNG MOOK CHOI, SEI HYUN BAIK, DONG SEOP CHOI, CHOL
SHIN, NAN HEE KIM, Seoul, Republic of Korea
Maturity onset diabetes of the young (MODY) is often misdiagnosed as
type 2 diabetes (T2D) and approximately 1-2% of individuals diagnosed with
T2D may have MODY. The most common causes of MODY in Europeans
are heterozygous mutations in HNF1A, GCK, HNF4A, and HNF1B. We are
systematically documenting the array of variation seen in these and other
monogenic diabetes genes in 5000 individuals diagnosed with T2D and
5000 controls from 5 ancestry groups that have undergone deep coverage
whole exome sequencing as part of the T2D-GENES Consortium. The array
of variation seen in these genes in the first 5328 sequenced individuals (2755
controls and 2572 cases) is not significantly different in cases and controls
as expected based on ascertainment (Table 1).
Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease.
Ethnicity and genetic factors may influence on the incidence and severity of
NAFLD. This study was aimed to identify genetic variants associated with
NAFLD by genome-wide association study (GWAS) in Korean population.
In 2,269 samples from the population-based cohort, the Korean Genome
Epidemiology Study, SNP markers with call rate (<95%), low MAF (<0.01) and
Hardy-Weinberg equilibrium (P < 1x10 -6) were excluded, leaving a total of
316,078 markers to be examined. Using unenhanced CT, the liver attenuation
index (LAI) was calculated. NAFLD was defined by LAI <5 HU.
SNPs in PNPLA3-SAMM50 gene (rs12483959, rs2076211, rs2281135,
rs2073081, rs1883350, rs2143571, rs2281298, rs16991236) in chromosome
22, and in NRBF2-JMJD1C gene (rs12416113, rs9414780, rs9629895, rs907,
rs10761745) in chromosome 10 were significantly associated with LAI after
adjusting for age, sex, and body mass index (p value 3*10 -6~7.8*10 -15). The
metabolic risk factors were not different according to haplotypes from
PNPLA3. In the logistic regression model, odds ratio for NAFLD in the lowLAI-haplotype group from PNPLA3 gene was increased compared to the
high-LAI-haplotype group after adjusting for metabolic risk factors. These
associations were seen consistently, regardless of obesity status or liver
function test. The log likelihood ratio test showed that the model with
PNPLA3 haplotype and metabolic risk factors fitted better than that with
metabolic factors only (p <0.001). In the imputation analysis, rs738409, the
known functional SNP were in linkage disequilibrium with several SNPs
found in the present this study.
We identified several genetic variants in PNPLA3-SAMM50, NRBF2JMJD1c genes associated with NAFLD in GWAS. These findings suggest
that several genetic variants may confer increased susceptibility to NAFLD
regardless of obesity and conventional metabolic risk factors in Koreans.
Table 1. Number of variants with MAF<0.005 observed split by effect on protein sequence
genes nonsense and nonsynony- nonsynonymous non-damagsynonymous
mous damaging
ing
# in cases/ # variants # in cases/ # variants # in cases/ # variants
# in controls
# in controls
# in controls
HNF1A
30/25
22
13/20
8
138/111
39
GCK
7/3
6
3/1
4
75/91
23
HNF4A
7/2
5
23/21
19
78/75
29
HNF1B
4/3
12
4/3
5
47/37
17
Within each gene, we tested the combined effect of the rare damaging
variants using SKAT. After correcting for multiple testing, this revealed no
genome-wide significant association with T2D in any of these genes with the
smallest being p=0.012 in HNF1A. However, sequencing demonstrates that a
wide array of variation is apparently well tolerated in MODY genes, and that
rare mutations in MODY genes are not likely to be a frequent cause of T2D.
We are undertaking parallel analyses for other monogenic diabetes genes,
including: INS, KCNJ11, ABCC8, PAX4, NEUROD1, FOXP3, and EIF2AK3. Cataloging the array of coding variation this large multiethnic sample provides
insight into the biological relationship of these genes to T2D.
1642-P
Identification of a Candidate Gene for Type 2 Diabetes using Outbred
Rats
LEAH C. SOLBERG WOODS, KATIE HOLL, SHIRNG-WERN TSAIH, SHUANG JIA,
MARY KALDUNKSI, MICHAEL TSCHANNEN, JAIME WENDT ANDRAE, RAYMOND HOFFMANN, PIPPA SIMPSON, HOWARD JACOB, MARTIN HESSNER,
Milwaukee, WI
1640-P
Genome-Wide Association Studies (GWAS) Meta-Analyses for A1c
Levels in European and African American Ancestry Samples Reveal
Novel Genetic Risk Variants
Despite the success of human genome wide association studies (GWAS),
much of the heritable variance for type 2 diabetes remains unknown. Outbred
animals such as heterogeneous stocks (HS) allow for rapid fine-mapping of
quantitative trait loci (QTL), and thus offer a complementary approach to
identify genes involved in complex traits. Our laboratory has used HS rats to
investigate a 60 Mb region on rat chromosome 1 that has previously been
implicated in glucose tolerance. We narrowed this region to a 3.1 Mb QTL
that maps fasting glucose and glucose tolerance and which sits within a
7.1 Mb QTL for fasting insulin and insulin resistance (1, 2). We hypothesized
that expression and sequence analysis would enable us to identify a novel
candidate gene within this region. Using the Affymetrix 230_2 array, we
measured expression levels in liver of HS rats that differed in response to
a glucose tolerance test. We identified one gene within this region, two
pore channel 2 (Tpcn2), that was differentially expressed between HS rats
with normal glucose and those with glucose intolerance and that mapped
as a cis-acting expression QTL. We then used sequence information from
the founder strains to identify a non-synonymous coding variant within this
gene. We found that this variant was associated with a 6-fold decrease
in expression levels as well as significantly increased fasting glucose and
insulin levels. Using data from human consortiums, DIAGRAM and MAGIC,
we found that variants within Tpcn2 are significantly associated with
increased fasting insulin levels in humans, indicating this gene may play a
role in human diabetes. Tpcn2 is a lysosomal channel involved in mediating
MARIE-FRANCE HIVERT, ELEANOR WHEELER, CHING-TI LIU, ON BEHALF OF
MAGIC AND AAGILE, Sherbrooke, QC, Canada, Cambridge, United Kingdom, Boston, MA
A1c is now recommended for type 2 diabetes (T2D) diagnosis. The MetaAnalyses of Glucose and Insulin-related traits Consortium (MAGIC) previously
undertook a GWAS meta-analysis of A1c levels in up to 45,000 non-diabetic
European individuals and revealed 10 loci (P<5x10-8). MAGIC has now
performed an updated meta-analysis in up to 132,914 European individuals.
In parallel, the African American Glucose and Insulin Genetic Epidemiology
(AAGILE) Consortium has performed a meta-analysis of GWAS for A1C in up
to 6845 non-diabetic individuals from 7 cohorts. Samples were genotyped
using standard GWAS platforms or the Metabochip. Variants were excluded
if minor allele frequency (MAF)<0.01, HWE<10-4, call rate<0.95, or failed
imputation. The European results confirm all 10 previously identified MAGIC
signals and identify 34 additional loci including some previously found to
be associated with red blood cell traits (eg. CTD1, P=1.2x10-27), glycemia
(eg. SLC2A2, P=1.9x10-11) or type 2 diabetes (eg. SLC30A8, P=1.6x10-18). In
AAGILE, a missense variation in G6PD (Val ==>Met) previously associated
with glucose-6-phosphatase dehydrogenase deficiency was strongly
associated with lower A1c levels (P=6.8x10-122) in line with higher red cell
turnover. This variant is monomorphic in populations of European descent but
common in African descent populations (YRI hapmap: MAF=0.22). Another
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A429
POSTERS
Supported by: VR; ALF; Novo Nordisk Foundation; ERC; NIH
Epidemiology/
Genetics
suggestive genome-wide significant locus includes SNPs in/near EPS15L1/
KLF2 (P=3.8x10-8). Current analyses combining European and African descent
samples using Meta-ANalysis of Transethnic Association Studies (MANTRA)
software are underway to increase power and to improve the resolution of
fine-mapping of causal variants by leveraging differences in local linkage
disequilibrium structure between ethnic groups. Our findings might influence
the use of A1c for T2D diagnosis in specific ethnic backgrounds.
GENETICS—TYPE 2 DIABETES
and subsequent genotype-phenotype correlation can be applied to identify
new T2D relevant genes and quantitative trait associations.
calcium release. To date, however, there is no known role for Tpcn2 in
regulating fasting glucose or insulin levels in the liver. Current work in the
laboratory is investigating the hypothesis that Tpcn2 is the causative gene
in this locus.
1. Solberg Woods LC, et al., Physiol Genomics 41: 102-108, 2010.
2. Solberg Woods LC, et al., Physiol Genomics 44: 1013-1026, 2012.
1645-P
Gene Expression and Metformin Efficacy in Type 2 Diabetes (T2D)
SABRINA PRUDENTE, ANDREA MASOTTI, MASSIMILIANO COPETTI, NUNZIA
CAPORARELLO, VITTORIA PROTO, LETIZIA DA SACCO, ELEONORA MORINI, LUANA MERCURI, DIEGO BAILETTI, ANTONIO PALENA, ROBERTO BARATTA, SALVATORE DE COSMO, FABIO PELLEGRINI, ORNELLA LUDOVICO, LUCIA FRITTITTA,
VINCENZO TRISCHITTA, San Giovanni Rotondo, Italy, Rome, Italy, Catania, Italy
Supported by: AHW (5520137); CRIPIR (2206339)
1643-P
Reduction of Relative Hyperglucagonemia by Leptin Efficiently Controls Hyperglycemia in the Akita Mouse
Though metformin is the “first choice” oral hypoglycemic agent (OHA)
in patients with T2D, its exact mechanism of action on glycemic control is
only partially known. We hypothesized that investigating mRNA expression
profiles could help address this issue. Accordingly, we measured mRNAs
levels in peripheral white blood cells (PWBC) from 60 T2D patients at
baseline and after 3-month metformin treatment (with all previous OHA
being discontinued for 5 days before baseline).
Whole gene expression was evaluated by using the Human Gene 1.0 ST
Arrays (Affymetrix) interrogating 28,869 genes.
Bioinformatic analysis was performed using R Bioconductor and other
home-made scripts. DAVID and GO databases were employed to obtain
functional classifications.
Clinical data.
Three-month metformin therapy was effective in ameliorating BMI,
fasting glucose, HOMA-IR index and HDL-cholesterol (p< 0.01 for all).
Gene expression data.
i) After metformin treatment, 1,763 genes were differentially expressed
as compared to baseline (FDR<0.01). Bioinformatic analysis by functional
classification showed that these genes belonged to several pathways among
which only one, the spliceosome pathway, remained significantly associated
after adjusting for multiple comparisons (p=1.10 -4). In addition, metformin
efficacy (% decrease of baseline glycemia) was directly correlated with
average down-regulation of genes belonging to the spliceosome pathway
(r=0.42, p<0.001).
ii) Baseline expression of 1,435 genes was correlated to metformin
efficacy; after multiple comparison adjustment, only the spliceosome
pathway remained significantly correlated to it (p=7.10 -12). At multivariate
analysis, baseline expression level of spliceosome genes accounted for 57%
variability of metformin efficacy.
In conclusion, the spliceosome pathway seems to be involved in metformin
efficacy. This finding paves the way for a better understanding of metformin
mechanisms of action and efficacy.
