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Txnip contributes to impaired glucose tolerance by upregulating the expression of genes
involved in hepatic gluconeogenesis in mice
01 Dec 2013 12:00 am
Abstract
Aims/hypothesis
Thioredoxin-interacting protein (TXNIP) is upregulated in the hyperglycaemic state and represses glucose
uptake, resulting in imbalanced glucose homeostasis. In this study, we propose a mechanism of how TXNIP
impairs hepatic glucose tolerance at the transcriptional level.
Methods
We administered adenoviral Txnip (Ad-Txnip) to normal mice and performed intraperitoneal glucose
tolerance tests (IPGTT), insulin tolerance tests (ITT) and pyruvate tolerance tests (PTT). After AdTxnip administration, the expression of genes involved in glucose metabolism, including G6pc and Gck,
was analysed using quantitative real-time PCR and western blot. To understand the
increased G6pcexpression in liver resulting from Txnip overexpression, we performed pull-down assays for
TXNIP and small heterodimer partner (SHP). Luciferase reporter assays and chromatin
immunoprecipitation using the Txnip promoter were performed to elucidate the interrelationship between
carbohydrate response element-binding protein (ChREBP) and transcription factor E3 (TFE3) in the
regulation of Txnip expression.
Results
Overabundance of TXNIP resulted in impaired glucose, insulin and pyruvate tolerance in normal mice. AdTxnip transduction upregulated G6pc expression and caused a decrease in Gck levels in the liver of normal
mice and primary hepatocytes. TXNIP increased G6pc expression by forming a complex with SHP, which is
known to be a negative modulator of gluconeogenesis. Txnip expression in mouse models of diabetes was
decreased by Ad-Tfe3 administration, suggesting that TFE3 may play a negative role through competition
with ChREBP at the E-box of the Txnip promoter.
Conclusions/interpretation
We demonstrated that TXNIP impairs glucose and insulin tolerance in mice by upregulating G6pc through
interaction with SHP.
JAMA Theme Issue on Diabetes—Call for Papers
27 Nov 2013 12:00 am
To coincide with the American Diabetes Association Scientific Sessions in June 2014,JAMA will publish a
theme issue on diabetes research. Our goals are to inform readers about the latest research in both type 1
and type 2 diabetes and to provide useful reviews of the current state of basic and clinical science
underlying diabetes treatments. The World Health Organization estimates that 350 million people worldwide
have diabetes. The international obesity epidemic has certainly accelerated the need to better understand
the epidemiology, identification, and treatment of diabetes.
A 10-s Sprint Performed After Moderate-Intensity Exercise Neither Increases nor
Decreases the Glucose Requirement to Prevent Late-Onset Hypoglycemia in Individuals
With Type 1 Diabetes
21 Nov 2013 08:01 pm
OBJECTIVE
To determine whether performing a 10-s sprint after moderate-intensity exercise increases the amount of
carbohydrate required to maintain euglycemia and prevent late-onset postexercise hypoglycemia relative to
moderate-intensity exercise alone.
RESEARCH DESIGN AND METHODS
Seven individuals with type 1 diabetes underwent a hyperinsulinemic-euglycemic clamp and performed 30
min of moderate-intensity exercise on two separate occasions followed by either a 10-s maximal sprint
effort or no sprint. During the following 8 h, glucose infusion rate to maintain euglycemia and rates of
glucose appearance and disappearance were measured continuously.
RESULTS
In response to exercise and throughout the 8-h recovery period, there were no differences in glucose
infusion rate, blood glucose levels, plasma insulin concentrations, and rates of glucose appearance and
disappearance between the two experimental conditions (P > 0.05).
CONCLUSIONS
A 10-s sprint performed after 30 min of moderate-intensity exercise does not affect the amount of
carbohydrate required to maintain euglycemia postexercise in individuals with type 1 diabetes.
A Critical Role for Thioredoxin Interacting Protein in Diabetes-Related Impairment of
Angiogenesis
06 Nov 2013 07:00 am
Impaired angiogenesis in ischemic tissue is a hallmark of diabetes mellitus. Thioredoxin interacting protein
(TXNIP) is an exquisitely glucose-sensitive gene that is overexpressed in diabetes. Since TXNIP modulates
the activity of the key angiogenic cytokine vascular endothelial growth factor (VEGF), we hypothesized that
hyperglycemia-induced dysregulation of TXNIP may play a role in the pathogenesis of impaired
angiogenesis in diabetes. In the current study, we report that high glucose-mediated overexpression of
TXNIP induces a widespread impairment in endothelial cell function and survival by reducing VEGF
production and sensitivity to VEGF action, findings which are rescued by silencing TXNIP with siRNA. High
glucose-induced endothelial cell dysfunction was recapitulated in normal glucose conditions by
overexpressing either TXNIP or a TXNIP C247S mutant unable to bind thioredoxin, suggesting that TXNIP
effects are largely independent of thioredoxin activity. In streptozotocin-induced diabetic mice, TXNIP
knockdown to non-diabetic levels rescued diabetes-related impairment of angiogenesis, arteriogenesis,
blood flow and functional recovery in an ischemic hindlimb. These findings were associated with in
vivorestoration of VEGF production to non-diabetic levels. These data implicate a critical role for TXNIP in
diabetes-related impairment of ischemia-mediated angiogenesis and identify TXNIP as a potential
therapeutic target for the vascular complications of diabetes mellitus.
A Novel Deletion of IGF1 in a Patient With Idiopathic Short Stature Provides Insight Into
IGF1 Haploinsufficiency
15 Nov 2013 05:47 pm
Context:
Short stature is a common reason for referral to pediatric endocrinology centers. Frequently, the underlying
etiology of short stature is unknown, resulting in a diagnosis of idiopathic short stature. Rare genetic defects
in the GH/IGF-1 axis have been found to cause short stature.
Objective:
The objective of this study was to identify the genetic etiology of short stature in a patient with ISS and to
review the clinical presentation of patients with genetic defects in IGF1, and specifically IGF-1
haploinsufficiency.
Design/Setting/Participants:
The index patient was evaluated at an academic medical center, and DNA was obtained from the proband
and both parents.
Intervention:
Genome-wide copy number analysis was performed in the proband with confirmatory quantitative PCR in
the proband and his parents.
Main Outcome Measure:
We measured novel copy number variants (CNVs) thought to explain the patient's short stature.
Results:
CNV analysis revealed that the proband carried a paternally inherited heterozygousIGF1 gene deletion. His
phenotypic features are consistent with those found in previous case reports of IGF-1 deficiency.
Conclusions:
This study, as the first case of a complete heterozygous 1GF1 deletion, provides insight into the effects of
true IGF-1 haploinsufficiency. Given the similarities in phenotype between the present proband and those
previously described, it is highly likely that his IGF1 deletion is the cause for his short stature. Broadly, this
study emphasizes how CNV analysis and other genetic sequencing techniques are evolving as an
important tool to identify genetic causes underlying human disease, allowing for improved diagnosis and
targeted treatment.
A Novel Y152C KCNJ5 Mutation Responsible for Familial Hyperaldosteronism Type III
05 Nov 2013 06:01 pm
Context:
Primary aldosteronism is a heterogeneous group of disorders comprising both sporadic and familial forms.
Mutations in the KCNJ5 gene, which encodes the inward rectifier K+ channel 4 (G protein-activated inward
rectifier K+ channel 4, Kir3.4), cause familial hyperaldosteronism type III (FH-III) and are involved in the
pathogenesis of sporadic aldosterone-producing adenomas.
Objective:
The objective of the study was to characterize the effects of a newly described KCNJ5mutation in vitro.
Patients and Methods:
The index case is a 62-year-old woman affected by primary aldosteronism, who underwent left
adrenalectomy after workup for adrenal adenoma. Exon 1 of KCNJ5was PCR amplified from adrenal tissue
and peripheral blood and sequenced. Electrophysiological and gene expression studies were performed to
establish the functional effects of the new mutation on the membrane potential and adrenal
cellCYP11B2 expression.
Results:
KCNJ5 sequencing in the index case revealed a new p.Y152C germline mutation; interestingly, the
phenotype of the patient was milder than most of the previously described FH-III families. The tyrosine-tocysteine substitution resulted in pathological Na+ permeability, cell membrane depolarization, and disturbed
intracellular Ca2+homeostasis, effects similar, albeit smaller, to the ones demonstrated for
other KCNJ5mutations. Gene expression studies revealed an increased expression of CYP11B2and its
transcriptional regulator NR4A2 in HAC15 adrenal cells overexpressing KCNJ5Y152C compared to the wildtype channel. The effect was clearly Ca2+-dependent, because it was abolished by the calcium channel
blocker nifedipine.
Conclusions:
Herein we describe a new germline mutation in KCNJ5 responsible for FH-III.
A cross-sectional study of glycaemic control, complications and psychosocial functioning
among 18- to 35-year-old adults with Type 1 diabetes
16 Nov 2013 09:39 am
Aims To describe the level of glycaemic control, complications and psychosocial functioning and the
relationships between these variables in the under-researched group of younger adults with Type 1
diabetes. Methods Local electronic health records provided data on age, gender, disease duration, HbA1c
and complications for 710 younger adults (18–35 years) with Type 1 diabetes. A questionnaire with wideranging psychometric scales was used to measure various aspects of psychosocial functioning: the burden
of diabetes-related problems, well-being, self-esteem, perceived competence in managing diabetes,
perceived autonomy support from health professionals and self-management motivations. Furthermore,
patients reported weekly self-monitored blood glucose measurements and insulin administration.
Associations between HbA1c, complication and psychosocial indicators were tested using linear and logistic
regression models, adjusted stepwise for confounders, including age, gender, diabetes duration, continuous
subcutaneous insulin infusion, smoking and BMI. Results In total, 406 (57%) participants responded. The
responders had a mean age of 27.1 (5.1) years, a mean diabetes duration of 13.5 (7.9) years and an
HbA1c of 74 mmol/mol (8.2%), with similar values for both genders (P = 0.87). Complications were
observed among women more commonly than among men (31.6 vs. 18.8%, P < 0.01), and high distress
levels were more prevalent among women compared with men (51.2 vs. 31.9%, P < 0.0001). Except for
perceived autonomy support, the psychosocial variables were all associated with HbA1c (P < 0.001).
Conclusions The high prevalence of poor glycaemic control, early complications and psychosocial distress
require health-promoting interventions tailored to the interrelated clinical and psychosocial needs of younger
adults with Type 1 diabetes. This article is protected by copyright. All rights reserved.
A cross-sectional study of the prevalence of cardiac valvular abnormalities in
hyperprolactinemic patients treated with ergot-derived dopamine agonists
01 Nov 2013 06:33 pm
Context:
Concern exists in the literature that the long-term use of ergot-derived dopamine agonist drugs for the
treatment of hyperprolactinemia may be associated with clinically significant valvular heart disease.
Objective:
To determine the prevalence of valvular heart abnormalities in patients taking dopamine agonists as
treatment for lactotrope pituitary tumors and to explore any associations with the cumulative dose of drug
used.