POSTERS
Epidemiology/
Genetics
CARLO COLOMBO, FABRIZIO BARBETTI, Rome, Italy
Heterozygous, gain-of-function mutations of the insulin gene that
cause insulin misfolding, trapping of insulin in the endoplasmic reticulum
(ER), ER-stress and beta cell apoptosis lead to insulin deficit and neonatal
diabetes (PNDM) in men. Two mouse models carry Ins2 gene mutations
with proteotoxic effect: the Akita mouse (Ins2/C96Y) and the Munich mouse
(Ins2/C95S). However, natural history of diabetes of Akita and Munich mouse
differs from that of patients with PNDM associated with proteotoxic INS
gene mutations: while in the latter diabetic ketoacidosis (DKA) is a frequent
mode of presentation and C-peptide declines over time to undetectable
levels in most patients, both Akita and Munich mouse survive through adult
life after diabetes onset. This is in contrast with mouse models of absolute
insulin deficiency like Ins1/Ins2 double knock out, that die with DKA 2 days
after birth.
We measured total plasma insulin in the Akita and wild type mice of
2,3,4 and 7 weeks of age and found that they were identical. Interestingly,
C-peptide 2 (that reflects Ins2 secretion) measured from 2 to 25 weeks from
birth was about 50% lower in Akita than wt mice (p<0.05, by T-test) while
C-peptide 1 level was normal. In contrast, plasma glucagon was higher in the
diabetic, 7-week old Akita mice than wt mice (97 vs 5 pg/ml, p<0.005).
We applied 3 treatments to Akita mice. A single dose of 10 nmol/kg
of exendin-4 to 3-week old Akita did not modify the course of diabetes.
Insulin pellets implanted at 18, 25 and 32 days of life kept plasma glucose
in the normal range until the end of observation period (42 d of life). Leptin,
delivered by osmotic pump (6 mg/d) in 3-week old Akita, kept plasma
glucose in the low-normal range for the entire observation period (32 d of
life), while glucagon was suppressed (38 pg/ml on leptin, vs 123 pg/ml no
leptin, p<0.001).
We conclude that hyperglucagonemia, likely due to the decreased
inhibitory tone on alpha cells by beta cells, is a main driver of hyperglycemia
in the Akita mouse.
1644-P
1646-P
High Throughput Functional Analysis of Coding Variants in PPARG
Identifies Novel Loss-of-Function Alleles that Associate With Diabetes Risk and Systolic Blood Pressure
Knowledge and Attitudes Towards Clinical Genomic Research
among Hispanics Affected by Type 2 Diabetes
AMIT MAJITHIA, JASON FLANNICK, DAVID ALTSHULER, JOHN R.B. PERRY,
GOT2D CONSORTIUM, Boston, MA, Exeter, United Kingdom
LILIANA URIBE-BRUCE, ISABEL GARCIA, LINDA GALLO, JILL WAALEN, JOHANNA EUYOQUE, PATRICIA GONZALEZ, ADDIE FORTMANN, JAMES SCHULTZ,
MONICA RUIZ, ATHENA PHILIS-TSIMIKAS, San Diego, CA, La Jolla, CA
Genetic variants identified in genome scale sequencing of large type 2
diabetes (T2D) case/control cohorts potentially enable discovery of new
genes underlying T2D pathogenesis. Identifying a few biologically functional
variants among many neutral variants is a key challenge. Model systems that
allow rapid assessment of variant function in disease-relevant bioassays are
needed.
We have developed an experimental platform for the rapid and parallel
introduction of candidate mutations into human SGBS pre-adipocytes that
can be flexibly combined with a variety of phenotypic assays. In this work, we
combine high content microscopy and automated image analysis to create
a high throughput, quantitative adipocyte differentiation assay. We validate
the performance of our assay by accurately identifying previously known
gain and loss-of-function (LOF) mutations in PPARG, a master regulator of
adipogenesis implicated in insulin resistance.
We then apply our platform to functionally characterize 10 novel, nonsynonymous variants in PPARG found from sequencing 1403 T2D cases and
1331 matched controls and identify 6 new LOF variants spanning both the
DNA and ligand-binding domains. We show that LOF variants in PPARG
cluster in T2D cases (estimated odds ratio 3.32, p=.006, N=7), whereas
non-LOF variants are more evenly distributed (estimated OR=1.87, N=4).
We perform genotype-phenotype correlations with this set of biologically
functional PPARG variants for blood pressure, BMI, waist-hip-ratio, and
serum triglycerides; variants that decrease PPARG function in our assay
inversely correlate with systolic blood pressure (r^2=-0.75 p=0.03). Our
strategy of variant discovery, high-throughput experimental characterization,
The discovery of more than 60 genetic risk variants for Type 2 Diabetes
(T2D) brings the promise of personalized medicine closer to the clinic, but
populations at disproportionately higher risk for T2D, such as Hispanics,
have been underrepresented in these studies. As part of an effort to foster
participation of underrepresented groups in genomic research, a culturallytailored community survey assessing knowledge of and attitudes towards
clinical genomic research was developed and administered to Hispanics with
T2D who attended federally qualified community health centers in Southern
California. Basic genetic knowledge evaluated included: genes influencing
disease individually and in human groups, DNA biobanks and clinical use of
genetic information. Attitude items included: interest in genetic research,
disease risk prediction and privacy concerns. IRB approval was obtained.
145 Hispanics completed the survey; 49% reported education up to middle
school and 91% chose to answer in Spanish. Mean knowledge score was 7
out of possible 12. Lower knowledge scores were associated with lower
levels of education (p=0.007) and lower (USA) acculturation (p=0.006)
(ANOVA). Mean positive attitude score was 6 out of 9 possible. Higher
positive attitudes towards genomic research were associated with higher
education (p<0.001) and higher acculturation (p=0.004). Age, gender, income
and religiosity were not significantly associated with knowledge or attitudes
in this community. 93% of participants stated that they would participate in
genomic research for altruistic reasons.
We conclude that there are gaps in knowledge about genomic research
among medically underserved Hispanics, which calls for tailored education
efforts to foster informed participation of this underrepresented group in T2D
&
For author disclosure information, see page 829.
A430
Guided Audio Tour poster
ADA-Funded Research
GENETICS—TYPE 2 DIABETES
genomic research. This group expresses positive attitudes towards clinical
genomic applications and interest in participating in genomic research to
help future generations.
1649-P
Investigation of Diabetes and Related Quantitative Trait Loci in
GWAS for Insulin Sensitivity and Insulin Clearance
Supported by: NIH (5KL2-RR025773-04)
The GUARDIAN Consortium (Genetics Underlying Diabetes in Hispanics)
seeks to identify genetic loci for insulin sensitivity and insulin clearance
(IC) in 7 Hispanic cohorts (BetaGene, IRAS, IRAS Family, TRIPOD, MACAD,
NIDDM-Athero, HTN-IR), totaling 4139 non-diabetic individuals in 1875
pedigrees. Insulin sensitivity (SI) and IC were measured by FSIGT with
minimal model analysis in the first 4 cohorts. Insulin sensitivity (M/I) and IC
were measured by euglycemic clamp in the latter 3. GWAS (Illumina Omni
Express) has been completed; meta-analysis (adjusted by age and sex) was
used to combine the IC results and the SI plus M/I results across cohorts.
Herein, we examined the top loci (P<10 -3) for IC and SI+M/I for ~100 previously
identified GWAS loci for T2D and related quantitative traits (fasting glucose,
fasting insulin, 2-hr glucose, HbA1c, adiponectin). Given that the latter loci
were largely discovered in non-Hispanic cohorts, we searched by region
rather by SNP. For index SNPs within a gene, we used a gene +/- 100 kb
window. For loci outside of genes, we used SNP +/- 200 kb. 12 SNPs in 4 loci
were associated with IC: 5 SNPs in PTPRD, 4 SNPs in CDKN2A/2B, 2 SNPs
in CDKAL1 (T2D loci), and 1 SNP in CITED2 (adiponectin locus). 6 SNPs in 5
loci were associated with SI+M/I: 2 in PTPRD, 1 in JAZF1, 1 in CHCHD9 (T2D
loci), 1 in PDGFC (fasting insulin locus), and 1 in CDH13 (adiponectin locus).
None of these were the index SNP found in the prior GWAS for these traits.
The PTPRD locus is of interest, as one SNP (rs7851513) was significantly
associated with both IC (P=2.7x10 -5) and SI+M/I (P=8.6x10 -4). These results
illustrate that a subset of loci identified for T2D and related traits (largely
in Europeans and East Asians) are also among the top signals in a GWAS
meta-analysis for physiologically measured insulin sensitivity and clearance
in Hispanics. Characterizing the function of these loci in Hispanics is the first
step in elucidating the genetic architecture of T2D in this high risk ethnic
group.
MARYSA LEYA, LOREN L. ARMSTRONG, DOUGLAS A. SCHEFTNER, WILLIAM L.
LOWE, M. GEOFFREY HAYES, LYNN P. LOWE, BOYD METZGER, ALAN R. DYER,
RACHEL LOWN-HECHT, Chicago, IL
Defining the genetic basis for gestational diabetes mellitus (GDM) may
not only provide an understanding of its underlying pathogenesis, but also
help determine a woman’s risk for GDM. Using data from the Hyperglycemia
and Adverse Pregnancy Outcome (HAPO) Study, we hypothesized that
type 2 diabetes mellitus (T2DM) susceptibility and plasma glucose genes
are associated with an increased risk of GDM. To address this hypothesis,
we used genome-wide SNP data and phenotype data collected from four
ancestry groups (European, Afro-Caribbean, Hispanic, and Thai) who
participated in the HAPO Study (n=4516). Genotypes for SNPs spanning
97 genes associated with T2DM susceptibility or plasma glucose levels
in nonpregnant adults were tested for association with GDM. GDM was
defined using the new International Association of Diabetes and Pregnancy
Study Group (IADPSG) criteria and determined using maternal oral glucose
tolerance test results at ~28 weeks gestation among HAPO participants. In
addition to cohort-specific analyses, a meta-analysis across all four ancestry
groups was also performed. Fifteen genes demonstrated association
(p < 10-3) with GDM in the meta-analysis. These genes include: RYR2
(rs3766878), SIX3/2 (rs2917764, rs2922016), PPARG (rs1151999), PDGFC
(rs17035317), RAI14 (rs368823), JAZF1 (rs6968494), CAMK1D (rs4364954),
GALNTL4 (rs4444072), CENTD2 (rs12808507), MTNR1B (rs10830963), IGF1
(rs7971494), PRC1 (rs11853073), WWOX (rs9319517), CMIP (rs4889360),
and BCL2 (rs4987864). While the SNPs identified in the meta-analysis did
not necessarily reach significance within each cohort, when considered
across all ancestry groups the P-value met the designated threshold for
significance. These data suggest that there are similarities between the
genetic underpinnings of GDM, as defined using the newly created IADPSG
criteria, and T2DM susceptibility and plasma glucose levels.
1650-P
Expression Analyses Suggest Self-Regulation of TCF7L2 Across
Type 2 Diabetes Associated Variant rs7903146
1648-P
QIANGHUA XIA, SANDRA DELIARD, MATTHEW E. JOHNSON, STRUAN F.A.
GRANT, Philadelphia, PA
Epigenetics of Fasting Insulin and Glucose Concentrations
BERTHA HIDALGO, MARGUERITE RYAN IRVIN, JIN SHA, EDMOND K. KABAGAMBE, DEGUI ZHI, STELLA ASLIBEKYAN, DEVIN ABSHER, HEMANT TIWARI,
DONNA K. ARNETT, Birmingham, AL, Nashville, TN, Huntsville, AL
Variation at the TCF7L2 locus have been established to be strongly and
robustly associated with type 2 diabetes (T2D). However, the mechanism of
action by which this risk is conferred has still to be elucidated.
Interestingly, the key 8q24 locus found to be the most strongly associated
genomic region with a number of cancers through GWAS has been shown
to contribute to the disease pathogenesis through mutation of an upstream
TCF7L2-binding element driving the transcription of the MYC gene. As such,
the fact that TCF7L2 regulates the key cancer locus poses the question: does
TCF7L2 also regulate the key T2D locus, i.e. itself, through a feedback loop?
Indeed, our previous results from ChIP-seq experiments identified several
TCF7L2 binding sites within the gene itself, particularly in intron 3 where the
genetic association with T2D has been localized to. Furthermore, our initial
findings from oligo-pull down experiments suggest the proteins binding
across the key associated and probably causal SNP, rs7903146, dimerize
with TCF7L2.
Dual luciferase reporter assays were performed in quadruplicate to
determine the transcriptional activity under the control of the genomic region
across rs7903146. Firefly luciferase constructs harboring each genomic
element were co-transfected with an internal control vector, plus TCF7L2 or/
and beta-catenin, into 293T cells. Beta-catenin was analyzed as it is a well
established key mediator of Wnt signaling via activation of TCF7L2.
Our results revealed that TCF7L2 or beta-catenin separately were not
sufficient to activate transcription. However, the combination of TCF7L2
and beta-catenin produced a striking increase of approximately 5 fold in
transcription levels.
These results suggest that the Wnt signaling pathway plays a crucial
role in the regulation of TCF7L2 expression and that a possible alteration
in this feedback mechanism via rs7903146 may at least in part explain the
functional mechanism through which this variant confers T2D risk.
Background: Despite identification and replication of multiple T2D
susceptibility loci in genome-wide association studies (GWAS), much remains
to be understood about the genetic background of T2D. Characterization of
epigenetic variation across the genome can advance our understanding of
genetic susceptibility to T2D.
Methods: As in previous genetic studies among healthy individuals, we
conducted an epigenome-wide association study (EWAS) on fasting insulin
and glucose among 544 non-diabetic men and women in the Genetics
of Lipid Lowering Drugs and Diet Network study. DNA was extracted
from CD4+ T-cells isolated from frozen lymphocytes. CpG methylation at
approximately 450,000 CpG sites was assayed using the Illumina Infinium
HumanMethylation450 Beadchip. We used the LMEKIN package in R to
implement a mixed model with methylation beta score (a measure of %
methylation) as the dependent variable. In this model, insulin or glucose
and covariates (age, sex, study site, and T-cell purity) were entered as fixed
effects and family structure as a random effect. A Bonferoni corrected
P-value of 1.1x10^-7 was considered significant.
Results: In adjusted analyses, CpG06500161 was significantly associated
with insulin (P=3.8x10^-8) and CpG01881899 approached genome-wide
significance (P=6.2x10^-5) for insulin. Both CpG sites were identified on
chromosome 21. Both CpG sites are found in the ATP-binding cassette
sub-family G member 1 gene. Decreased function of ATP-binding cassette
(ABC) transporters is associated with impaired insulin secretion and may
explain the observed association. None of the CpG sites investigated was
associated with fasting glucose after correction for multiple testing.
Conclusions: Our findings suggest that differential methylation of
CpG06500161within the ABCG1 locus may be associated with fasting insulin
and merits further evaluation.
Supported by: NIH (1U01HL072524)
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A431
POSTERS
1647-P
Association of Plasma Glucose and Type 2 Diabetes Susceptibility
Genes With Gestational Diabetes
Epidemiology/
Genetics
MARK O. GOODARZI, NAN WANG, CARL D. LANGEFELD, JINRUI CUI, ANNY H.
XIANG, TALIN HARITUNIANS, YII-DER I. CHEN, KENT D. TAYLOR, JILL M. NORRIS, THOMAS A. BUCHANAN, DONALD W. BOWDEN, LESLIE J. RAFFEL, XIUQING
GUO, RICHARD M. WATANABE, JEROME I. ROTTER, LYNNE E. WAGENKNECHT,
Los Angeles, CA, Winston-Salem, NC, Pasadena, CA, Aurora, CO
GENETICS—TYPE 2 DIABETES
1651-P
1653-P
Genetic Variation Associated With Metformin Treatment Response
Genotype-Associated TCF7L2 Splice Variants and Lipid Metabolism
Provide Fine-Tuning of Wnt Pathway Regulation in Pancreatic BetaCells
POSTERS
Epidemiology/
Genetics
NIENKE VAN LEEUWEN, GIEL NIJPELS, JACQUELINE M. DEKKER, ESTHER VAN ‘T
RIET, KAIXIN ZHOU, EWAN R. PEARSON, LEEN M. ‘T HART, Leiden, Netherlands,
Amsterdam, Netherlands, Dundee, United Kingdom
PETER A. ANTINOZZI, WAYNE D. GRAHAM, ELLEN N. DOVER, Winston-Salem, NC
Metformin is the first line treatment for type 2 diabetes. Unfortunately
the glycaemic response to metformin is highly variable between individuals
and genetic factors appeared to be involved in this variability. A genomewide association study (GWAS) by Zhou et al identified a locus near the ATM
gene associated with metformin treatment response in T2D patients. In
addition to the ATM locus other loci reached borderline significance (p<10 -5)
and await confirmation in other studies. In the current study we aimed to
replicate the effect of these genetic loci on metformin treatment response
in T2D patients.
Eleven SNPs with a minor allele frequency >5% in the by GWAS identified
loci were measured in 620 patients on metformin monotherapy from the
Diabetes Care System (n=7500), a large longitudinal cohort of Dutch type
2 diabetic subjects, using a Sequenom assay. We assessed if the ability to
reach the treatment target of HbA1c ≤7% within one year after initiation
of therapy was associated with genetic variation using logistic regression
with baseline HbA1c, GFR and metformin dose as covariates. In addition to
the previously reported replication of the ATM gene association we found
that rs10007566 a SNP located between the SEPSECS and LGI2 genes on
chromosome 4 is associated with treatment failure (OR=0.69 95% CI 0.530.89, p=0.005). This is in line with the original finding in the GWAS study and
a meta-analysis combining our results with the published GWAS results in an
OR=0.71 (95% CI 0.61-0.82, p=5.2*10 -7). Interestingly, SEPSECS is required
for selenoprotein biosynthesis, a protein that is associated with T2D. There
was no significant effect on treatment response observed with the other
measured SNPs in our study, however five SNPs showed a trend in the same
direction as in the original finding.
In conclusion, using this large cohort of Dutch patients with type 2
diabetes, we have replicated that genetic variation near the SEPSECS/LGI2
genes is associated with metformin treatment failure.
Wnt signaling is a tightly coordinated pathway which transcriptionally
regulates cellular programs of proliferation and differentiation. TCF7L2 is
a transcription factor in the Wnt pathway and is one of the leading T2Dassociated candidate genes. Previous studies have demonstrated the impact
of genotype on the abundance of specific TCF7L2 splice variants, and here
we evaluate the potency of these variants on a TCF reporter assay in β-cells.
Expression of seven TCF7L2 variants comprising various exon combinations
were evaluated in the INS1E β-cell line and differentially increased
luciferase-based TCF reporter activity across a broad range (from 1.2 to
16 fold increases over basal levels). The presence of exon 4 in the splice
variant decreases activity 80% as compared to matched variants lacking
the exon. The presence of exon 4 containing variants was confirmed in
human islets by RNA-Seq. Interestingly, when evaluated against a different
reporter construct derived from the AXIN2 gene, a highly divergent ranking
of potencies was observed for the seven variants compared to the initial
reporter construct. This observation suggests that a given splice variant has
differential effects across multiple TCF-responsive genes and each TCF7L2
variant may induce an altered gene expression profile.
In INS1E cells, we observe that TCF reporter activity is dependent on the
presence of Wnt ligand. Recent structural biology findings have shown an
essential role of lipids mediating Wnt ligand interactions with its receptors.
To evaluate if lipid signaling can attenuate Wnt activity in β-cells, we
pharmacologically perturbed lipid metabolism and observed a dosedependent decrease in TCF reporter activity. Altogether, we demonstrate
Wnt ligand stimulates transcriptional activity in β-cells and both lipids and
the abundance of specific TCF7L2 isoforms can modulate this activity.
Supported by: NIH/NIDDK (DK080151)
1654-P
Supported by: Dutch Diabetes Research Foundation; ZonMw
A Genome-Wide Association Study of Glycemic Response to Oral
Glucose Tolerance Test in Gestational Diabetes Mellitus Women
1652-P
SOO HEON KWAK, SUNG-HOON KIM, SUNG HEE CHOI, BO KYUNG KOO, HYE
SEUNG JUNG, YOUNG MIN CHO, EUN ROH, YOON JI KIM, EUN KY KIM, TAE
JUNG OH, MIN KYEONG KIM, SU MIN HONG, KYONG SOO PARK, HAK CHUL
JANG, Seoul, Republic of Korea, Seoungnam-Si, Republic of Korea, Gyeonggi-Do,
Republic of Korea
Improved Performance of Precise Measures of Glucose Homeostasis over Surrogate Indices to Identify the Genetic Basis of Type 2
Diabetes: The GUARDIAN Consortium
NICHOLETTE D. PALMER, LYNNE E. WAGENKNECHT, CARL D. LANGEFELD,
THOMAS A. BUCHANAN, ANNY H. XIANG, HOOMAN ALLAYEE, RICHARD BERGMAN, LESLIE J. RAFFEL, YII-DER I. CHEN, MARK O. GOODARZI, TASHA FINGERLIN, KENT D. TAYLOR, TALIN HARITUNIANS, RICHARD M. WATANABE, DONALD
W. BOWDEN, Winston-Salem, NC, La Canada, CA, Pasadena, CA, Los Angeles, CA,
Aurora, CO
Women with gestational diabetes mellitus (GDM) is thought to have
reduced beta-cell insulin secretion that is insufficient to compensate for
the increased insulin resistance during pregnancy. As these women do not
use any anti-diabetic medication at the time of oral glucose tolerance test
(OGTT), it is a unique opportunity to investigate the association between
genetic variants and the severity of altered glucose homeostasis. We
performed a two-stage genome-wide association analysis in 1,382 Korean
GDM women. Study subjects underwent 100-g OGTT for diagnosis of GDM
and both glucose and insulin levels were determined at 0-, 1-, and 2-hour of
OGTT. Genotyping was performed using Affymetrix Genome-Wide Human
SNP array 5.0 in stage 1 subjects (N=468) and by TaqMan method in stage 2
subjects (N=914). Variables that were investigated include fasting glucose,
fasting insulin, index of beta-cell function (HOMA-B), index of insulin
resistance (HOMA-IR), area under the curve (AUC) of glucose, and AUC
of insulin. A variant in CA10, rs736146, was significantly associated with
fasting glucose in stage 1 analysis (beta=-0.31 P=1.82E-06). However, this
association was not significant in stage 2 subjects (beta=-0.01 P=0.13). The
overall effect of this variant in fasting glucose was beta=-0.04 P=4.22E-05.