Design:
A cross-sectional echocardiographic study was performed in a large group of patients who were receiving
dopamine agonist therapy for hyperprolactinemia. Studies were performed in accordance with the British
Society of Echocardiography minimum dataset for a standard adult transthoracic echocardiogram. Poisson
regression was used to calculate relative risks according to quartiles of dopamine agonist cumulative dose
using the lowest cumulative dose quartile as the reference group.
Setting:
Twenty-eight centers of secondary/tertiary endocrine care across the UK.
Results:
Data from 747 patients (251 male, median age 42, IQR 34-52) were collected. 601 patients had taken
cabergoline alone; 36 had been treated with bromocriptine alone; and 110 had received both drugs at some
stage. Median cumulative cabergoline dose was 152 mg (IQR 50-348) and for bromocriptine was 7815 mg
(IQR 1764-20477). A total of 28 cases of moderate valvular stenosis or regurgitation were observed in 24
(3.2%) of patients. No associations were observed between cumulative doses of DA agonist used and the
age-corrected prevalence of any valvular abnormality.
Conclusion:
This large UK cross-sectional study does not support a clinically-concerning association between the use of
dopamine agonists for the treatment of hyperprolactinemia and cardiac valvulopathy.
A paradigm shift in the monitoring of patients with Acromegaly: Last available growth
hormone may overestimate risk
15 Nov 2013 05:48 pm
Context:
Acromegaly is associated with reduced life expectancy, which has been reported to be normalized if
treatment is successful in controlling GH/IGF-I levels.
Objective:
Most previous studies have invariably used the last available GH/IGF-I, which may be biased as it only
assesses exposure at a single point in time. We compared the last available GH/IGF-I analysis to a ‘time
dependent’ and cumulative method, during follow up to assess risk of mortality in the West Midlands
Acromegaly study (n=501).
Results:
Using the last available GH there was a statistically significant increase in mortality comparing groups as
low as GH≤1μg/litre vs. >1μg/litre (RR 1.8,p=0.03). This was not the case when using the ‘time-dependent
method’, where only comparisons of GH values of GH ≤5μg/litre vs. >5μg/litre were suggestive of being
associated with an increased risk of mortality (RR=1.5,p=0.08). When the time dependent GH method of
analysis was used the RR of mortality at each level was lower and the associated p value less significant.
Irrespective of using last available or time dependent method, when IGF-I was divided into levels according
to quartile or arbitrary cutoffs, there was no significant increase in mortality with higher levels.
Conclusions:
This study emphasizes the potential bias of using the latest available GH/IGF-I levels to predict mortality.
Our study again highlights the limitations of IGF-I in predicting mortality.
A2B adenosine receptors prevent insulin resistance by inhibiting adipose tissue
inflammation via maintaining alternative macrophage activation
05 Nov 2013 09:04 pm
Obesity causes increased classical and decreased alternative macrophage activation, which in turn cause
insulin resistance in target organs. Because A2B adenosine receptors (AR)s are important regulators of
macrophage activation, we examined the role of A2BARs in adipose tissue inflammation and insulin
resistance. A2BAR deletion impaired glucose and lipid metabolism in mice fed chow but not a high fat diet,
which was paralleled by dysregulation of the adipokine system and increased classical macrophage
activation and inhibited alternative macrophage activation. The expression of alternative macrophage
activation-specific transcriptions factors, including CCAAT/enhancer binding protein β, interferon regulatory
factor 4, and peroxisome proliferator-activated receptor was decreased in A2BAR deficient mice.
Furthermore, inin vitro studies, we found that stimulation of A2BARs suppressed free fatty acid-induced
deleterious inflammatory and metabolic activation of macrophages. Moreover, AR activation upregulated
the interleukin-4-induced expression of CCAAT/enhancer binding protein β, interferon regulatory factor 4,
and peroxisome proliferator-activated receptor in macrophages. Altogether, our results indicate that
therapeutic strategies targeting A2BARs hold promise for preventing adipose tissue inflammation and insulin
resistance.
ATLANTIC-DIP: Excessive gestational weight gain and pregnancy outcomes in women with
gestational or pregestational diabetes mellitus
01 Nov 2013 06:33 pm
Context:
Women who have diabetes mellitus during pregnancy are at higher risk of adverse outcomes. Excessive
gestational weight gain (GWG) is also emerging as a risk factor for maternofetal complications and in 2009,
the Institute of Medicine (IOM) published recommendations for appropriate GWG. It is unclear if excessive
GWG confers additional risk to women with diabetes in pregnancy and if IOM recommendations are
applicable to this population.
Objectives:
To examine whether excessive GWG in pregnancies complicated by diabetes mellitus is associated with
higher adverse obstetric outcomes.
Design:
Observational study.
Setting:
Five antenatal centres along the Irish Atlantic seaboard.
Participants:
802 women with diabetes in pregnancy.
Main outcome measure:
Maternal outcomes examined included pre-eclampsia, gestational hypertension and cesearean delivery.
Foetal outcomes included large for gestational age (LGA), macrosomia and small for gestational age
(SGA).
Results:
Excessive GWG was noted in 59% women. In all women, excessive GWG resulted in higher odds for LGA
[adjusted odds ratio (aOR) 2.01, 95% confidence intervals (CI) 1.24-3.25 in GDM; aOR 3.97,CI 1.85-8.53 in
PGDM] and macrosomia (aOR 2.17,CI 1.32-3.55 in GDM; aOR 3.58,CI 1.77-7.24 in PGDM). Excessive
GWG was also associated with increased odds for gestational hypertension (aOR 1.72,CI 1.04-2.85) in
women with GDM and treatment with insulin further increased the odds for LGA (aOR 2.80,CI 1.23-6.38)
and macrosomia (aOR 5.63,CI 2.16-14.69) in this group.
Conclusion:
We show that in the already high-risk settings of both GDM and PGDM, excessive GWG confers an additive
risk for LGA birthweight, macrosomia and gestational hypertension.
Acceleration of the Loss of the First-Phase Insulin Response During the Progression to
Type 1 Diabetes in Diabetes Prevention Trial-Type 1 Participants
21 Nov 2013 08:01 pm
We studied the change in the first-phase insulin response (FPIR) during the progression to type 1 diabetes
(T1D). Seventy-four oral insulin trial progressors to T1D from the Diabetes Prevention Trial–Type 1 with at
least one FPIR measurement after baseline and before diagnosis were studied. The FPIR was examined
longitudinally in 26 progressors who had FPIR measurements during each of the 3 years before diagnosis.
The association between the change from the baseline FPIR to the last FPIR and time to diagnosis was
studied in the remainder (n = 48). The 74 progressors had lower baseline FPIR values than nonprogressors
(n = 270), with adjustments made for age and BMI. In the longitudinal analysis of the 26 progressors, there
was a greater decline in the FPIR from 1.5 to 0.5 years before diagnosis than from 2.5 to 1.5 years before
diagnosis. This accelerated decline was also evident in a regression analysis of the 48 remaining
progressors in whom the rate of decline became more marked with the approaching diagnosis. The patterns
of decline were similar between the longitudinal and regression analyses. There is an acceleration of
decline in the FPIR during the progression to T1D, which becomes especially marked between 1.5 and 0.5
years before diagnosis.
Activating AKT2 mutation: Hypoinsulinaemic hypoketotic hypoglycaemia
27 Nov 2013 04:43 pm
Background:
Hyperinsulinaemic hypoglycaemia (HH), characterized by unregulated insulin secretion, is an important
cause of persistent and severe hypoglycaemia. The biochemical picture of HH is hypoketotic
hypofattyacidaemic hypoglycaemia along with elevated serum insulin. Not infrequently, serum insulin might
be undetectable in HH despite the presence of evidence of insulin action (suppressed ketogenesis and
lipolysis). However autonomous activity of the downstream insulin signalling pathway without the presence
of the ligand (insulin) will give rise to the same clinical and biochemical picture, apart from undetectable
serum insulin/c-peptide. AKT2, a serine/threonine protein kinase, is involved downstream to insulin
receptor, in mediating the physiological effects of insulin.
Aim:
We describe the second report of an activating AKT2 mutation leading to hypoinsulinaemic hypoketotic
hypoglycaemia.
Patients and Methods:
The proband presented with hemihypertrophy and symptomatic hypoglycaemia. Investigations confirmed
evidence of insulin action, despite absence of detectable serum insulin on multiple occasions. Molecular
genetic testing for common causes of HH (ABCC8, KCNJ11 and GLUD1) was negative. Sequencing
of AKT2 identified a de novo mosaic c.49G>A (p.E17K) mutation, consistent with the clinical and
biochemical phenotype.
Conclusions:
This is the second report of activating AKT2 mutation leading to hypoinsulinaemic hypoketotic
hypofattyacidaemic hypoglycaemia. In patients presenting clinical and biochemical picture of HH with
undetectable serum insulin, consideration of autonomous activation of downstream insulin signalling
pathway should be made.
Adipocyte Mitochondrial Function is Reduced in Human Obesity Independent of Fat Cell
Size
25 Nov 2013 05:52 pm
Context:
It has been suggested that mitochondrial dysfunctional in adipocytes contribute to obesity-related metabolic
complications. However, obesity results in adipocyte hypertrophy, large and small adipocytes from the
same depot have different characteristics, raising the possibility that obesity-related mitochondrial defects
are an inherent function of large adipocytes.
Objective:
to examine whether obesity, independent of fat cell size and fat depot, is associated with mitochondria
dysfunction.
Design:
cross-sectional comparison.
Setting:
Academic medical center.
Patients or Other Participants:
omental (OM) and/or abdominal subcutaneous (SQ) adipose samples were collected from 20, age-matched
obese and non-obese non-diabetic men and women undergoing either elective abdominal surgery or
research needle biopsy.
Intervention:
None.
Main Outcome Measures:
mitochondrial DNA abundance, oxygen consumption rates (OCR) and citrate synthase (CS) activity from
populations of large and small adipocytes (separated with differential floatation).
Results:
For both omental and subcutaneous adipocytes, at the cell and organelle level, OCR and CS activity were
significantly reduced in cells from obese compared with non-obese volunteers, even when matched for cell
size by comparing large adipocytes from non-obese and small adipocytes from obese. Adipocyte
mitochondrial content was not significantly different between obese and non-obese volunteers.
Mitochondrial function and content parameters were not different between small and large cells, omental
and subcutaneous adipocytes from the same person.
Conclusion:
Adipocyte mitochondrial oxidative capacity is reduced in obese compared to non-obese adults and this
difference is not due to cell size differences. Adipocyte mitochondrial dysfunction in obesity is therefore
related to overall adiposity rather than adipocyte hypertrophy.