A variant in ARL8B, rs13093380, was significantly associated with fasting
insulin in stage 1 subjects (beta=0.34 P=5.10E-6). This variant was also
significant in stage 2 analysis (beta=0.11 P=0.035) with overall effect of
beta=0.19 P=9.96E-06. In addition, this variant was associated with HOMAIR (overall beta=0.19 P=9.33E-06). A variant in HHEX, rs7911264, was
significantly associated with increased AUC of glucose (overall beta=0.17
P=6.84E-05) and decreased AUC of insulin (overall beta=-0.19 P=1.24E-05).
These findings require further replication studies and functional investigation
regarding the role of these variants are warranted.
Type 2 Diabetes (T2D) is characterized by insulin resistance and
compounded by beta-cell dysfunction. To date, genetic analyses have
focused on T2D status and surrogate measures of insulin resistance and
beta-cell function derived from plasma glucose and insulin. Alternatively,
we investigated the genetic basis of dynamic measures of insulin secretion
in Hispanic Americans from the GUARDIAN (Genetics Underlying Diabetes
in Hispanics) Consortium. Beta-cell function was measured as acute insulin
response (AIR) to glucose challenge from the frequently sampled intravenous
glucose tolerance test in 2,548 subjects. Complimentary measures included
fasting glucose and insulin and HOMA2B which characterize betacell function at basal steady state. GWAS data from four independent
cohorts (709,358 variants) was tested for association using meta-analysis
approaches. We examined 60 previously documented T2D loci and compared
associations between dynamic and fasting measures. Two genome-wide
significant signals were identified for AIR in the MTNR1B gene (rs10830963,
P=9.5E-12; rs1387153, P=1.4E-9; variance explained=2.06%). In contrast,
nominal signals were observed for surrogate indices of glucose (rs10830963,
P=1.5E-6), insulin (rs4869272, P=0.0032) or HOMA2B (rs560887, P=1.3E-4).
Variants in CDKAL1 (rs9368222, P=4.7E-6), KCNQ1 (rs163184, P=2.7E-4)
and TCF7L2 (rs7903146, P=5.1E-4) were nominally associated with AIR but
showed no evidence of association with surrogate indices (P>0.010). These
results suggest a specific role for these genes in first phase insulin release.
This work highlights the improved power of precise measures of glucose
homeostasis to identify T2D susceptibility loci in significantly smaller sample
sizes. In addition, it suggests more comprehensive metabolic testing and
associated genetic analysis can provide insight into the metabolic pathways
influenced by specific genes.
Supported by: Korea Healthcare Technology R&D Project (A111362)
Supported by: NIH (DK085175), (DK081350), (DK097524)
&
For author disclosure information, see page 829.
A432
Guided Audio Tour poster
ADA-Funded Research
GENETICS—TYPE 2 DIABETES
1655-P
1657-P
Usefulness of Genetic Risk Score Constructed from 47 Loci for Type
2 Diabetes in Non-Obese, Older Japanese Individuals
Type 2 Diabetes Genetic Associations in the Ashkenazi Jewish
Population
MINAKO IMAMURA, MINORU IWATA, HIROSHI MAEGAWA, HIROTAKA WATADA, HIROSHI HIROSE, YASUSHI TANAKA, KAZUYUKI TOBE, KOHEI KAKU, ATSUNORI KASHIWAGI, RYUZO KAWAMORI, SHIRO MAEDA, Yokohama, Japan,
Toyama, Japan, Otsu, Japan, Tokyo, Japan, Kawasaki, Japan, Okayama, Japan
TONI I. POLLIN, DANNY BEN AVRAHAM, NIR BARZILAI, BENJAMIN GLASER, GIL
ATZMON, THE T2D-GENES CONSORTIUM, Baltimore, MD, Bronx, NY, Jerusalem,
Israel
Multiple genome-wide association studies have identified more than
50 loci associated with Type 2 Diabetes Mellitus (T2DM). We genotyped
2375 Ashkenazi Jewish subjects (1182 T2DM and 1193 non-diabetic) using
the Metabochip SNP array. 70 cases and 58 controls were excluded due to
cryptic relatedness, ethnic outliers, sex assignment errors or poor quality
DNA. SNPs which were monomorphic, had call rates <0.90 or were not
in Hardy-Weinberg Equilibrium (p<10-7) were excluded, leaving 144,775
SNPS for this analysis. Logistic regression analysis with an additive model
adjusted for age and sex yielded 50 SNPs in 19 distinct chromosomal regions
associated with T2DM at p <0.0001 with odds ratios ranging from 1.31 to
2.30, including several variants in the TCF7L2 region with p <10-7, the most
significantly being rs7903146 in TCF7L2 (OR = 1.50, p = 3 x 10-8). Of 99 T2DMassociated SNPs identified in the recent T2DM Metabochip meta-analysis
and successfully genotyped in the Ashkenazi Jewish sample, 24 (24%)
were nominally (p <0.05) associated with type 2 diabetes, all directionally
consistent with previous reports, with ORs ranging from 1.15 to 1.50. In
conclusion, some but not all SNPs previously associated with T2DM were
nominally replicated in The Ashkenazi population, including TCF7L2 SNP
rs7903146 at genome-wide significance.
To investigate a clinical usefulness of currently available genetic
information, we examined a combined effect of type 2 diabetes (T2D)
susceptible loci by constructing genetic risk score (GRS) in a Japanese
population. First, we examined up to 11,532 Japanese individuals for 55
T2D susceptible single nucleotide polymorphisms (SNPs), and selected 47
SNPs which showed consistent effect direction with the original reports
[Odds Ratio (OR)>1]. GRS was constructed in 2,648 T2D cases and 1,802
controls, whose genotype information for the 47 SNPs was complete, by
counting the number of risk alleles of the 47 SNPs in each individual. The
GRS was significantly associated with T2D [p =7.22 × 10 -44, OR per risk
allele = 1.12, 95%Confidence Interval (CI) = 1.10- 1.13]. In Receiver Operating
Characteristic (ROC) analysis, the area under the curve (AUC) for GRS alone
(model 1) was 0.623, whereas the AUC for age, sex and BMI (model 2) was
0.743. The addition of the GRS to model 2 (model 3) resulted in a small, but
significant increase in the AUC (AUC for model 3 = 0.774, p-value for model 2
vs model 3 = 1.85×10 -15, ΔAUC (model 3- model 2) = 0.031). In an age or BMI
stratified analysis, effect of the GRS was stronger in older (age ə 50, AUC for
model 1 = 0.635, model 2 = 0.623, model 3 = 0.684. p-value for model 2 vs 3 =
1.58×10 -11, ΔAUC = 0.061), or in non-obese individuals (BMI < 25 , AUC for
model 1 = 0.640, model 2 = 0.769, model 3 = 0.800. p-value for model 2 vs 3 =
5.06×10 -12, ΔAUC = 0.031). The GRS was also significantly associated with
age of diagnosis (AOD) in 1,073 T2D (β = - 0.17, S.E. = 0.085, p = 0.046) or with
fasting plasma glucose in 812 controls (β = 0.168, s.e. = 0.073, p = 0.021).
In conclusion, the GRS was significantly associated with T2D risk and
T2D-related traits in the Japanese. Although currently available genetic
information is still not sufficient for the prediction of T2D onset, the
information may be more useful in non-obese, older individuals.
Supported by: Grant-in-Aid for Scientific Research (C23591361); MEXT (Japan)
The SIGMA Diabetes Consortium recently reported a GMA in Hispanics
(American Society for Human Genetics, 2012), which identified a novel
missense variant (rs13342232) associated with T2D in SLC16A11, an
uncharacterized member of a family of mono-caboxylic acid transporters.
SLC16A1-4 are involved in proton-linked transport of lactate and pyruvate
giving SLC16A11 strong biologic relevance. The Genetics Underlying
Diabetes in Hispanics (GUARDIAN) Consortium, comprised of 7 cohorts,
aims to identify genetic loci underlying T2D-related QTs in 4139 nondiabetic subjects from 1875 Hispanic families. QTs of primary interest are
insulin sensitivity and metabolic clearance rate of insulin (MCRI), but also
include fasting glucose and fasting insulin. Insulin sensitivity was measured
by FSIGT with minimal model or by euglycemic clamp. Genotyping was
performed using Illumina OmniExpress and a GMA was conducted combining
individual cohort association results using METAL. We examined 150 SNPs
within SLC16A11 (~2.3kb) and the 250 kb flanking regions. None of the SNPs
within SLC16A11 were associated with any T2D-related QT. We found 2
proxy SNPs (r2 = 1.0) for rs13342232, but the strongest association was
with fasting glucose (P = 0.19). rs2047774, 82 kb upstream of SLC16A11 and
near ASGR2, showed evidence for association with insulin sensitivity (P =
7.0×10 -4); while rs8078000, 337 bp upstream of SLC16A11, showed more
modest evidence for association with insulin sensitivity (P = 1.3×10 -3). These
2 SNPs were not in LD (r2 = 0.01) nor in LD with the tag SNPs for rs13342232
(r2 < 0.05). Our results suggest SLC16A11 is not associated with insulin
sensitivity, MCRI, fasting glucose or fasting insulin in Hispanic Americans.
In contrast, we observed an association with insulin sensitivity near ASGR2,
a hepatic asialoglycoprotein receptor mediating endocytosis and lysosomal
degradation of glycoproteins.
1656-P
A Genome-Wide Association Study of Glycemic Response to Rosiglitazone
SOO HEON KWAK, EUN ROH, EUN SEOK KANG, CHENG HU, MIN KYONG MOON,
EUN YOUNG CHOE, RONG ZHANG, YOUNG MIN CHO, HYE SEUNG JUNG, EUN
K.Y. KIM, YOON JI KIM, TAE JUNG OH, MIN KYEONG KIM, SU MIN HONG, WEIPING JIA, HYUN CHUL LEE, KYONG SOO PARK, Seoul, Republic of Korea, Shanghai,
China
Rosiglitazone is a thiazolidinedione anti-diabetic drug that acts as an
insulin sensitizer. It binds to peroxisome proliferator-activated receptor
gamma and activates expression of its target genes. There are individual
variations in response to this medication and genetic predisposition could
be one of the factors that contribute to this variation. We performed a twostage genome-wide association analysis in 434 East Asians type 2 diabetes
patients. Study subjects received rosiglitazone 4mg/day for 4-6 months
and glycemic response was evaluated before and after the treatment using
fasting glucose and HbA1c. Responders were defined as those with 20%
decrease in fasting glucose or 15% decrease in HbA1c after 4-6 months of
rosiglitazone treatment. We performed a case-control genetic association
analysis as well as quantitative trait analysis for the change in fasting glucose
or HbA1c level. Among the 195 stage 1 subjects (SNUH), 139 (71.3%) were
classified as responders and 56 (28.7%) as non-responders. Stage 1 subjects
were genotyped using Affymetrix Genome-Wide Human SNP array 5.0. We
selected 8 genetic variants for follow-up genotyping in 146 independent
Korean subjects (YUMC) and 93 Chinese subjects (SJTU). A intronic variant
(rs11676659) in STAT4 (signaling transducer and activator of transcription 4)
had strong association with overall non-response to rosiglitazone in stage
1 subjects (OR=4.35, P=9.83E-06). Although the direction of its association
was the same, it did not have significant association in stage 2 samples
(YUMC OR=1.32 P=0.44, SJTU OR=1.95 P=0.29). The effect of this variant
estimated by meta-analysis of three studies was OR=2.43 P=9.83E-05. This
variant was also associated with attenuated fasting glucose lowering effect
in the meta-analysis of three studies (beta=0.74 P=7.58E-05). This finding
requires further replication studies and functional investigation regarding
the role of STAT4 in rosiglitazone response is warranted.
1659-P
DPP4 Gene Variation Affects GLP-1 Secretion, Insulin Secretion,
and Glucose Tolerance in Humans With High Body Adiposity
HARALD STAIGER, KATRIN STAIGER, ANJA BÖHM, MARTIN HENI, KATARZYNA
LINDER, FAUSTO MACHICAO, NORBERT STEFAN, ANDREAS FRITSCHE, HANSULRICH HÄRING, Tübingen, Germany
Dipeptidyl-peptidase 4 (DPP-4) cleaves and inactivates the insulinotropic
hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide
(GIP), collectively termed incretins. DPP-4 inhibitors entered clinical
practise as approved therapeutics for type 2 diabetes in 2006. However,
interindividual variance in the responsiveness to DPP-4 inhibitors was
Supported by: Korea National Project for Personalized Genomic Medicine
(A111218-GM09)
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A433
POSTERS
NAN WANG, MARK O. GOODARZI, CARL D. LANGEFELD, XIUQING GUO, TALIN
HARITUNIANS, JEROME I. ROTTER, TASHA E. FINGERLIN, LESLIE J. RAFFEL, IDA
CHEN, LYNNE E. WAGENKNECHT, RICHARD M. WATANABE, Los Angeles, CA,
Winston-Salem, NC, Aurora, CO
Epidemiology/
Genetics
1658-P
A Genome-Wide Meta-Analysis (GMA) Shows No Evidence of Association Between Newly Identified Type 2 Diabetes (T2D) Locus
SLC16A11 and T2D-Related Quantitative Traits (QTs) in Hispanic
Americans
GENETICS—TYPE 2 DIABETES
T2D, including dietary pattern, physical activity, alcohol intake, usual sleep
duration, smoking status, and body mass index. A multivariable logistic
regression model was used to estimate odds of diabetes risk for each level
of the genetic and lifestyle scores, and the interaction between them. Both
scores were associated with diabetes odds (p<.0001 for both). The test of
multiplicative interaction between the genetic and lifestyle scores did not
reach significance (p=.08). The table shows the proportion of T2D cases and
the odds ratios for T2D according to the levels of the genetic and lifestyle
risk. Our data suggest that lifestyle modification is highly efficacious for
preventing T2D, independent of genetic risk.
reported. Thus, we asked whether genetic variation in the DPP4 gene affects
incretin levels, insulin secretion, and glucose tolerance in participants of the
TÜbingen Family study for type 2 diabetes (TÜF).
Fourteen common (minor allele frequency ≥0.05) DPP4 tagging single
nucleotide polymorphisms (SNPs) were genotyped in 1,976 non-diabetic TÜF
participants characterized by oral glucose tolerance tests and bioimpedance
measurements. In a subgroup of 168 subjects, plasma incretin levels were
determined.
We identified a variant, i.e., SNP rs6741949, in intron 2 of the DPP4 gene
that, after correction for multiple comparisons and appropriate adjustment,
revealed a significant genotype-body fat interaction effect on glucosestimulated plasma GLP-1 levels (p=0.0021). Notably, no genotype-BMI
interaction effects were detected (p=0.8). After stratification for body
fat content, the SNP negatively affected glucose-stimulated GLP-1 levels
(p=0.0229), insulin secretion (p=0.0061), and glucose tolerance (p=0.0208) in
subjects with high body fat content only.
In conclusion, a common variant, i.e., SNP rs6741949, in the DPP4 gene
interacts with body adiposity and negatively affects glucose-stimulated
GLP-1 levels, insulin secretion, and glucose tolerance. Even though its
mechanism remains to be shown, the SNP could possibly underlie the
reported interindividual variance in responsiveness to DPP-4 inhibitors,
especially in subjects with high body fat content.
1660-P
Variation in PPARG Is Associated With Longitudinal Change in Insulin Resistance, Independent of Adiposity, in Mexican Americans
Supported by: NIH (R01DK080720), (R01CA55069), (R35CA53890), (R01CA80205),
(R01CA144034)
POSTERS
Epidemiology/
Genetics
MARY HELEN BLACK, JUN WU, MIWA TAKAYANAGI, KENT D. TAYLOR, TALIN
HARITUNIANS, ENRIQUE TRIGO, JEAN M. LAWRENCE, RICHARD M. WATANABE,
THOMAS A. BUCHANAN, ANNY H. XIANG, Pasadena, CA, Los Angeles, CA
1662-P
Peroxisome Proliferator-Activated Receptor-gamma (PPARG) is a known
susceptibility locus for type 2 diabetes (T2D). Although cross-sectional
associations have been reported for Pro12Ala and other variants in the
region, longitudinal studies are lacking. We examined the effects of variation
in PPARG on longitudinal changes in anthropometric and metabolic traits in
a subset of 378 BetaGene participants (mean age: 39.8 ± 8.3 years; 74.5%
female) with follow-up phenotyping (median length of follow-up: 4.2 years,
IQR: 3.4-5.6). Phenotypes include body fat assessed by DXA, and insulin
sensitivity (SI), acute insulin response and β-cell function (disposition index;
DI) estimated from FSIGTs with Minimal Model analysis. Sixteen tag SNPs
capturing variation in a 135 kb region surrounding PPARG were tested for
association with rates of change in anthropometric and metabolic traits,
adjusting for age and sex. An additive genetic model was assumed for SNPs
with MAF > 15%, and a dominant model was used otherwise. All p-values
reported are Bonferroni-corrected for the number of tag SNPs tested. Three
SNPs, rs2920500, rs17793951 and rs1151996, were significantly associated
with the rate of change in SI (p=0.032, p=0.012 and p=0.005, respectively), but
not with changes in adiposity (all p>0.99). rs17793951 also had a significant
effect on change in DI over time (p=0.037). Further adjustment for baseline
and/or changes in adiposity over time did not alter these results. rs2120825
was associated with the rate of change in BMI (p=0.041), and showed trend
for association with changes in body fat percentage (p=0.12) and SI (p=0.14).
rs1306470 (captures Pro12Ala, pairwise r2=0.9) was not significantly
associated with the rate of change in any anthropometric or metabolic traits
(all p>0.17). These data provide evidence that variation in PPARG contributes
to declining SI and deteriorating β-cell function, independent of adiposity, in
Mexican Americans at risk for T2D.
Genetic Basis of Diabetes Resistance and Sensitivity in Obese
Mice
OLIVER KLUTH, HEIKE VOGEL, DANIELA MATZKE, STEPHAN SCHERNECK, DANIEL KAISER, HANS-GEORG JOOST, ANNETTE SCHÜRMANN, Nuthetal, Germany
New Zealand Obese (NZO) mice are diabetes prone but can be protected
from β-cell loss by carbohydrate restriction, whereas obese mice on C57BL/6background (B6-ob/ob) never develop diabetes. Our aim was to elucidate the
pathogenesis of β-cell loss in the NZO strain and to clarify how B6-ob/ob mice
are protected from T2D. NZO and B6-ob/ob mice were fed a fat-enriched,
carbohydrate-free diet up to week 18 to generate obesity but without β-cell
failure. Subsequently, the mice received a diabetogenic carbohydratecontaining diet for up to 32 days. Alterations in p-AKT and PDX1 levels were
investigated in islets. Transcriptome analysis was performed with islet RNA
from both strains fed with or without carbohydrates for 2 days. Differentially
expressed genes mapping to quantitative trait loci in a F2 generation of NZO
and C57BL/6 were identified. Glucolipotoxicity caused loss of NZO islets due
to impaired AKT-signaling, decreased PDX1 and apoptosis. In contrast, islets
from B6-ob/ob mice maintained normal levels of p-AKT and PDX1 in their islets.
Transcriptome analysis of islet-RNA indicated that only B6-ob/ob mice respond
to carbohydrates with an upregulation of genes involved in β-cell proliferation.
Moreover, 7 genes that were almost exclusively expressed in NZO islets were
identified within loci for obesity and hyperglycaemia on chromosomes 1, 11,
15, and 19. Amongst them is Ifi202b which we recently discovered as novel
adiposity gene. Due to a microdeletion of Ifi202b, it is not expressed in B6-ob/
ob islets. Data obtained by characterizing recombinant congenic mice indicate
that the presence of Ifi202b suppresses the induction of compensatory β-cell
proliferation under glucolipotoxic conditions. Impaired AKT-signaling and lack
of glucose-dependent induction of β-cell proliferation are responsible for β-cell
loss in diabetes-susceptible mice. The loss of function of Ifi202b that appears
to inhibit cell division protects diabetes-resistant mice from hyperglycaemia.
1661-P
Interactions of Type 2 Diabetes Susceptibility Loci and Lifestyle in
Singaporean Chinese
MARK A. PEREIRA, CHRIS HSU, DANIEL STRAM, ANDREW O. ODEGAARD, MARK
SEIELSTAD, M. WOON-PUAY KOH, YIK YING TEO, E. SHYONG TAI, JIANJUN LIU,
JIAN-MIN YUAN, MYRON D. GROSS, Minneapolis, MN, Los Angeles, CA, San
Francisco, CA, Singapore, Singapore, Pittsburgh, PA
The Relationship between Serum BDNF and Cognitive Impairment
Depends on the BDNF Val66Met Polymorphism in T2DM Patients
Little is known about gene-environment interactions for type 2
diabetes(T2D). We studied whether the association between previously
identified T2D single-nucleotide polymorphisms (SNPs), and SNPs in
nearby regions, with risk of incident T2D would be modified by lifestyle in
Singaporean Chinese. Using an Affymetrix GW ASI SNP array augmented by
imputation based on the 1,000 genomes project we successfully genotyped
or imputed (with R2≥ 0.8) over 7.5 million SNPs in 4678 participants (2338
cases with T2D and 2340 controls). We selected 98 genotyped or imputed
T2D-related SNPs (p<10-5) from the NHGRI GWAS Catalog for replication.
A 9-point lifestyle index was created from 6 independent predictors of
Studies suggest that brain-derived neurotrophic factor (BDNF) plays an
important role in modulating synaptic transmission and activity-dependent
neuroplasticity underlying learning and memory in the hippocampus. Type 2
diabetes (T2DM) is associated with cognitive impairment in many domains,
and has an increased risk of vascular dementia and Alzheimer disease, which
may result from decreased BDNF and its Val66Met polymorphism. However,
the correlations of cognitive impairment with serum BDNF and its Val66Met
polymorphism have not been investigated in T2DM.
1663-P
YAN FENG ZHEN, HUI FANG, XING YU LIU, XIANG YANG ZHANG, DONG HAO
ZHOU, SHAO XIONG ZHENG, Tangshan, China, Houston, TX, Tianjin, China
&
For author disclosure information, see page 829.
A434
Guided Audio Tour poster
ADA-Funded Research
GENETICS—TYPE 2 DIABETES
We compared 311 patients with T2DM to 346 normal controls on
serum BDNF levels and the Repeatable Battery for the Assessment of
Neuropsychological Status (RBANS). BDNF Val66Met polymorphism was
examined using the PCR-RFLP method in all subjects.