Adipocyte XBP1s Promotes Adiponectin Multimerization and Systemic Glucose
Homeostasis
15 Nov 2013 05:47 pm
The physiological role of the spliced form of X-box-binding protein 1 (XBP1s), a key transcription factor of
the endoplasmic reticulum (ER) stress response, in adipose tissue remains largely unknown. Here we show
that overexpression of XBP1s promotes adiponectin multimerization in adipocytes, thereby regulating
systemic glucose homeostasis. Ectopic expression of XBP1s in adipocytes improves glucose tolerance and
insulin sensitivity in both lean and obese (ob/ob) mice. The beneficial effect of adipocyte XBP1s on glucose
homeostasis is associated with elevated serum levels of HMW adiponectin and indeed, is adiponectin
dependent. Mechanistically, XBP1s promotes adiponectin multimerization rather than activating its
transcription likely through a direct regulation of the expression of several ER-chaperones involved in
adiponectin maturation, including Grp78, Pdia6, ERp44 and DsbA-L. Thus, we conclude that XBP1s is an
important regulator of adiponectin multimerization, which may lead to a new therapeutic approach for the
treatment of type 2 diabetes and hypoadiponectinemia.
Adipose Dipeptidyl Peptidase-4 and Obesity: Correlation with insulin resistance and depotspecific release from adipose tissue in vivo and in vitro
21 Nov 2013 08:01 pm
OBJECTIVE
To study expression of the recently identified adipokine dipeptidyl peptidase-4 (DPP4) in subcutaneous
adipose tissue (SAT) and visceral adipose tissue (VAT) of patients with various BMIs and insulin
sensitivities, as well as to assess circulating DPP4 in relation to obesity and insulin sensitivity.
RESEARCH DESIGN AND METHODS
DPP4 expression was measured in SAT and VAT from 196 subjects with a wide range of BMIs and insulin
sensitivities. DPP4 release was measured ex vivo in paired biopsies from SAT and VAT as well as in vivo
from SAT of lean and obese patients. Circulating DPP4 was measured in insulin-sensitive and insulinresistant BMI-matched obese patients.
RESULTS
DPP4 expression was positively correlated with BMI in both SAT and VAT, with VAT consistently displaying
higher expression than SAT. Ex vivo release of DPP4 from adipose tissue explants was higher in VAT than
in SAT in both lean and obese patients, with obese patients displaying higher DPP4 release than lean
controls. Net release of DPP4 from adipose tissue was also demonstrated in vivo with greater release in
obese subjects than in lean subjects and in women than in men. Insulin-sensitive obese patients had
significantly lower circulating DPP4 than did obesity-matched insulin-resistant patients. In this experiment,
DPP4 positively correlated with the amount of VAT, adipocyte size, and adipose tissue inflammation.
CONCLUSIONS
DPP4, a novel adipokine, has a higher release from VAT that is particularly pronounced in obese and
insulin-resistant patients. Our data suggest that DPP4 may be a marker for visceral obesity, insulin
resistance, and the metabolic syndrome.
Adipose Inflammation in Obesity: Relationship With Circulating Levels of Inflammatory
Markers and Association With Surgery-Induced Weight Loss
15 Nov 2013 05:48 pm
Context:
The inflammatory state of the adipose tissue is believed to contribute to systemic low-grade inflammation in
obesity.
Objective:
This study assessed the relationship between adipose and circulating inflammatory markers as well as the
influence of adipose inflammation on bariatric surgery-induced weight reduction.
Design:
This was a cross-sectional and longitudinal study (up to 14 mo).
Setting:
The study was conducted in the digestive/bariatric surgery department of the Tivoli and Jean Villar clinics,
Bordeaux, France.
Patients:
Thirty-seven obese patients [body mass index (BMI) > 35–40 kg/m2)] seeking bariatric surgery were
included. Twenty-eight of them were successively followed up at 1–3 months after surgery and 25 between
6 and 14 months after surgery.
Main Outcome Measures:
Fasting serum samples were collected before surgery to assess concentrations of inflammatory markers.
Samples of visceral adipose tissue were extracted during surgery and gene expression of cytokines and
immune cell markers were evaluated using quantitative RT-PCR. Pre- and postsurgery weight and BMI
were collected.
Results:
Gene expressions of several cytokines were strongly intercorrelated in the visceral adipose tissue. Adipose
expression of macrophage and T cell markers were related to adipose expression of TNF-α and IL-1
receptor antagonist (P < .01) and to systemic levels of TNF-α (P < .01) and IL-6 (P < .05). A higher
inflammatory state of the adipose tissue predicted a lower BMI reduction after surgery (P < .05), notably at
early stages after surgery.
Conclusions:
These findings support the involvement of macrophages and T cells in adipose inflammation and provide
new information regarding the role of the visceral adipose tissue in the inflammatory state of obesity and its
impact on obesity treatment outcomes, such as surgery-induced weight loss.
Adipose Mesenchymal Stromal Cells Isolated From Type 2 Diabetic Patients Display
Reduced Fibrinolytic Activity
21 Nov 2013 08:01 pm
Stem cells have been successfully used for the treatment of critical limb ischemia (CLI). We conducted a
clinical trial to determine the feasibility of using autologous adipose-derived mesenchymal stromal cells
(AdMSCs) for the treatment of CLI. Unexpectedly, two diabetic patients developed peripheral
microthrombosis. This adverse effect, which contrasts with the reported antithrombotic properties of MSCs,
may stem from the diabetic environment that alters the fibrinolytic activity of AdMSCs, thereby increasing
the probability of developing thrombosis. Here, we confirm this premise by demonstrating that diabetic
AdMSCs cultured in the presence of blood sera expressed and released higher levels of plasminogen
activator inhibitor type 1, reduced levels of tissue plasminogen activator, and lower d -dimer formation
compared with nondiabetic AdMSCs. Thus, to establish an appropriate cell therapy for diabetic patients, we
recommend including new preclinical safety tests, such as the d -dimer and/or the tissue plasminogen
activator-to-plasminogen activator inhibitor type 1 ratio tests, to assess fibrinolytic activity of cells before
implantation.
Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT): Urinary screening and
baseline biochemical and cardiovascular assessments
06 Nov 2013 01:31 pm
Objective
To assess the association between early increases in albumin excretion and cardiovascular (CV) and renal
markers in a large cohort of young people with type 1 diabetes.
Research Design and Methods
As part of preliminary screening for a multicentre, randomized controlled trial of statins/ACE inhibitors, we
measured albumin-creatinine ratio (ACR) in 6 early morning urine samples from 3,353 adolescents (10-16
years) and calculated tertiles based on an established algorithm. From those subjects deemed to be at
higher risk (upper ACR tertile) we recruited 400 into the intervention study (Trial cohort). From those
subjects deemed to be at lower risk (middle-lower ACR tertiles) we recruited 329 to the Observation cohort.
At baseline vascular measurements (carotid intima-media thickness, pulse wave velocity (PWV), flowmediated dilatation, digital pulse amplitude tonometry), renal (symmetric dimethylarginine, cystatin C,
creatinine) and CVD markers (lipids and apolipoproteins (Apo)A-1 and B, C-Reactive Protein, asymmetric
dimethylarginine) were assessed.
Results
Age- and sex-adjusted PWV was higher in the Trial than in the Observational cohort (5.00±0.84 vs
4.86±0.70m/s, p=0.021). Similarly, non-HDL-cholesterol (2.95±0.83 vs 2.81±0.78mmol/l, p=0.02) and
ApoB/ApoA-1 ratio (0.50±0.14 vs 0.47±0.11, p=0.04) were higher in the Trial cohort. Cystatin C and
creatinine were decreased (0.88±0.13 vs 0.90±0.13ng/ml, p=0.04; 51.81±10.45 vs 55.35±11.05mmol/l,
p<0.001) and eGFR (137.05±23.89 vs 129.31±22.41ml/min/1.73m2, p<0.001) increased in the Trial
compared to the Observational cohort.
Conclusions
Our data demonstrate that in adolescents with type 1 diabetes, the group with the highest tertile of albumin
excretion showed more evidence of early renal and CV disease than those in the lower tertiles.
Age at type 2 diabetes onset and glycaemic control: results from the National Health and
Nutrition Examination Survey (NHANES) 2005–2010
01 Dec 2013 12:00 am
Abstract
Aims/hypothesis
We tested the hypothesis that age younger than 65 years at type 2 diabetes diagnosis is associated with
worse subsequent glycaemic control.
Methods
A cross-sectional analysis of data from participants in the 2005–2010 National Health and Nutrition
Examination Survey was performed. For adults with self-reported diabetes, we dichotomised age at
diabetes diagnosis as younger (<65 years) vs older (≥65 years). The primary outcome of interest was
HbA1c >9.0% (75 mmol/mol). Secondary outcomes were HbA1c >8.0% (64 mmol/mol) and >7.0%
(53 mmol/mol). We used multivariable logistic regression for analysis.
Results
Among 1,438 adults with diabetes, a higher proportion of those <65 years at diagnosis compared with those
≥65 at diagnosis had an HbA1c >9.0% (14.4% vs 2.5%, p < 0.001). After adjustment for sex, race/ethnicity,
education, income, insurance, usual source of care, hyperglycaemia medication, duration of diabetes,
family history, BMI and waist circumference, age <65 years at diagnosis remained significantly associated
with greater odds of HbA1c >9.0% (OR 3.22, 95% CI 1.54, 6.72), HbA1c >8.0% (OR 2.72, 95% CI 1.43, 5.16)
and HbA1c >7.0% (OR 1.92, 95% CI 1.18, 3.11). The younger group reported fewer comorbidities, but were
less likely to report good health (OR 0.54, 95% CI 0.36, 0.83).
Conclusions/interpretation
Younger age at type 2 diabetes diagnosis is significantly associated with worse subsequent glycaemic
control. Because patients who are younger at diagnosis have fewer competing comorbidities and
complications, safe, aggressive, individualised treatment could benefit this higher-risk group.
Age-dependent decline in acyl-ghrelin concentrations and reduced association of acylghrelin and growth hormone in healthy older adults
27 Nov 2013 04:43 pm
Background:
Acyl-ghrelin is thought to have both orexigenic effects and to stimulate growth hormone (GH) release. A
possible cause of the anorexia of aging is an age-dependent decrease in circulating acyl-ghrelin levels.
Objectives:
The purpose of the study was to compare acyl-ghrelin and GH concentrations between healthy old and
young adults and to examine the relationship of acyl-ghrelin and GH secretion in both age groups.
Methods:
Six healthy older adults (ages 62–74, BMI range 20.9 - 29 kg/m2) and eight healthy young men (ages 18–
28, BMI range 20.6 - 26.2 kg/m2) had frequent blood samples drawn for hormone measurements every 10
min for 24 hr. Ghrelin was measured in an in-house two-site sandwich ELISA specific for full-length acylghrelin. GH was measured in a sensitive assay (Immulite 2000) and GH peaks were determined by
deconvolution analysis. The acyl-ghrelin/GH association was estimated from correlations between
amplitudes of individual GH secretory events and the average acyl-ghrelin concentration in the 60-min
interval preceding each GH burst.
Results:
24-h mean (± SEM) GH (0.48 ± 0.14 vs. 2.2 ± 0.3 μ g/L, p<0.005) and acyl-ghrelin (14.7 ± 2.3 vs. 27.8 ± 3.9
pg/mL, p<0.05) levels were significantly lower in older adults compared to young. 24-h cortisol
concentrations were higher in the old than the young (15.1 ± 1.0 vs. 10.6 ± 0.9 μ g/dL, respectively), p<0.01.