We found that serum BDNF levels in T2DM patients were significantly
lower than that of normal controls (p<0.001). The total score and nearly all
indexes (all p<0.01) except for attention and visuospatial/constructional
indexes (all p>0.05) of RBANS were markedly decreased in T2DM compared
to normal controls. Serum BDNF was positively associated with delayed
memory index score in patients with T2DM (p<0.05). The delayed memory
index score was significantly lower in Val/Val carriers than the Met/Met
carriers (p<0.05). Furthermore, among Met homozygote patients, BDNF
levels were positively associated with the delayed memory index score
(β=0.29, t=2.21, p=0.033), but inversely associated with the RBANS total
score (β=-0.92, t=-3.40, p=0.002) among Val homozygote patients.
Our results indicate that BDNF may be involved in the pathophysiology of
cognitive impairment, especially delayed memory in T2DM. The relationship
between serum BDNF and cognitive impairment depends on the presence of
BDNF Val66Met polymorphism in T2DM patients.
Nominally statistically significant associations were seen with SNPs in
FTO (rs1421085, b=1.9% increase in BMI per risk allele, r=0.05, P=0.020)
and TMEM18 (rs2867125, b=2.8% r=0.06, P=0.0007); these associations are
consistent with those reported in other populations. The multiallelic score
was also associated with BMI (b=0.5%, r=0.06, P=0.002), and it remained
nominally significant, though attenuated, when the FTO and TMEM18 SNPs
were excluded from consideration (b=0.3%, r=0.04, P=0.048).
This study suggests that common genetic variants established as
associated with obesity in Europeans also influence variation in BMI in Pima
Indians. The strongest associations are with variants in FTO and TMEM18,
but these results suggest that many other variants, though not individually
significant, may play a modest role in obesity in this population.
1664-P
Type 2 diabetes (T2D) is a chronic, heterogeneous disease and a major risk
factor for cardiovascular diseases. The underlying mechanisms leading to
progression to T2D are not fully elucidated. We hypothesized that genetic
risk factors play a role in glycemic deterioration and that validated genetic
variants are associated with T2D progression in American Indians. Using
prospective data of the Strong Heart Family Study (2 to 3 visits, up to 10
years of follow up), we identified 434 individuals defined as progressors
(T2D incident cases or persistent impaired fasting glucose [IFG]), 1,011
controls (normal fasting glycemia [NFG] at all visits) and 566 individuals
with transitory IFG (prospectively transition from NFG to IFG or IFG to NFG).
We estimated heritability (h2) of the traits, segregation in pedigrees and
evidence for association with 17 validated variants from T2D genome wide
association studies. We noted high heritability for T2D progression (h2=0.63)
but little contribution of genetic factors to transitory IFG (h2=0.09). At least
three variants (in WFS1, TSPAN8 and MTNR1B) were significantly associated
with T2D progression in adjusted analyses accounting for multiple testing.
Our findings provide evidence for generalization of validated T2D variants to
T2D progression in American Indians, a population with high rates of obesity
and T2D, and suggest phenotypic heterogeneity of the IFG trait which may
have implications for genetic studies when diagnosis is based on a single
time-point measure.
1666-P
Genetic Determinants of Progressive Deterioration of Glycemia in
American Indians
GABRIELA DA SILVA XAVIER, ANGELES MONDRAGON, RYAN MITCHELL, DAVID HODSON, JORGE FERRER, BERNARD THORENS, JAMES MCGINTY, PAUL
FRENCH, GUY A. RUTTER, London, United Kingdom, Barcelona, Spain, Lausanne,
Switzerland
Single nucleotide polymorphisms in the transcription factor T-cell factor 7
like-2 (TCF7L2) gene, including rs7903146, are associated with an elevated
risk of type 2 diabetes in man. TCF7L2 encodes a member of the TCF family
of transcription factors involved in the control of cell growth and signalling
downstream of wingless-type MMTV integration site family (Wnt) receptors.
Mice inactivated for Tcf7l2 throughout the pancreas using Pdx1.Cre-mediated
recombination display impaired glucose tolerance, beta cell expansion and
insulin secretion, particularly in response to GLP-1. To achieve deletion more
specifically in the adult pancreatic beta cell we have used here mice in which
Cre recombinase was knocked-in at the Ins1 locus. Compared to littermate
controls Ins1.Cre::Tcf7L2fl/fl mice bred on a C57BL/6 background displayed
impaired intraperitoneal glucose tolerance by 16 weeks (increase in AUC of
13.6 ± 2.8 %, n=6 mice per genotype), and impaired oral glucose tolerance
from 8 weeks (increase in AUC of 10.6 ± 1.3 %, n=6), values similar to those
previously observed in Pdx1.Cre::Tcf7l2fl/fl mice (where glucose intolerance
was observed at 20 and 12 weeks when glucose was administered by the
intraperitoneal or oral route, respectively). These findings provide further
evidence for a cell-autonomous role for Tcf7L2 in the beta cell and suggest
that lowered levels of active TCF7L2 in these cells may contribute to the
effects of the risk allele. The impact of Tcf7l2 deletion on isolated islet
function, pancreatic beta cell mass, and the effect of maintenance on a high
(60 %) fat diet are currently under investigation.
Supported by: NIH
1667-P
A Common Variant Near ATM Is Associated With Metformin Treatment Response in Type 2 Diabetes
SIMIN ZHANG, DEHONG CAI, YAN LI, XIAOHUI GUO, QING SU, LIXIN GUO, QUANMIN LI, DONG ZHAO, HONGMEI LI, JIANGMING LANG, BO FENG, JING LIN, YAJUN LI, XUEYAO HAN, LINONG JI, Beijing, China, Guangzhou, China, Shanghai,
China, Foshan, China
Supported by: EFSD; Wellcome Trust; MRC
Objective: A recent genome-wide association study in Caucasian has
identified a novel genetic loci near ATM for metformin treatment response
of type 2 diabetes (T2D). Our purpose was to determine whether the SNP can
be replicated in Chinese Han population.
Methods: In this study, 145 newly diagnosed Chinese Han subjects with
type 2 diabetes (HBA1C<10%) without treatment were included. All the
patients were administered with metformin monotherapy for 16 weeks.
Measure the HbA1c level on baseline and 16 weeks. The patients were
divided into efficient group and inefficient group according to the reduction of
HbA1c level after metformin treatment. The SNP rs11212617 was genotyped
by Goldengate chip in 145 T2D patients. The association of rs11212617
with metformin response in T2D was analyzed by logistic regression after
adjustment by BMI, sex and age at baseline.
Results: After 16 weeks treatment, the mean of HbA1c level decreased
from 8.33±0.8% to 6.53±0.6%, the median of reduction was 1.8%. The
HbA1c reduction of 71 subjects were more than 1.8% (efficient group) and
74 subjects of 145 patients were less than 1.8% (inefficient group). This
case-control study showed that there was significent difference in allele
frequence between these two groups. The patients with minor allele A have
better glycemia response to metformin than the patients without allele A.
with a Odd Ratio (OR, 95%CI) 2.5(1.47-4.24) and p value = 0.0007 after adjust
for BMI, age, sex.
Conclusions: In our study, the variant rs11212617 near ATM gene was
observed to be associated with glycemia control ability of metformin in
1665-P
Analysis of Established Obesity Variants in American Indians
ROBERT L. HANSON, SAYUKO KOBES, WILLIAM C. KNOWLER, CLIFTON BOGARDUS, LESLIE J. BAIER, Phoenix, AZ
Several single nucleotide polymorphisms (SNPs) are reproducibly
associated with body mass index (BMI) in European and European-derived
populations. There is little information, however, on their relationships with
BMI in American Indian populations, many of which have a high prevalence
of obesity.
We genotyped a “sentinel” SNP at 27 of the established obesity loci in
3227 Pima Indians (1868 women, 1359 men, mean age=36.3 years) who had
participated in a longitudinal study; the maximum BMI observed over the
course of the study was taken as a measure of obesity (mean BMI=37.5
kg/m2). Eight SNPs (at MC4R, PCSK1, LRP1B, CADM2, SLC39A8, QCPTL and
FANCL) had minor allele frequency<0.01; the remaining 19 SNPs were
analyzed for association with BMI. A linear mixed model, accounting for
familial relationships, was used to calculate the correlation of BMI with the
number of risk alleles, as determined by previous studies, and the effect
of each risk allele (b), expressed as a multiplier, on BMI. A multiallelic risk
score, constructed by summing the number of risk alleles over all loci, was
also analyzed.
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A435
POSTERS
Defective Glucose Homeostasis in Mice Inactivated Selectively for
Tcf7L2 in the Adult Beta Cell With an Ins1-Controlled Cre
Epidemiology/
Genetics
NORA FRANCESCHINI, KARIN HAACK, HARALD H.H. GORING, V. SAROJA VORUGANTI, SANDRA LASTON, LYLE G. BEST, RICHARD R. FABSITZ, JAMES B. MEIGS,
JAMES B. PANKOW, SHELLEY A. COLE, Chapel Hill, NC, San Antonio, TX, Timber
Lake, SD, Bethesda, MD, Boston, MA, Minneapolis, MN
GENETICS—TYPE 2 DIABETES
Chinese Han population with T2D. The results should be replicated further
within large scale sample.
1670-P
Identification and Functional Characterization of Hepatocyte Nuclear Factor-1B (MODY 5) Gene Mutations in Indian Diabetic Patients
With Renal Abnormalities
1668-P
SEKAR KANTHIMATHI, KANDASAMY BALAMURUGAN, COIMBATORE SUBRAMANIAM SHANTHI RANI, VISWANATHAN MOHAN, VENKATESAN RADHA,
Chennai, India
TCF7L2 Gene Polymorphisms May Influence the Risk of Type 2 Diabetes Mellitus by Effect on Insulin Sensitivity Independently from
BMI and Body Fat Content
Mutations in the HNF1B have been reported to be responsible for
maturity-onset diabetes of the young (MODY5) associated with renal
abnormalities. We aimed to identify and functionally characterize the HNF1B
mutations in a cohort of 40 unrelated diabetic patients with various renal
abnormalities seen at our centre. Direct sequencing of HNF1B revealed 3
known heterozygous mutations namely -67C>T, R165H, IVS2nt+2insT and 1
novel mutation N321D in these patients. The promoter mutation -67C>T was
identified in a patient with focal and segmental glomerulosclerosis. The
functional consequence of this mutation is unclear. The R165H mutation
was identified in a patient with bilateral small kidneys and left renal cortical
cyst. This mutation has been shown to disrupt protein folding/stability.
The IVS2nt+2insT splice site mutation was found in the proband with dual
collecting system in the right kidney and small sized left kidney with renal
cyst and is known to result in a truncated protein lacking transactivation
domain. A novel homozygous mutation N321D was identified in a patient
with renal aplasia. The amino acid asparagine (N) residue at position 321 is
evolutionarily conserved among human, rat and mouse species, therefore
we further characterized this mutation to determine its function and
molecular pathophysiology. We investigated the transcriptional activity
of N321D mutation (both heterozygous and homozygous state) on human
Glut2 and Rat albumin promoter in HeLa and Hek293 cells. The wild type and
N321D mutant proteins exhibited equal level of transactivation potential in
HeLa and Hek293 cell lines. Western blot analysis also showed similar level
of wild type and N321D mutant protein expression, indicating the protein
stability to be normal in the mutant. Subcellular localization assays also
revealed normal transportation of protein to the nucleus. This is the first
major study of HNF1B mutations (MODY5) from India.
POSTERS
Epidemiology/
Genetics
ADAM KRETOWSKI, EDYTA ADAMSKA, NATALIA WAWRUSIEWICZ-KURYLONEK, ANNA CITKO, JOANNA GOSCIK, KATARZYNA MALISZEWSKA, JULIUSZ
WILK, MAGDALENA WASZCZENIUK, DANUTA LIPINSKA, JUSTYNA PLISZKA,
MICHAL CIBOROWSKI, MARIA GORSKA, Bialystok, Poland
The genome-wide association studies have recently expanded the
number of genetic susceptibility loci for type 2 diabetes and obesity.
Transcription factor 7-like 2 (TCF7L2) gene seems to be one of the most
predictive identifiable factors promoting T2DM development. It has been
suggested that TCF7L2 influences pancreatic β-cell function but the effect
of genetic variants of TCF7L2 on metabolic syndrome development is not
well characterized among subjects with obesity. The aim of our study was
to analyze whether genetic variants of the TCF7L2 gene influence fasting
leptin levels and insulin sensitivity in nondiabetic obese/overweight
subjects. We genotyped previously identified TCF7L2 SNPs: rs7901695
and rs7903146 in 944 subjects (463 women, 481 men), who underwent
anthropometry (BMI) and body composition analysis: percent of body fat,
visceral and subcutaneous abdominal adipose tissue by multi-frequency
bio-impedance method. In the present study we found that subjects with
TT rs7903146 TCF7L2 homozygotes presented significantly higher fasting
levels of leptin (29.7 vs. 19.7 ng/ml, p=0,035) and higher homa-IR (3.9 vs. 2.6,
p=0,009), despite the lack of differences in BMI, body fat content and body
fat distribution. Moreover In the logistic regression analysis presence of CC
genotype of rs7901695 TCF7L2 predicted higher IR independently from BMI,
gender and caloric intake (p<0.01). We believe that our study may help to
understand the pathways that TCF7L2 gene influence the risk of T2DM and
provide personalized treatments and prevention strategies to fight against
type 2 diabetes.
Supported by: MNiSzW (4774/B/P01/2009/37)
1671-P
Application of MODY Probability Calculator for Japanese Patients
With MODY3
1669-P
Genome-Wide Association Study Identifies Susceptibility Loci for
Type 2 Diabetes and Impaired Glucose Regulation in Young Korean
Women
NAOKO IWASAKI, MIHO TAKIZAWA, RISA IDE, MAKIKO OGATA, YASUKO UCHIGATA, Tokyo, Japan
Maturity-onset diabetes of the young type (MODY) is a subtype of
diabetes caused by a single gene disorder typically with autosomal dominant
inheritance and younger age of onset without obesity. A diagnosis of MODY
is confirmed by a genetic testing, however, its cost and availability limit to
perform the genetic testing. Recently, MODY probability calculator was
developed to estimate the positive predictive value for genetic testing for
patients suspected with MODY (http://www.diabetesgenes.org/). The aim
of the study was to validate its efficacy in Japanese patients with MODY,
since the calculator was developed on European Caucasian cohort. Twenty
patients (16 families) were identified the mutations in HNF1A, including
one subject who has not develop diabetes at current age of 36 years, and
three patients who were diagnosed with diabetes at older than 30 years.
After excluding those four individuals, we used 16 patients for the study.
The mean age at diagnosis and BMI were 16.9 ± 6.6 years and 20.3 ± 2.1.
Parental family history was observed in 15 families (94%). Nine patients were
referred by school health checking for urinary glucose. For the calculation, 12
patients who had full information were used and four cases who do not have
information for current treatment, we run all possible patterns and then
calculate the mean provability. Among 12 subjects with full parameters, 11
subjects showed >75.5% positive predictive value. One patient who showed
1.9% was diagnosed at 9 years of age and started insulin immediately, in
addition, GAD antibody had not tested at the onset year of 1975. She had a
mother with diabetes. Mean probability score for the remaining 4 subjects
were 56.8%, 21.3%, 50.5% and 58.6%, and mean positive predictive value
with 16 patients was 63.7%. MODY probability calculator developed for
Caucasian MODY can be applicable in Japanese patients with MODY.
More than half of MODY3 subjects were initially detected by school health
checkup.
HYEJIN LEE, YEON-AH SUNG, JEE-YOUNG OH, Seoul, Republic of Korea
The global epidemic of type 2 diabetes mellitus (T2DM) and prediabetes is
one of the most challenging problems of recent days. Substantial evidence
suggests that T2DM is a multifactorial disease with a strong genetic
component. The aim of this study was to identify causative genes of T2DM
and impaired glucose regulation (IGR: impaired fasting glucose (IFG) and
impaired glucose tolerance (IGT)) in young Korean women.
We conducted genome-wide association study (GWAS) of T2DM and IGR
in 2,000 young Korean women (17 T2DM, 123 IFG or IGT, and 1780 controls,
mean age: 25±5 years (16~39 years)). DNA from individuals was genotyped
using the Illumina HumanOmni1 Quad array. After quality-control procedures,
we retained genotypes for 636,870 SNPs. PLINK was employed to conduct
association tests for the allele data with logistic regression.
We identified strong evidence of associations between T2DM/IGR and
one loci (7p 15.3, rs730497; P value = 7.154 x 10 -9, OR = 2.153), and weak
association between T2DM/IGR and multiple SNPs (rs 4607517, rs1004558,
rs2348424, rs6875501, rs758982, rs10786907, rs16827528, rs10476783,
rs6872336, rs10210850, rs6759214, rs4344883, rs3866790, rs12209009,
rs4402698, P value = 9.62 x 10 -7 ~ 8.159 x 10 -6). At 7p15.3, rs730497 located
within glucokinase (GCK) gene, which is associated with T2DM, maturity
onset diabetes of the young, type 2 (MODY2). Although we could not find the
previously identified T2DM associated genes, we found that GCK gene was
associated with T2DM and IGR in young Korean women. We might consider
that the pathogenesis for the development of hyperglycemia in young
women may be different from typical T2DM. However further replication
studies are needed to confirm these findings.
Supported by: MEXT (Japan); Ministry of Health and Welfare (Japan)
&
For author disclosure information, see page 829.
A436
Guided Audio Tour poster
ADA-Funded Research
GENETICS—TYPE 2 DIABETES
1672-P
1674-P
Serum Resistin Is Positively Associated With Peripheral Neutrophil
and Monocyte Counts Independent of Resistin SNP-420 and SNP358: The Toon Genome Study
The IRS1 G972R Polymorphism and Glomerular Filtration Rate in Patients With Type 2 Diabetes Mellitus
SALVATORE DE COSMO, SABRINA PRUDENTE, OLGA LAMACCHIA, LAURA
PUCCI, DANIELA LUCCHESI, CHRISTINE MENDONCA, DIEGO BAILETTI, MASSIMILIANO COPETTI, FABIO PELLEGRINI, MAURO CIGNARELLI, GIUSEPPE PENNO,
ALESSANDRO DORIA, VINCENZO TRISCHITTA, San Giovanni Rotondo, Italy, Foggia, Italy, Pisa, Italy, Boston, MA
RYOICHI KAWAMURA, YASUHARU TABARA, WATARU NISHIDA, ISAO SAITO,
YASUNORI TAKATA, MAYO AIBIKI, YUKINOBU NOMI, YUKO KADOTA, AI OKAMOTO, TATSUYA NISHIMIYA, HIROSHI ONUMA, TETSURO MIKI, TAKESHI TANIGAWA, HARUHIKO OSAWA, Toon, Ehime, Japan, Kyoto, Japan
Resistin, secreted from adipocytes, induces insulin resistance in mice. We
reported that single nucleotide polymorphism (SNP) -420 (rs1862513) in the
human resistin gene was associated with type 2 diabetes susceptibility (Am
J Hum Genet 75: 678, 2004). In the general Japanese population, circulating
resistin was strongly associated with SNP-420 and SNP-358 (rs3219175)
(PLoS ONE 5: e9718, 2010). In humans, resistin is predominantly expressed in
macrophages. However, the association between either serum resistin or its
SNPs and differential white blood cell (WBC) count in general populations
remains to be elucidated.
The Toon Genome Study is a cohort study for surveying risk factors for
cardiovascular diseases and diabetes in community based subjects. In this
study, 1,982 residents aged 30-79 years were enrolled from 2009 to 2012,
and written informed consent was obtained. Serum resistin was measured
by ELISA. SNPs were analyzed by TaqMan assays.
Serum resistin was positively correlated with WBC count (r=0.31,
P<0.0001). Precisely, serum resistin was mainly correlated with the neutrophil
and monocyte counts (r=0.34, 0.19, both P<0.0001). Resistin SNP-420 and
SNP-358 were not associated with WBC count and its components, whereas
serum resistin was strongly determined by these SNPs (SNP-420 CC/CG/GG,
n=853/885/228, WBC 5420/5401/5421 [×1000/µl, ANOVA P=0.96], resistin
9.3/13.4/17.9 [ng/ml, P<0.0001]; SNP-358 GG/GA/AA, n=1,213/667/89, WBC
5401/5434/5415 [P=0.88], resistin 9.2/16.0/23.7 [P<0.0001]). A multiple
regression analysis showed that serum resistin was associated with total
WBC, neutrophil, and monocyte counts after adjusted for age, sex, BMI,
smoking, other metabolic risk factors, and SNP-420 and SNP-358.
In summary, serum resistin was mainly associated with neutrophil and
monocyte counts independent of resistin SNP-420 and SNP-358. Serum
resistin appeared to be derived from WBC in humans.
In Mexican Americans, the IRS1 G972R polymorphism (rs1801278) has
been associated to such a marked reduction in glomerular filtration rate
(GFR) (i.e. β=-13 ml/min/1.73 m2) to be considered a major determinant of
kidney function. To study whether such strong effect can also be observed
among individuals of European ancestry, we investigated a total of 3,973
White patients with type 2 diabetes. Standardized serum creatinine was
measured by the modified kinetic Jaffè reaction and estimated GFR (eGFR)
calculated by the MDRD formula; rs1801278 was genotyped by TaqMan
assay. A nominally significant association was observed, with R972 carriers
showing a modestly lower eGFR level as compared to other subjects (β=2.27 ml/min/1.73 m2, p=0.038). Our data indicate that IRS1 G972R is not as
strong a determinant of GFR in diabetic patients of European ancestry as
in Mexican Americans. Since we had 100% power to detect the previously
reported association, the risk that our finding is a false negative one is
minimal. Rather, our data does suggest that White diabetic patients carrying
R972 variant have a modestly reduced GFR, thus pointing to IRS1 as a typical
minor gene in the context of a multifactorial disease. Further studies are
needed before the observed association is defined as established.
The aim of our study was to investigate association between polymorphic
markers (PM) of genes involved in production of vasoactive factors (NO,
angiotensin II) and insulin secretion and/or sensitivity with development of
chronic kidney disease (CKD) and obesity in type 2 diabetic (T2D) patients.