The ghrelin/GH association was more than 3-fold lower in the older group compared to the young adults
(0.16 ± 0.12 vs. 0.69 ± 0.04), p<0.001.
Conclusions:
These results provide further evidence of an age-dependent decline in circulating acyl-ghrelin levels, which
might play a role both in the decline of GH and in the anorexia of aging. Our data also suggest that with
normal aging, endogenous acyl-ghrelin levels are less tightly linked to GH regulation.
Age-related differences in glycaemic control in diabetes
01 Dec 2013 12:00 am
Aldose Reductase drives hyperacetylation of Egr-1 in hyperglycemia and consequent
upregulation of proinflammatory and prothrombotic signals
01 Nov 2013 07:24 pm
Sustained increases in glucose flux via the aldose reductase (AR) pathway have been linked to diabetic
vascular complications. Previous studies revealed that glucose flux via AR mediates endothelial dysfunction
and leads to lesional haemorrhage in diabetic (DM) human AR (hAR) expressing mice in an apoE-/background. Our studies revealed sustained activation of Egr-1 with subsequent induction of its
downstream target genes tissue factor (TF) and Vascular Cell Adhesion Molecule1 (VCAM1) in DM apoE-/hAR mice aortas and in high glucose-treated primary murine aortic endothelial cells expressing hAR.
Furthermore, we observed that flux via AR impaired NAD+homeostasis and reduced activity of
NAD+ dependent deacetylase sirt-1 leading to acetylation and prolonged expression of Egr-1 in
hyperglycemic conditions. In conclusion, our data demonstrate a novel mechanism by which glucose flux
via AR triggers activation, acetylation and prolonged expression of Egr1 leading to proinflammatory and
prothrombotic responses in diabetic atherosclerosis.
Alternative splicing and differential expression of the islet autoantigen IGRP between
pancreas and thymus contributes to immunogenicity of pancreatic islets but not
diabetogenicity in humans
01 Dec 2013 12:00 am
Abstract
Aims/hypothesis
Thymic expression of self-antigens during T-lymphocyte development is believed to be crucial for
preventing autoimmunity. It has been suggested that G6PC2, the gene encoding islet-specific glucose-6phosphatase catalytic subunit-related protein (IGRP), is differentially spliced between pancreatic beta cells
and the thymus. This may contribute to incomplete elimination of IGRP-specific T lymphocytes in the
thymus, predisposing individuals to type 1 diabetes. We tested whether specific splice variation in islets vs
thymus correlates with loss of tolerance to IGRP in type 1 diabetes.
Methods
Expression of G6PC2 splice variants was compared among thymus, purified medullary thymic epithelial
cells and pancreatic islets by RT-PCR. Differential immunogenicity of IGRP splice variants was tested in
patients and healthy individuals for autoantibodies and specific cytotoxic T lymphocytes using radiobinding
assays and HLA class I multimers, respectively.
Results
Previously reported G6PC2 splice variants, including full-length G6PC2, were confirmed, albeit that they
occurred in both pancreas and thymus, rather than islets alone. Yet, their expression levels were profoundly
greater in islets than in thymus. Moreover, three novel G6PC2 variants were discovered that occur in islets
only, leading to protein truncations, frame shifts and neo-sequences prone to immunogenicity. However,
autoantibodies to novel or known IGRP splice variants did not differ between patients and healthy
individuals, and similar frequencies of IGRP-specific cytotoxic T lymphocytes could be detected in both
patients with type 1 diabetes and healthy individuals.
Conclusions/interpretation
We propose that post-transcriptional variation of tissue-specific self-proteins may affect negative thymic
selection, although this need not necessarily lead to disease.
Ambulatory Treatment of Type 2 Diabetes Mellitus in the United States, 1997-2012
22 Nov 2013 06:34 pm
Background
Type 2 diabetes is increasingly common and associated with substantial morbidity and mortality.
Methods
We conducted descriptive analyses of cross-sectional data using the IMS Health National Disease and
Therapeutic Index, a nationally representative audit of ambulatory physician practices in the US. We
focused on visits for diabetes among patients 35 years or older. We used the IMS Health National
Prescription Audit of pharmacy dispensing to derive information about drug expenditures.
Results
Ambulatory diabetes visits increased from 23 million [M] treatment visits in 1997 (95% confidence intervals
[CI], 21-25M) to 35M (CI 32-37M) in 2007 and declined to 31M visits by 2012 (CI 27-31M). Between 1997
and 2012 biguanide use increased, from 23% (20-26%) to 53% (50-56%) of treatment visits. Glitazone use
grew from 6% (CI 4-8%) in 1997 to 41% (CI 39-43%) of all visits in 2005, but declined to 16% (CI 8-12%) by
2012. Since 2005, DPP-4 inhibitor use increased steadily, representing 21% (CI 18-23%) of treatment visits
by 2012. GLP-1 agonists accounted for 4% of treatment visits in 2012. Visits where two or more drug
compounds were used increased nearly 40% from 1997 to 2012. Between 2008 and 2012, drug
expenditures increased 61%, driven primarily by use of insulin glargine and DPP-4 inhibitors.
Conclusions
Declining sulfonylurea and glitazone use has been offset by increases in DPP-4 inhibitor use and, to a
lesser degree, use of GLP-1 agonists. Treatment of diabetes has grown in complexity while older
treatments continue to be replaced or supplemented by newer therapies.
An Adult Female With Resistance to Thyroid Hormone Mediated by Defective Thyroid
Hormone Receptor {alpha}
05 Nov 2013 06:01 pm
Context:
The first human cases (female, age 6 y; father and daughter, ages 47 and 11 y, respectively) with growth
retardation/short stature, skeletal dysplasia, constipation, and defective thyroid receptor α (TRα) have been
recently described.
Objective:
A 45-year-old, short, overweight female with cognitive impairment, epilepsy, and constipation was
investigated.
Design and Intervention:
Clinical, biochemical, and radiological assessment and THRA sequencing were undertaken. The patient's
thyroid status and her biochemical and physiological parameters were evaluated at baseline and after
T4 therapy.
Results:
The patient exhibits disproportionate short stature, macrocephaly, low free T 4/free T3ratio and rT3 levels,
together with subnormal heart and basal metabolic rate. She is heterozygous for a novel
frameshift/premature stop (Ala382ProfsX7) THRA mutation, generating a mutant TRα with constitutive
corepressor binding and negligible coactivator recruitment, which inhibits its wild-type counterpart in a
dominant-negative manner—both in vitro and in mutation-containing patient blood mononuclear cells
studied ex vivo. Her alertness and constipation responded to T 4 therapy, which readily suppressed TSH
levels, raised basal metabolic rate, and normalized elevated muscle creatine kinase, but cardiac
parameters (heart rate, contractility) remained relatively refractory. The patient and a previous childhood
case showed reduced red cell mass with macrocytosis unresponsive to T 4 therapy.
Conclusions:
Clinical (short stature, macrocephaly, constipation) and biochemical (low free T 4/free T3 ratio, subnormal
rT3) findings that are congruent with previous cases and newly recognized features (epilepsy) in this adult
female with defective TRα define a shared phenotype in TRα-mediated resistance to thyroid hormone, with
differential tissue responses to T4 treatment.
An Update on the Molecular Actions of Fenofibrate and Its Clinical Effects on Diabetic
Retinopathy and Other Microvascular End Points in Patients With Diabetes
21 Nov 2013 08:01 pm
The drug fenofibrate has received major attention as a novel medical treatment for diabetic retinopathy (DR)
and other diabetes-induced microvascular complications. This interest stems from two recent large, welldesigned clinical trials that demonstrated large reductions in the progression of DR and the need for laser
intervention, in addition to a reduction in renal and neurological outcomes, in patients with type 2 diabetes.
In both trials, the greatest benefit on DR progression was observed in those patients with DR at baseline.
Originally considered a lipid-modifying drug, it now appears that multiple mechanisms may underpin the
benefit of fenofibrate on diabetic microvascular end points. Fenofibrate regulates the expression of many
different genes, with a range of beneficial effects on lipid control, inflammation, angiogenesis, and cell
apoptosis. These factors are believed to be important in the development of DR regardless of the
underlying diabetes etiology. Cell experiments have demonstrated improved survival of retinal endothelial
and pigment epithelial cells in conjunction with reduced stress signaling under diabetic conditions. Further,
fenofibrate improves retinal outcomes in rodent models of diabetes and retinal neovascularization. Given
the results of these preclinical studies, further clinical trials are needed to establish the benefits of
fenofibrate in other forms of diabetes, including type 1 diabetes. In DR management, fenofibrate could be a
useful adjunctive treatment to modifiable risk factor control and regular ophthalmic review. Its incorporation
into clinical practice should be continually revised as more information becomes available.
Antagonizing Wnt Pathway in Diabetic Retinopathy
21 Nov 2013 08:01 pm
Anthocyanin supplementation improves HDL-associated paraoxonase 1 activity and
enhances cholesterol efflux capacity in subjects with hypercholesterolemia
27 Nov 2013 04:43 pm
Context and Objective:
Paraoxonase 1 (PON1), an enzyme associated with high-density lipoprotein (HDL-PON1), is reported to
have antioxidant and cardioprotective properties. The aim of the present study was to investigate the effects
of anthocyanins on the HDL-PON1 activity and cholesterol efflux capacity in hypercholesterolemic subjects.
Design and Participants:
A total of 122 hypercholesterolemic subjects were given 160 mg of anthocyanins twice daily or placebo (n =
61 of each group) for 24 wk in a double-blind, randomized, placebo-controlled trial. Participants and
investigators were masked to treatment allocation.
Results:
Anthocyanin consumption significantly increased HDL cholesterol and decreased LDL cholesterol
concentrations compared with placebo (P < 0.018 and P<0.001, respectively). Anthocyanin
supplementation also increased the activity of HDL-PON1 compared with placebo (P<0.001). Furthermore,
cholesterol efflux capacity was increased more in the anthocyanin group (20.0% increase) than in the
placebo group (0.2% increase) (P<0.001). The negative correlations established between HDL-PON1
activity and the levels of lipid hydroperoxides associated with HDL confirm the relationship between PON1
activity and lipid peroxidation of lipoproteins. Furthermore, a strong positive correlation was noted between
increased HDL-PON1 activity and improved cholesterol efflux capacity both before and after adjustment for
HDL cholesterol and apolipoprotein AI in anthocyanin-treated subjects (both P < 0.001). Inhibition of HDLPON1 activity strongly prevented the antioxidant ability of HDL and attenuated the cholesterol efflux
capacity of subjects from anthocyanin group.
Conclusions:
Our observations suggest that the alterations of PON1 activity by anthocyanin observed in
hypercholesterolemic HDL reflect a shift to an improvement of cholesterol efflux capacity of HDL and may
provide a link between anthocyanin and cardioprotective effects.
Antiangiogenic and Antineuroinflammatory Effects of Kallistatin Through Interactions With
the Canonical Wnt Pathway
21 Nov 2013 08:01 pm
Kallistatin is a member of the serine proteinase inhibitor superfamily. Kallistatin levels have been shown to
be decreased in the vitreous while increased in the circulation of patients with diabetic retinopathy (DR).
Overactivation of the Wnt pathway is known to play pathogenic roles in DR. To investigate the role of
kallistatin in DR and in Wnt pathway activation, we generated kallistatin transgenic (kallistatin-TG) mice
overexpressing kallistatin in multiple tissues including the retina. In the oxygen-induced retinopathy (OIR)
model, kallistatin overexpression attenuated ischemia-induced retinal neovascularization. In diabetic
kallistatin-TG mice, kallistatin overexpression ameliorated retinal vascular leakage, leukostasis, and
overexpression of vascular endothelial growth factor and intracellular adhesion molecule. Furthermore,
kallistatin overexpression also suppressed Wnt pathway activation in the retinas of the OIR and diabetic
models. In diabetic Wnt reporter (BAT-gal) mice, kallistatin overexpression suppressed retinal Wnt reporter
activity. In cultured retinal cells, kallistatin blocked Wnt pathway activation induced by high glucose and by
Wnt ligand. Coprecipitation and ligand-binding assays both showed that kallistatin binds to a Wnt
coreceptor LRP6 with high affinity (Kd = 4.5 nmol/L). These observations suggest that kallistatin is an
endogenous antagonist of LRP6 and inhibitor of Wnt signaling. The blockade of Wnt signaling may
represent a mechanism for its antiangiogenic and antineuroinflammatory effects.
Are Cathepsin K Inhibitors Just Another Class of Anti-Resorptives?
05 Nov 2013 06:01 pm
Aromatic L-Amino Acid Decarboxylase Deficiency Is a Cause of Long-Fasting
Hypoglycemia
05 Nov 2013 06:01 pm
Objective/Context:
Long-fasting hypoglycemia in children may be induced by neurotransmitter disorders.
Case Report:
A 5-year-old girl with a medical history of chronic diarrhea presented three episodes of severe
hypoglycemia (20 mg/dL) between ages 3 and 5 years. She became pale and sweaty with hypothermia
(33.5°C), bradycardia (45 bpm), and acidosis and presented a generalized seizure. During the 17-hour fast
test performed to determine the etiology of her hypoglycemia, insulin and C-peptide were appropriately low,
and human GH, IGF-I, cortisol, amino acids, and acylcarnitines were in the usual range for fasting duration.
However, the presence of vanillactic and vanilpyruvic acids in urine led us to investigate the metabolism of
dopamine and serotonin in the cerebrospinal fluid. Indeed, these results indicated an aromatic L-amino acid
decarboxylase deficiency that impairs the synthesis of serotonin, dopamine, and catecholamines. The
diagnosis was confirmed by the low aromatic L-amino acid decarboxylase (AADC) enzyme activity in
plasma (5 pmol/min/mL; reference value, 20–130) and the presence of two heterozygous mutations,
c.97G>C (p.V33L, inherited from her father) and c.1385G>C (p.R462P, inherited from her mother) in
the DCC gene. She was supplemented with pyridoxine and raw cornstarch (1 g/kg) at evening dinner to
reduce the night fast. The episodes of hypoglycemia and the chronic diarrhea were suppressed.
Conclusion:
Here is the first case report of long-fasting hypoglycemia due to a nontypical AADC deficiency.
Hypoglycemia was severe, but the other neurological clinical hallmarks present in AADC-deficient patients
were mild to moderate. Thus, neurotransmitter disorders should be considered in any patients presenting
hypoglycemia with urine excretion of vanillactic acid.
Artificial Sweeteners Have No Effect on Gastric Emptying, Glucagon-Like Peptide-1, or
Glycemia After Oral Glucose in Healthy Humans
21 Nov 2013 08:01 pm
Assessment of Thyroid Function During First-Trimester Pregnancy: What Is the Rational
Upper Limit of Serum TSH During the First Trimester in Chinese Pregnant Women?
25 Nov 2013 05:52 pm
Context:
Guidelines of the American Thyroid Association (ATA) proposed that the upper limit of the TSH reference
range should be 2.5 mIU/L in first trimester, but the reported ranges in China are significantly higher.
Objective:
Our objective was to establish a rational reference range of serum TSH for diagnosis of subclinical
hypothyroidism in the first trimester of pregnant women in China.
Design:
We screened 4800 pregnant women in the first trimester and 2000 women who planned to become
pregnant and evaluated 535 pregnant women in follow-up visits during the second and third trimester.
Results:
Median concentrations of serum TSH decreased significantly from the seventh week of gestation. The
median of TSH from 4 to 6 weeks was significantly higher than from 7 to 12 weeks (2.15 [0.56–5.31] mIU/L
vs 1.47 [0.10–4.34] mIU/L, P < .001); however, there was no significant difference compared with
nonpregnant women (2.07 [0.69–5.64] mIU/L; P = .784). The median of free T4 was not significantly altered
in the first trimester. The prevalence of subclinical hypothyroidism in the 4800 pregnant women was 27.8%
on the diagnostic criteria of TSH >2.5 mIU/L and 4.0% using the reference interval derived by our laboratory
(0.14–4.87 mIU/L).Additionally, of 118 pregnant women who had serum TSH >2.5 mIU/L in the first
trimester, only 30.0% and 20.3% of them at the 20th and 30th week of gestation had TSH >3.0 mIU/L.
Conclusions:
The reference range for nonpregnant women can be used for the assessment of pregnant women at 4 to 6
weeks of gestation. The upper limit of serum TSH in the first trimester was much higher than 2.5 mIU/L in
Chinese pregnant women.
Association Between Excessive Daytime Sleepiness and Severe Hypoglycemia in People
With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study
21 Nov 2013 08:01 pm
OBJECTIVE
Sleep-disordered breathing and sleepiness cause metabolic, cognitive, and behavioral disturbance. Sleepdisordered breathing is common in type 2 diabetes, a condition that requires adherence to complex dietary,
behavioral, and drug treatment regimens. Hypoglycemia is an important side effect of treatment, causing
physical and psychological harm and limiting ability to achieve optimal glycemic control. We hypothesized
that sleep disorder might increase the risk of hypoglycemia through effects on self-management and
glucose regulation.
RESEARCH DESIGN AND METHODS
People with type 2 diabetes (n = 898) completed questionnaires to assess sleep-disordered breathing,
daytime sleepiness, and occurrence of severe hypoglycemia.
RESULTS
Subjects who scored highly on the Epworth Sleepiness Scale were significantly more likely to have suffered
from severe hypoglycemia. This was a significant predictor of severe hypoglycemia in regression analysis
including the variables age, sex, duration of diabetes, HbA1c, BMI, and treatment type.
CONCLUSIONS
Daytime sleepiness may be a novel risk factor for hypoglycemia.
Association Between Vitamin D Metabolism Gene Polymorphisms and Risk of Islet
Autoimmunity and Progression to Type 1 Diabetes: The Diabetes Autoimmunity Study in
the Young (DAISY)
05 Nov 2013 06:01 pm
Context:
Vitamin D metabolism genes have been associated with type 1 diabetes (T1D) risk; however, these genes
have not been investigated for association with the preclinical phase of T1D, islet autoimmunity (IA).
Studies of vitamin D metabolism genes may elucidate the role of vitamin D in complex diseases.
Objective:
The objective of the study was to explore the association between seven vitamin D metabolism gene singlenucleotide polymorphisms (SNPs) and the risk of IA and progression to T1D.
Design:
The Diabetes Autoimmunity Study in the Young is a longitudinal, observational study.
Setting:
Newborn screening for human leukocyte antigen, sibling and offspring recruitment, and follow-up took place
in Denver, Colorado.
Participants:
A total of 1708 children at increased genetic risk of T1D participated in the study: 148 developed IA and 62
IA-positive children progressed to T1D.
Main Outcome Measures:
IA, defined as positivity for glutamic acid decarboxylase, insulin, or IA-2 autoantibodies on two or more
consecutive visits, and T1D, diagnosed by a physician, were the main outcome measures.
Results:
The risk of IA was associated with DHCR7/NADSYN1 rs12785878 and CYP27B1rs4646536 [hazard ratio
1.36, 95% confidence interval 1.08–1.73 (for each additional minor allele) and hazard ratio 0.59, 95%
confidence interval 0.39–0.89 (for A/G compared with the A/A genotype), respectively]. None of the vitamin
D SNPs typed was associated with progression to T1D in IA-positive children. Six of the seven SNPs were
significantly associated with 25-hydroxyvitamin D levels.
Conclusions:
DHCR7/NADSYN1 rs12785878 and CYP27B1 rs4646536 may play an important role in islet autoimmunity,
the preclinical phase of T1D. These findings should be replicated in larger cohorts for confirmation.
Association between Serum 25-hydroxyvitamin D Level and Subclinical Cardiovascular
Disease in Primary Hyperparathyroidism
27 Nov 2013 04:43 pm
Context:
Vitamin D deficiency (25OHD) may be a modifiable cardiovascular (CV) risk factor. 25OHD insufficiency
(20–29ng/ml) and deficiency (<20ng/ml) are common in primary hyperparathyroidism (PHPT), but their
association with CV disease in PHPT has not been systematically investigated.
Objective:
This study evaluated whether low 25OHD is associated with subclinical CV disease in PHPT.
Design:
This is a cross-sectional analysis of PHPT patients with and without low 25OHD.
Settings and Participants:
We studied 110 PHPT patients in a university hospital setting.
Outcome Measures:
We measured carotid intima-media thickness; carotid plaque presence/thickness; carotid strain and
stiffness; left ventricular mass index (LVMI); cardiac systolic and diastolic function and mitral annular
calcification.
Results:
Low 25OHD levels (<30ng/ml) were observed in 28%, but only 9% had 25OHD deficiency (<20ng/ml). In
the whole group, 25OHD levels negatively correlated with BMI (r=-0.33, p=0.0005), PTH (r=-0.30, p=0.001),
calcium (r=-0.29, p=0.002), renal function and PHPT duration. CV indices were normal except for carotid
intima-media thickness, stiffness and plaque thickness, which were increased regardless of 25OHD status.
Isovolumic relaxation time (IVRT) was the only CV measure associated with 25OHD (r=-0.26, p=0.01).
Those with 25OHD<20 ng/ml had more severe PHPT and a higher rate of nephrolithiasis. Those with
25OHD<30ng/ml were younger, had higher BMI, lower serum phosphate, and were more likely to be male,
non-white and Hispanic. Other than lower tissue Doppler e' and higher IVRT within normal in those with
25OHD<30 vs. >30ng/ml, there were no differences in CV indices utilizing either 25OHD threshold.
Conclusions:
Patients with mild PHPT have subclinical carotid abnormalities, but low 25OHD is not associated with
abnormal carotid or cardiac measures. To the extent that PTH levels differentiated those with 25OHD<20
but not 30ng/ml, these data support a 25OHD threshold of 20ng/ml as clinically relevant in PHPT.