We enrolled 444 T2D patients. PM I/D in ACE gene and ecNOS4a/4b in
NOS3 gene were analyzed among 263 patients divided in 2 groups: with
and without CKD (n=78/175) based on glomerular filtration rate (GFR) < and
≥ 60 ml/min/1.73m2 calculated by MDRD formula. PM in PPARG2, KCNJ11,
TCF7L2 and SLC30A8 genes were analyzed among 181 patients which also
were divided in 2 groups: with and without obesity (n=101/80) based on BMI
≥ 30 and < 30 kg/m². PM studied using PCR. Differences in alleles/genotypes
frequencies were assessed by χ² and odds ratio (OR) were calculated.
The main clinical parameters, such as age, sex, HbA1c, serum levels of
cholesterol and triglycerides, blood pressure level were similar between all
the groups. There were no association of CKD development with I/D in ACE
gene, whereas we observed significant differences in alleles/genotypes
distribution of ecNOS4a/4b in NOS3 gene between groups with and without
CKD: the prevalence of allele 4b and genotype 4b/4b in patients without
CKD: OR=0,45, 95%CI: 0,3-0,7 and OR=0,12, 95%CI: 0,02-0,9, respectively;
while allele 4a and genotype 4a/4a did as risk factors: χ²=10,42; =0.001;
OR=2,2, 95%CI: 1,4-3,6; genotype 4a/4a: χ²=10,28; =0.006; OR=2,21, 95%CI:
1,2-3,9. We also found an excess of genotype pro/pro of PPARG2 gene in
group with obesity: 59% vs. 51%; OR = 1,27; 95%CI: 1,02-2,08.
We conclude that T2D patients might have genetic susceptibility to
CKD development caused by polymorphism ecNOS4a/4b in NOS3 gene
with protective role of allele 4b and genotype 4b/4b; while obesity might
be determined by polymorphism of PPARG2 gene with pro/pro genotype
considered as a risk factor.
1673-P
Deficiency of Urokinase Plasminogen Activator Linked to Development of Type 2 DM
JIN-SHUEN CHEN, LI-CHIEN CHANG, CHUNG-ZE WU, TZU-LING TSENG, DEE
PEI, NAIN-FENG CHU, Taipei, Taiwan, Hsinchu, Taiwan, New Taipei City, Taiwan,
Taitung, Taiwan
Urokinase plasminogen activator (uPA) not only triggers a proteolysis
cascade, but is also linked to pleiotropic functions, such as the development
of inflammatory and immune responses. In the present study, we examined
whether uPA plays a role in the production of type 2 DM in mice and cell
models as well as in a limited survey of clinical cases. In mice models, wild
type (C) and uPA knockout (uPA-/-) mice were both fed a high-fat diet and
treated with streptozotocin and nicotinamide for development of type 2 DM.
For the development of type 2 DM, the success rate of development of type 2
DM was significantly higher in group uPA-/- than in group C. The group uPA-/mice treated with uPA plasmid showed resistance to developing type 2 DM,
which was similar to the result of group C. Furthermore, in clinical cases, the
plasma level of uPA in the obese children was significantly lower than in the
thin group. Taken together, we suggest that low plasma uPA may be a risk
factor for the production of type 2 DM. For the study of insulin resistance
and secretion, in cell model, the NIT-1 β cell was treated by uPA siRNA, the
rate of insulin secretion was significantly decreased compared to the cell
line without treatment. In mice models, the HOMA-IR in group C and uPA-/both increased daily with the high-fat diet. The HOMA-β in group uPA-/- was
significantly lower than in group C before induction. Furthermore, HOMA-β
in uPA-/- mice was still low one month after induction, as compared with
HOMA-β , which was restored slightly in group C, suggesting uPA-/- lacks
the ability to regenerate β cells. Similarly, IHC stain of insulin in islet cells of
wild type mice showed insulin particles increased one month after induction,
but insulin particles in islet cell in uPA-/- mice were still fewer than those in
the group C. In conclusion, uPA plays an important role in insulin secretion,
β cell regeneration and development of type 2 DM. Supplement of uPA may
delay development of type 2 DM, and offer one strategy for prevention and
treatment of type 2 DM in the future.
1676-P
Joint Effects of Known Type 2 Diabetes Susceptibility Loci in a
Genome-Wide Association Study of Singaporean Chinese: The Singapore Chinese Health Study
ZHANGHUA CHEN, MYRON D. GROSS, MARK A. PEREIRA, MARK SEIELSTAD,
WOON-PUAY KOH, YIK-YING TEO, E. SHYONG TAI, JIANJUN LIU, KHAI KOON
HENG, WEE YANG MEAH, XIAO YIN CHEN, CHANG HUA WONG, HONG BOON
TOH, JIAN-MIN YUAN, DANIEL O. STRAM, Los Angeles, CA, Minneapolis, MN,
San Francisco, CA, Singapore, Singapore, Pittsburgh, PA
Supported by: NSC (100-2314-B-016-020)
ADA-Funded Research
&
Genome-wide association studies (GWAS) have identified genetic factors
in type 2 diabetes (T2D), but mostly among populations of European descent
rather than ethnic groups with higher risk of diabetes. We tested whether
For author disclosure information, see page 829.
Guided Audio Tour poster
A437
POSTERS
ANNA ZHELEZNYAKOVA, OLGA VIKULOVA, SVETLANA SAVELEVA, VALERIY
NOSIKOV, MARINA SHESTAKOVA, Moscow, Russian Federation
Epidemiology/
Genetics
1675-P
Polymorphisms in NOS3 and PPARG2 Genes Contribute to Genetic
Susceptibility to the Development of Chronic Kidney Disease and
Obesity in Type 2 Diabetic Patients
IMMUNOLOGY
CATEGORY
the previously identified T2D single-nucleotide polymorphisms (SNPs) and
SNPs found in regions near identified T2D SNPs were associated with T2D
within the Singapore Chinese Health Study. Using an Affymetrix GW ASI
SNP array, we successfully genotyped 507,509 SNPs in 4678 participants
(2338 cases with physician-diagnosed T2D and 2340 controls with glycated
hemoglobin < 6.0%). Imputation using 1000 genomes project data was
conducted for a fine-mapping analysis. We selected 98 T2D-related SNPs
(p<10 -5) from the NHGRI GWAS Catalog for replication. Forty-four SNPs were
genotyped and 54 SNPs were imputed with r 2>0.80. Positive associations
between counts of the reported risk allele and T2D status were found for
73 of the 98 T2D SNPs; of which 24 were significant (p<.05). Combining
the reported risk alleles of the 98 SNPs into an unweighted risk score we
estimated a relative risk per allele of 1.025 (p=7.5×10 -10). Individuals in the
highest quintile of the risk allele distribution were at 1.6-fold greater risk
(p=0.0001) of T2D compared with those in the lowest quintile. Conditional
analysis was performed for SNPs within 50kb of an index GWAS SNP by
fitting both the nearby and the GWAS SNPs in logistic regression. Several
potentially novel independent associations (remaining significant after
multiple correction) were indicated and may be reflecting new signals in
some of the same regions containing already known T2D SNPs. In conclusion,
we replicated many of the previously reported diabetes-related SNPs and
their joint effects in Singaporean Chinese and identified potentially novel
candidate SNPs that are associated with T2D risk in an ethnic group with a
high risk of diabetes. Further replication of novel SNPs is planned.
IMMUNOLOGY
Guided Audio Tour: Immunometabolism (Posters: 1678-P to 1683-P), see
page 19.
&
JEFFREY D. FELDSTEIN, STEPHEN N. DAVIS, JENNIFER WHITMORE, HANY
ZAYED, Berkeley, CA, Baltimore, MD
Inflammation of the beta cells allegedly leads to less insulin production
and secretion. The new anti-interleukin-1β (IL-1β) monoclonal antibody,
gevokizumab, was evaluated in patients with type 2 diabetes uncontrolled
on metformin alone. In a parallel, double-blind, placebo-controlled phase
II trial, 421 patients were randomly allocated to monthly subcutaneous
injections of placebo or gevokizumab at doses of 0.01, 0.03, 0.1, or 0.3 mg/
kg for 6 months.
There were no drug-related serious adverse events. Incidence of infection
in the gevokizumab and placebo groups were comparable (26% vs 24%), with
nasopharyngitis being the most frequent. The principal objective in terms
of reduction of hemoglobin A1c, fasting plasma glucose, fasting proinsulin/
insulin ratio, or C peptide was not reached. In contrast, six months’ treatment
with gevokizumab was associated with a rapid, prolonged, and significant
decrease in high-sensitivity C reactive protein (hs-CRP) in all groups versus
placebo (all p<0.02).Patients who were on RAAS modulators, statins or both
had a similar sustained strong responsive decrease in hs-CRP.
Gevokizumab, an IL-1β modulating antibody, had a marked antiinflammatory effect measured by hs-CRP. The significant observed decrease
in inflammatory status demonstrated by a sharp extended decrease in hs-CRP
in these patients may potentially have beneficial cardiovascular effects. The
role of anti-inflammatory drugs in diabetes still needs to be demonstrated.
Studies using cardiovascular end-points needs to be further evaluated.
1677-P
Core Clock Gene Expression in Muscle and Adipose Tissue are Correlated With Metabolic Traits
POSTERS
BRIAN A. GRICE, MAXIMILIAN HOHENADEL, CLINTON C. MASON, JONATHAN
KRAKOFF, ROBERT C. WILLIAMS, ROBERT L. HANSON, Phoenix, AZ
Immunology/
Transplantation
1678-P
Anti-Inflammatory Effect of Monthly Subcutaneous Gevokizumab in
Subjects With Type 2 Diabetes Mellitus on Stable Metformin
Circadian rhythm refers to biologic and metabolic processes with
entrained 24 hour oscillations. We investigated whether mRNA expression
levels of core clock genes in human adipose and muscle tissue are correlated
with metabolic traits.
Participants with biopsies were Pima Indians recruited for a study of the
etiology of type 2 diabetes and when biopsied were non-diabetic, aged
18 years or older, healthy by medical examination and on no medications.
Biopsies were performed fasting between 8 and 9 a.m. RNA expression from
muscle (n=219) and adipose (n=209) tissue was measured using Affymetrix
GeneChip Human Exon 1.0 array.
In total we selected 12 core clock genes, represented by both Bass et
al. (Science 2012) and Kegg Pathways, for analysis. Metabolic traits were
percent fat (by DXA or underwater weighing), fasting and 2-hour plasma
glucose, and insulin action (by euglycemic-hyperinsulinemic clamp). An
F-test with 12 degrees of freedom was performed to test the null hypothesis
of no association between the metabolic trait and expression of any of the
clock genes. If we rejected the null hypothesis we considered a p<0.05 to
be significant for trait expression correlations, otherwise significance after
Bonferroni correction was p<0.004. Several clock genes were associated
with metabolic traits (figure 1). These results indicate that the expression of
clock genes may play a role in metabolism.
1679-P
WITHDRAWN
&
1680-P
Elevated RBP4 Levels Cause Insulin Resistance by Activating Antigen-Presenting Cells (APCs) and Proinflammatory Responses in
Adipose Tissue In Vivo
PEDRO M. VIEIRA, MARK M. YORE, PETER DWYER, ISMAIL SYED, KERRY
WELLENSTEIN, ODILE D. PERONI, BARBARA KAHN, Boston, MA
Supported by: NIH
RBP4, an adipocyte- and liver-secreted protein which is highly associated
with insulin resistance, was recently shown to activate proinflammatory
pathways. We aimed to determine the mechanism for RBP4-induced
&
For author disclosure information, see page 829.
A438
Guided Audio Tour poster
ADA-Funded Research