Association between lung capacity measurements and abnormal glucose metabolism:
findings from the Crossroads study
18 Nov 2013 12:15 am
Aim To examine the association between lung function and metabolic syndrome/Type 2 diabetes. Methods
A total of 1454 adults from rural Victoria, Australia, from randomly selected households included in the
Crossroads study, provided spirometric measurements including forced vital capacity, forced expiratory
volume in 1 s, predicted percentage value of forced expiratory volume in 1 s and forced vital capacity
predicted percentage value. Assessments also included HbA1c, metabolic syndrome components and a 75g oral glucose tolerance test. The area under the receiver-operating characteristic curves for waist
circumference were compared with those for combinations of waist circumference and raw spirometric
measures (forced vital capacity and forced expiratory volume in 1 s) for identifying metabolic syndrome or
Type 2 diabetes. Results Partipants with a greater number of metabolic syndrome components were more
likely to have reduced lung function, particularly if Type 2 diabetes was present: the predicted value of
forced expiratory volume in 1 s decreased by 5–6% for participants with 2–4 metabolic syndrome
components, and by 9% for those with Type 2 diabetes. The risk of metabolic syndrome or Type 2 diabetes
was inversely associated with higher spirometry values (forced expiratory volume in 1 s percentage
predicted value: odds ratio for 2–4 metabolic syndrome components 0.36–0.21 in women and 0.32–0.30
men; the odds ratio for Type 2 diabetes was 0.36 in women and 0.28 in men). Receiver-operating
characteristic curve analysis for identifying metabolic syndrome and Type 2 diabetes revealed significant
differences between the area under the receiver-operating characteristic curve with waist circumference
alone and that for the combination of waist circumference with lung capacity measures. Conclusion
Pulmonary function is lower in people with metabolic syndrome and Type 2 diabetes. Spirometry variables
are independent predictors of metabolic syndrome and Type 2 diabetes.
Association of Obstructive Sleep Apnea and Glucose Metabolism in Subjects With or
Without Obesity
21 Nov 2013 08:01 pm
OBJECTIVE
The purpose of this study was to investigate whether the impact of obstructive sleep apnea (OSA) on
glucose metabolism was different according to the presence or absence of obesity.
RESEARCH DESIGN AND METHODS
A total of 1,344 subjects >40 years old from the Korean Genome and Epidemiology Study were included.
OSA was detected by home portable sleep monitoring. Plasma glucose, HbA1c, and insulin resistance were
compared according to OSA and obesity status. The associations between OSA and impaired fasting
glucose (IFG), impaired glucose tolerance (IGT), IFG + IGT, and diabetes were evaluated in subjects with
and without obesity after adjusting for several confounding variables. The effect of visceral obesity on this
association was evaluated in 820 subjects who underwent abdominal computed tomography scanning.
RESULTS
In subjects without obesity, fasting glucose, 2-h glucose after 75-g glucose loading, and HbA1c were higher
in those with OSA than in those without after controlling for age, sex, and BMI. In addition, the presence of
OSA in nonobese subjects was associated with a higher prevalence of IFG + IGT and diabetes after
adjusting for several confounding variables (odds ratio 3.15 [95% CI 1.44–6.90] and 2.24 [1.43–3.50] for
IFG + IGT and diabetes, respectively). Further adjustment for visceral fat area did not modify this
association. In contrast, in those with obesity, none of the abnormal glucose tolerance categories were
associated with OSA.
CONCLUSIONS
The presence of OSA in nonobese individuals is significantly associated with impaired glucose metabolism,
which can be responsible for future risk for diabetes and cardiovascular disease.
Associations Between Ethnicity, Body Composition, and Bone Mineral Density in a
Southeast Asian Population
05 Nov 2013 06:01 pm
Context and Objective:
Chinese men in Singapore have a higher incidence of hip fractures than Malay and Indian men. We
investigated whether there were corresponding ethnic differences in peak bone mineral density (BMD) in
young men and whether differences in body composition influenced peak BMD.
Design and Setting:
This was a cross-sectional study of healthy volunteers in a tertiary medical center.
Participants:
A total of 100 Chinese, 82 Malay, and 80 Indian men aged 21 to 40 years, with body mass index between
18 and 30 kg/m2 underwent dual-energy x-ray absorptiometry to assess BMD, lean mass (LM) and fat mass
(FM), and magnetic resonance imaging to quantify abdominal subcutaneous and visceral adipose tissue.
Multiple linear regression models, with adjustment for age and height (as a proxy for skeletal size), were
used.
Results:
Malay and Indian men had significantly higher BMD than Chinese men at the lumbar spine (Malay: B, 0.06
± 0.02, P = .001; Indian: B, 0.03 ± 0.02, P = .049), femoral neck (Malay: B 0.04 ± 0.02, P = .034; Indian: B,
0.04 ± 0.02, P = .041), hip (Malay: B, 0.05 ± 0.02, P = .016; Indian: B, 0.06 ± 0.02, P = .001), and ultradistal
radius (Malay: B, 0.03 ± 0.01, P < .001; Indian: B, 0.02 ± 0.01, P = .029), and this difference was retained
after adjustment for LM and FM, except in Malay men at the femoral neck and in Indian men at the
ultradistal radius. LM was an important independent determinant of BMD at all sites, whereas FM,
subcutaneous adipose tissue, and visceral adipose tissue were not significantly associated with BMD at any
site.
Conclusions:
Lower peak BMD in Chinese men may partly explain the higher fracture incidence in this ethnic group.
Further studies are needed to elucidate the reasons for these ethnic differences in bone accumulation.
Associations between bone mineral density and subclinical atherosclerosis: a crosssectional study of a Chinese population
18 Nov 2013 06:35 pm
Context:
The significance of associations between bone mineral density (BMD) and atherosclerosis in Asian
population is less clear.
Objective:
The aim of this study was to explore the population-level associations between BMD and subclinical
atherosclerosis.
Design and Setting:
This was a community-based cross-sectional study conducted in Shenyang, China.
Participants:
A total of 385 Chinese women and men aged 37–87 years were studied.
Main Outcome Measures:
The BMD was measured at the total hip and lumbar spine using dual-energy x-ray absorptiometry. The
ankle-brachial index (ABI), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT) were
measured to assess atherosclerosis. Multiple regression analysis was applied to study the associations.
Multicolinearity was examined using the variance inflation factor, condition index, and variance proportions.
Factor analysis and principal component regression were used to remove the problem of multicolinearity.
Results:
The differences of ABI, PWV, and CIMT among the normal BMD, osteopenia, and osteoporosis groups
were not found. Total hip BMD was correlated with ABI in women after adjustment for age (r=0.156). Sexspecific regression models included adjustment for age, body mass index, cigarette smoking, alcohol
consumption, menopausal status (women), systolic blood pressure, diastolic blood pressure, triglycerides,
total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting blood
glucose, serum uric acid, estimated glomerular filtration rate, high-sensitivity C-reactive protein, and
fibrinogen. Total hip BMD was associated with ABI in women after adjustment for age (per standard
deviation decrease in ABI: –0.130 g/cm2, P=0.022), but the association was borderline significant after full
adjustment (P=0.045). Total hip BMD and lumbar spine BMD were not associated with ABI, PWV, and
CIMT after full adjustment in participants without a fracture history. The risk of osteoporosis was not
associated with ABI, PWV, and CIMT.
Conclusions:
Low BMD is not associated with subclinical atherosclerosis as assessed by ABI, PWV, and CIMT.
Bardoxolone Methyl in Type 2 Diabetes and Stage 4 Chronic Kidney Disease
09 Nov 2013 02:30 pm
New England Journal of Medicine, Volume 0, Issue 0, Ahead of Print.
Bariatric Surgery and the Mechanism of Diabetes Remission: Are We Getting There?
05 Nov 2013 06:01 pm
Basal and Meal-Stimulated Ghrelin, PYY, CCK Levels and Satiety in Lean Women With
Polycystic Ovary Syndrome: Effect of Low-Dose Oral Contraceptive
05 Nov 2013 06:01 pm
Context:
Ghrelin is an orexigenic peptide that stimulates food intake, whereas peptide YY (PYY) and cholecystokinin
(CCK) are anorexigenic gut hormones. Patients with polycystic ovary syndrome (PCOS) appear to have
alterations in appetite regulation.
Objective:
We aimed to determine whether fasting or meal-stimulated ghrelin, PYY, CCK, and satiety responses are
different between lean PCOS patients and healthy women. We also aimed to assess the potential effect of
oral contraceptive use on these hormones and satiety response.
Design and Setting:
We conducted a prospective observational study in a university practice.
Patients:
Eighteen lean PCOS patients and 18 healthy control women matched for age and body mass index
underwent measurements of circulating ghrelin, PYY, CCK, and satiety index (SI) before and after a
standardized mixed meal at 0, 15, 30, 45, 60, 90, 120, and 180 minutes.
Interventions:
For PCOS patients who were treated with ethinyl estradiol 30 μg/drospirenone 3 mg for 3 months,
measurements were repeated.
Main Outcome:
We measured ghrelin, PYY, and CCK levels and SI.
Results:
At baseline, fasting ghrelin, PYY, CCK, and SI values in PCOS patients were not different from controls.
Meal-stimulated PYY, CCK, and SI were also not different between the groups, whereas PCOS patients
had significantly lower meal-stimulated ghrelin levels compared to controls (P = .04). Ghrelin, PYY, CCK,
and SI did not show a significant change after treatment with ethinyl estradiol/drospirenone for 3 months.
Conclusions:
Basal and stimulated hunger and satiety hormones in lean PCOS patients are not different from lean
healthy women, except for a lower meal-stimulated ghrelin response. Short-term use of a low-dose oral
contraceptive does not have an effect on appetite regulation of PCOS.
Beneficial and Adverse Effects of Testosterone on the Cardiovascular System in Men
05 Nov 2013 06:01 pm
Context:
The widespread use of T therapy, particularly in aging males, necessitates knowledge of the relationship
between T and the cardiovascular system.
Evidence Acquisition:
The review is based on a 1970 to 2013 PubMed search with terms related to androgens in combination with
cardiovascular disease, including T, dihydrotestosterone, trial, mortality, cardiovascular disease, myocardial
infarction, blood pressure, endothelial function, dyslipidemia, thrombosis, ventricular function, and
arrhythmia. Original articles, systematic reviews and meta-analyses, and relevant citations were screened.
Evidence Synthesis:
Low T has been linked to increased blood pressure, dyslipidemia, atherosclerosis, arrhythmia, thrombosis,
endothelial dysfunction, as well as to impaired left ventricular function. On the one hand, a modest
association is suggested between low endogenous T and incident cardiovascular disease or cardiovascular
mortality, implying unrecognized beneficial T effects, residual confounding, or a relationship with health
status. On the other hand, treatments with T to restore "normal concentrations" have so far not been proven
to be beneficial with respect to cardiovascular disease; neither have they definitely shown specific adverse
cardiovascular effects. The cardiovascular risk-benefit profile of T therapy remains largely evasive in view of
a lack of well-designed and adequately powered randomized clinical trials.
Conclusions:
The important knowledge gap as to the exact relationship between T and cardiovascular disease would
support a cautious, restrained approach to T therapy in aging men, pending clarification of benefits and
risks by adequately powered clinical trials of sufficient duration.
Beta cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome
13 Nov 2013 02:50 pm
Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1and characterized by
insulin-dependent diabetes mellitus, optic atrophy and deafness. To investigate the cause of beta cell
failure, we used induced pluripotent stem (iPS) cells to create insulin-producing cells from individuals with
Wolfram syndrome. WFS1-deficient beta cells showed increased levels of endoplasmic reticulum (ER)
stress molecules, and decreased insulin content. Upon exposure to experimental ER stress, Wolfram beta
cells showed impaired insulin processing and failed to increase insulin secretion in response to glucose and
other secretagogues. Importantly, 4-phenyl butyric acid, a chemical protein folding and trafficking
chaperone, restored normal insulin synthesis and the ability to upregulate insulin secretion. These studies
show that ER stress plays a central role in beta cell failure in Wolfram syndrome and indicate that chemical
chaperones might have therapeutic relevance under conditions of ER stress in Wolfram syndrome and
other forms of diabetes.
Bilateral Oophorectomy and the Risk of Incident Diabetes in Postmenopausal Women
05 Nov 2013 08:29 pm
OBJECTIVE
Ovarian hormones regulate glucose uptake and insulin sensitivity. Despite the high frequency of surgical
menopause, its relationship with diabetes has not been extensively investigated. We assessed the
association between hysterectomy with/or without bilateral oophorectomy (BSO) status, menopausal age
and reproductive lifespan with incident diabetes.
RESEARCH DESIGN AND METHODS
Data was from a cohort of 2,597 postmenopausal women enrolled in the NHANES I Epidemiologic Followup Study without diabetes mellitus at baseline. Cox proportional hazard regression models were used to
calculate adjusted Hazard ratios and 95% confidence intervals.
RESULTS
After a median follow-up of 9.2 years, the incidence of diabetes (in cases per 1000 person years) was 7.4
for women with no hysterectomy or BSO, 8.2 for hysterectomy alone and 8.5 for hysterectomy with BSO.
Hysterectomy status was associated positively with diabetes (HR: 1.66, CI: 1.23-2.23). However the
elevated risk was restricted to women with both hysterectomy and BSO after adjustment for relevant
confounders (HR: 1.57, CI: 1.03, 2.41). An earlier age at menopause and a shorter reproductive lifespan
also exhibited a linear relationship with the development of diabetes irrespective of type of menopause
(PTREND = 0.001).
CONCLUSIONS
Women with hysterectomy concomitant with BSO may represent a unique population with elevated risk for
diabetes and other chronic diseases. Therefore the decision to remove the ovaries at the time of
hysterectomy for benign conditions during the premenopausal years should be balanced with the risk of
diabetes and its potential complications. Furthermore, the mechanism linking BSO to diabetes mellitus
needs to be clarified
Bioavailability of Vitamin D2 and D3 in Healthy Volunteers, a Randomized PlaceboControlled Trial
05 Nov 2013 06:01 pm
Background:
The bioequivalence of the different forms of vitamin D, ergocalciferol (vitamin D2) and cholecalciferol
(vitamin D3), has been questioned. Earlier studies have suggested that vitamin D2 is less biologically active
than vitamin D3.
Objective and Design:
In a parallel study, we tested the effects of supplementation with 50-μg/d doses of vitamin D2 or D3 or a
placebo over a period of 8 weeks on 25(OH)D2, 25(OH)D3, their sum 25(OH)D (primary outcome variables),
and PTH in healthy volunteers applying a double-blind, randomized study design. The study was conducted
during the winter of 2012 in Halle (Saale), Germany, at latitude 51°47N, when UVB irradiation is virtually
absent. Blood samples for the determinations of vitamin D status and PTH were collected at baseline and
after 4 and 8 weeks of supplementation.
Results:
In the placebo group (n = 19), 25(OH)D3 decreased from 39.4 ± 14.2 to 31.1 ± 12.4 nmol/L after 8 weeks
(P < .01). In the vitamin D3 group (n = 42), the concentrations of 25(OH)D3 increased from 41.5 ± 22.8
nmol/L at baseline to 88.0 ± 22.1 nmol/L after 8 weeks (P < .01). In the group receiving vitamin D2 (n = 46),
the 25(OH)D2concentrations increased significantly, whereas the 25(OH)D3 concentration fell from 36.4 ±
13.3 nmol/L at baseline to 16.6 ± 6.3 nmol/L after 8 weeks (P < .01). The total 25(OH)D was not different
between the groups at baseline but differed significantly between the groups after 4 and 8 weeks (P < .001).
Conclusions:
Vitamin D3 increases the total 25(OH)D concentration more than vitamin D2. Vitamin D2 supplementation
was associated with a decrease in 25(OH)D3, which can explain the different effect on total 25(OH)D.
Biomarkers for Type 2 Diabetes and Impaired Fasting Glucose Using a Nontargeted
Metabolomics Approach
21 Nov 2013 08:01 pm
Using a nontargeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel
molecular markers that arise before and after hyperglycemia in a large population-based cohort of 2,204
females (115 type 2 diabetic [T2D] case subjects, 192 individuals with impaired fasting glucose [IFG], and
1,897 control subjects) from TwinsUK. Forty-two metabolites from three major fuel sources (carbohydrates,
lipids, and proteins) were found to significantly correlate with T2D after adjusting for multiple testing; of
these, 22 were previously reported as associated with T2D or insulin resistance. Fourteen metabolites were
found to be associated with IFG. Among the metabolites identified, the branched-chain keto-acid metabolite
3-methyl-2-oxovalerate was the strongest predictive biomarker for IFG after glucose (odds ratio [OR] 1.65
[95% CI 1.39–1.95], P = 8.46 x 10–9) and was moderately heritable (h2 = 0.20). The association was
replicated in an independent population (n = 720, OR 1.68 [ 1.34–2.11], P = 6.52 x 10–6) and validated in
189 twins with urine metabolomics taken at the same time as plasma (OR 1.87 [1.27–2.75], P = 1 x 10–3).
Results confirm an important role for catabolism of branched-chain amino acids in T2D and IFG. In
conclusion, this T2D-IFG biomarker study has surveyed the broadest panel of nontargeted metabolites to
date, revealing both novel and known associated metabolites and providing potential novel targets for
clinical prediction and a deeper understanding of causal mechanisms.
Birth Defects After Early Pregnancy Use of Antithyroid Drugs: A Danish Nationwide Study
05 Nov 2013 06:01 pm
Introduction:
Hyperthyroidism in pregnant women should be adequately treated to prevent maternal and fetal
complications, but teratogenic effects of antithyroid drug (ATD) treatment have been described. Evidence is
still lacking in regard to the safety and choice of ATD in early pregnancy.
Objective:
Our objective was to determine to which degree the use of methimazole (MMI)/carbimazole (CMZ) and
propylthiouracil (PTU) in early pregnancy is associated with an increased prevalence of birth defects.
Methods:
This Danish nationwide register-based cohort study included 817 093 children live-born from 1996 to 2008.
Exposure groups were assigned according to maternal ATD use in early pregnancy: PTU (n = 564);
MMI/CMZ (n = 1097); MMI/CMZ and PTU (shifted in early pregnancy [n = 159]); no ATD (ATD use, but not
in pregnancy [n = 3543]); and nonexposed (never ATD use [n = 811 730]). Multivariate logistic regression
was used to estimate adjusted odds ratio (OR) with 95% confidence interval (95% CI) for diagnosis of a
birth defect before 2 years of age in exposed versus nonexposed children.
Results:
The prevalence of birth defects was high in children exposed to ATD in early pregnancy (PTU, 8.0%;
MMI/CMZ, 9.1%; MMI/CMZ and PTU, 10.1%; no ATD, 5.4%; nonexposed, 5.7%; P < .001). Both maternal
use of MMI/CMZ (adjusted OR = 1.66 [95% CI 1.35–2.04]) and PTU (1.41 [1.03–1.92]) and maternal shift
between MMI/CMZ and PTU in early pregnancy (1.82 [1.08–3.07]) were associated with an increased OR
of birth defects. MMI/CMZ and PTU were associated with urinary system malformation, and PTU with
malformations in the face and neck region. Choanal atresia, esophageal atresia, omphalocele,
omphalomesenteric duct anomalies, and aplasia cutis were common in MMI/CMZ-exposed children
(combined, adjusted OR = 21.8 [13.4–35.4]).
Conclusions:
Both MMI/CMZ and PTU were associated with birth defects, but the spectrum of malformations differed.
More studies are needed to corroborate results in regard to early pregnancy shift from MMI/CMZ to PTU.
New ATD with fewer side effects should be developed.
Both Dietary Protein and Fat Increase Postprandial Glucose Excursions in Children With
Type 1 Diabetes, and the Effect Is Additive
21 Nov 2013 08:01 pm
OBJECTIVE
To determine the separate and combined effects of high-protein (HP) and high-fat (HF) meals, with the
same carbohydrate content, on postprandial glycemia in children using intensive insulin therapy (IIT).
RESEARCH DESIGN AND METHODS
Thirty-three subjects aged 8–17 years were given 4 test breakfasts with the same carbohydrate amount but
varying protein and fat quantities: low fat (LF)/low protein (LP), LF/HP, HF/LP, and HF/HP. LF and HF
meals contained 4 g and 35 g fat. LP and HP meals contained 5 g and 40 g protein. An individually
standardized insulin dose was given for each meal. Postprandial glycemia was assessed by 5-h continuous
glucose monitoring.
RESULTS
Compared with the LF/LP meal, mean glucose excursions were greater from 180 min after the LF/HP meal
(2.4 mmol/L [95% CI 1.1–3.7] vs. 0.5 mmol/L [–0.8 to 1.8]; P = 0.02) and from 210 min after the HF/LP meal
(1.8 mmol/L [0.3–3.2] vs. –0.5 mmol/L [–1.9 to 0.8]; P = 0.01). The HF/HP meal resulted in higher glucose
excursions from 180 min to 300 min (P < 0.04) compared with all other meals. There was a reduction in the
risk of hypoglycemia after the HP meals (odds ratio 0.16 [95% CI 0.06–0.41]; P < 0.001).
CONCLUSIONS
Meals high in protein or fat increase glucose excursions in youth using IIT from 3 h to 5 h postmeal. Protein
and fat have an additive impact on the delayed postprandial glycemic rise. Protein had a protective effect on
the development of hypoglycemia.
Brain Atrophy in Type 2 Diabetes: Regional distribution and influence on cognition
21 Nov 2013 08:01 pm
OBJECTIVE
Type 2 diabetes (T2DM) is associated with brain atrophy and cerebrovascular disease. We aimed to define
the regional distribution of brain atrophy in T2DM and to examine whether atrophy or cerebrovascular
lesions are feasible links between T2DM and cognitive function.
RESEARCH DESIGN AND METHODS
This cross-sectional study used magnetic resonance imaging (MRI) scans and cognitive tests in 350
participants with T2DM and 363 participants without T2DM. With voxel-based morphometry, we studied the
regional distribution of atrophy in T2DM. We measured cerebrovascular lesions (infarcts, microbleeds, and
white matter hyperintensity [WMH] volume) and atrophy (gray matter, white matter, and hippocampal
volumes) while blinded to T2DM status. With use of multivariable regression, we examined for mediation or
effect modification of the association between T2DM and cognitive measures by MRI measures.
RESULTS
T2DM was associated with more cerebral infarcts and lower total gray, white, and hippocampal volumes
(all P < 0.05) but not with microbleeds or WMH. T2DM-related gray matter loss was distributed mainly in
medial temporal, anterior cingulate, and medial frontal lobes, and white matter loss was distributed in frontal
and temporal regions. T2DM was associated with poorer visuospatial construction, planning, visual
memory, and speed (P ≤ 0.05) independent of age, sex, education, and vascular risk factors. The strength
of these associations was attenuated by almost one-half when adjusted for hippocampal and total gray
volumes but was unchanged by adjustment for cerebrovascular lesions or white matter volume.
CONCLUSIONS
Cortical atrophy in T2DM resembles patterns seen in preclinical Alzheimer disease. Neurodegeneration
rather than cerebrovascular lesions may play a key role in T2DM-related cognitive impairment.
Brain MRI Correlates of Cognitive Dysfunction in Type 2 Diabetes: The Needle Recovered
From the Haystack?
21 Nov 2013 08:01 pm
Bronchial Carcinoid and Primary Hyperparathyroidism
05 Nov 2013 06:01 pm
Bullosis diabeticorum
30 Nov 2013 12:02 pm
Publication date: 30 November–6 December 2013
Source:The Lancet, Volume 382, Issue 9907
Author(s): Ahmed Toufic Kurdi
Burden of Diabetic foot Ulcers for Medicare and Private Insurers
01 Nov 2013 07:26 pm
OBJECTIVE
Estimate the annual, per-patient incremental burden of diabetic foot ulcers (DFUs).
METHODS
DFU patients and non-DFU patients with diabetes (controls) were selected using two de-identified
databases: ages 65+ from a 5% random sample of Medicare beneficiaries (Standard Analytical Files,
1/2007-12/2010) and ages 18-64 from a privately-insured population (OptumInsight, 1/2007-9/2011).
Demographics, comorbidities, resource use, and costs from the payer perspective incurred during the 12
months prior to a DFU episode were identified. DFU patients were matched to controls with similar pre-DFU
characteristics using a propensity score methodology. Per-patient incremental clinical outcomes (e.g.,
amputation, medical resource utilization) and healthcare costs (2012 USD) during the 12-month follow-up
period were measured among the matched cohorts.
RESULTS
Data for 27,878 matched pairs of Medicare and 4,536 matched pairs of privately-insured patients were
analyzed. During the 12-month follow-up period, DFU patients had more days hospitalized (+138.2%
Medicare, +173.5% private), days requiring home healthcare (+85.4% Medicare, +230.0% private),
emergency department visits (+40.6% Medicare, +109.0% private), and outpatient/physician office visits
(+35.1% Medicare, +42.5% private) than matched controls. Among matched patients, 3.8% of Medicare
and 5.0% of privately-insured DFU patients received lower limb amputations. Increased utilization resulted
in DFU patients having $11,710 in incremental annual healthcare costs for Medicare, and $16,883 for
private insurance, compared with matched controls. Privately-insured matched DFU patients incurred
excess work-loss costs of $3,259.
CONCLUSION
These findings document that DFU imposes substantial burden on public and private payers, ranging from
$9-$13 billion in addition to the costs associated with diabetes itself.
Calcium and Vitamin D Supplementation in Postmenopausal Women
05 Nov 2013 06:01 pm
Context:
Bone health is influenced by the intake of both calcium and vitamin D.
Objective:
Our objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone
turnover.
Setting, Patients, and Design:
At an ambulatory research center, 159 postmenopausal healthy white women participated in this doubleblind, placebo-controlled parallel, longitudinal factorial study that was 6 months in duration.
Interventions:
Subjects were randomly allocated to 4 groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo,
3) vitamin D3 (100 μg) plus placebo, and 4) vitamin D3 and calcium. Serum and urine were collected fasting
and 2 hours after a calcium load at baseline and at 3 and 6 months.
Main Outcome Measures:
Serum PTH, cross-linked C-telopeptide (CTX), and procollagen type I N-terminal propeptide (P1NP) were
measured.
Results:
Before study medication, a calcium load resulted in a decline in PTH and CTX and an increase in urinary
calcium excretion. Serum CTX and P1NP declined over time with calcium supplementation but did not
change with increased vitamin D intake. There was a decline in PTH in the vitamin D groups in the fasting
state compared with placebo. Suppression of PTH was greater after a calcium load in the vitamin D groups.
A calcium load decreased PTH and CTX and raised urinary calcium.
Conclusions:
Fasting PTH declines with vitamin D supplementation. PTH declines after calcium intake. Supplementation
of the diet with 1200 mg calcium/d reduces bone turnover markers, whereas supplementation with up to100
μg vitamin D3/d does not.
Can POMC methylation be used as an early predictor of metabolic syndrome?
12 Nov 2013 07:28 pm
OBJECTIVE
The objectives of this study were to compare early predictive marker of the metabolic syndrome with
proopiomelanocortin (POMC) methylation status and to determine the association between birth weight,
ponderal index and cord blood methylation status.
RESEARCH DESIGN AND METHODS
We collected pregnancy outcome data from pregnant women, cord blood samples at delivery, and blood
from children (7-9 years old; n = 90) through a prospective cohort study at Ewha Woman’s University,
MokDong Hospital (Seoul, Korea), from 2003 to 2005. POMC methylation was assessed by
pyrosequencing. We divided subjects into three groups according to cord blood POMC methylation: the low
methylation (< 10thpercentile), mid methylation, and high methylation (> 90th percentile) groups. We
analyzed the association of POMC methylation status at birth with adiposity and metabolic components
using analysis of covariance (ANCOVA) and multiple linear regression analysis.
RESULTS
Birth weights (p = 0.01) and ponderal indices (p = 0.01) in the high POMC methylation group were
significantly lower than in the mid POMC methylation group. In terms of metabolic components of childhood,
blood triglycerides (57.97, 67.29 vs. 113.89 mg/dL;p = 0.03, 0.01) and insulin (7.10, 7.64 vs. 10.13
μIU/mL; p = 0.05, 0.02) at childhood were significantly higher in the high POMC methylation group than in
the low and mid POMC methylation group.
CONCLUSIONS
High POMC methylation in cord blood was associated with lower birth weight and children with high POMC
methylation in cord blood showed higher triglycerides and higher insulin concentrations in blood. Thus,
POMC methylation status in cord blood may be an early predictive marker of future metabolic syndrome.
Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have
adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial.
Diabetes Care 2013;36:2508-2515
21 Nov 2013 08:01 pm
Cardiovascular Risk Factors Are Associated With Increased Arterial Stiffness in Youth With
Type 1 Diabetes: The SEARCH CVD study
21 Nov 2013 08:01 pm
OBJECTIVE
To evaluate if presence of cardiovascular (CV) risk factors and their clustering as metabolic syndrome
(MetS) is associated with increased arterial stiffness and accelerated progression over time among youth
with type 1 diabetes.
RESEARCH DESIGN AND METHODS
Longitudinal study of 298 youth with type 1 diabetes (age 14.5 years; 46.3% female; duration 4.8 years),
with two research visits conducted 5 years apart. CV factors included: waist circumference, blood pressure
(BP), fasting lipids (HDL cholesterol, LDL cholesterol [LDL-c], triglycerides), albumin/creatinine ratio, and
HbA1c. MetS was based on Adult Treatment Panel III criteria modified for youth. Pulse wave velocity (PWV)
in the carotid–femoral segment was measured by tonometry. Mixed models were used to assess the rate of
progression in PWV and the association between CV factors and PWV over time.
RESULTS
PWV increased significantly over time (0.145 m/s/year; P < 0.0001). MetS (P = 0.0035), large waist (P <
0.0001), and elevated BP (P = 0.0003) at baseline were each associated with worse PWV over time. These
baseline factors, however, did not significantly influence the rate of progression. Increases in waist
circumference (P < 0.0001), LDL-c levels (P = 0.0156), and declining glucose control (HbA1c; P = 0.0419)
were independently associated with higher PWV over time.
CONCLUSIONS
Presence, clustering, and worsening of CV risk factors are associated with increased arterial stiffness over
time in youth with type 1 diabetes. Whether improvement in CV risk factors early in life will slow the
progression of arterial stiffness and reduce the burden of CV disease in this population requires further
study.
Cardiovascular Risk in Adult Patients With Growth Hormone (GH) Deficiency and Following
Substitution with GH--An Update
11 Nov 2013 05:44 pm
Context:
GH deficiency (GHD) of the adult is a clinical condition characterized by the presence of several traditional
and emerging cardiovascular risk factors that can significantly increase cardiovascular morbidity and
mortality. It is still an open issue whether GH replacement is able not only to improve cardiovascular risk
factors but also to decrease cardiovascular morbidity and mortality.
Evidence Acquisition:
The major source of data acquisition included PubMed research strategies. Original articles, systematic
reviews and meta-analyses, and included relevant citations were screened.
Evidence Synthesis:
In untreated GHD, cardiovascular risk is increased due to abnormal lipid profile (increased total and lowdensity lipoprotein cholesterol, increased triglycerides, and reduced high-density lipoprotein cholesterol)
and impaired glucose metabolism. Emerging cardiovascular risk factors/markers such as proinflammatory
cytokines, C-reactive protein, and adipokines are also increased in GHD patients. Increased cardiovascular
morbidity and mortality have also been reported in GHD. GH treatment has been shown to improve both
traditional and emerging cardiovascular risk factors and markers. However, evidence on the effects of GH
replacement on cardiovascular events and mortality is limited.
Conclusion:
The GHD population may be considered at high cardiovascular risk, and GH substitution may be expected
to bring an added value to patients with hypopituitarism in terms of cardiovascular protection. However, due
to somewhat inherent to this group of patients limitations of the available data there is too limited evidence
(rarely coming from randomized and controlled studies) to recommend GH treatment based on the
cardiovascular status of the patients.
Catalase activity, allelic variations in the catalase gene and risk of kidney complications in
patients with type 1 diabetes
01 Dec 2013 12:00 am
Abstract
Aims/hypothesis
Oxidative stress is involved in the pathogenesis of diabetic nephropathy. The antioxidant enzyme catalase
plays a key role in redox regulation in the kidney. We investigated associations of catalase gene (CAT)
polymorphisms and plasma catalase activity with diabetic nephropathy in type 1 diabetic patients.
Methods
We genotyped nine single nucleotide polymorphisms (SNPs) in the CAT region in participants from the
Survival Genetic Nephropathy (SURGENE) (340 French participants, 10 year follow-up) and the Génétique
de la Néphropathie Diabétique (GENEDIAB) (444 Belgian and French participants, 8 year follow-up) study
cohorts. Replication was performed in a Brazilian cross-sectional cohort (n = 451). Baseline plasma catalase
activity was measured in SURGENE (n = 120) and GENEDIAB (n = 391) participants.
Results
The A allele of rs7947841 was associated with the prevalence of incipient (OR 2.79, 95% CI 1.21,
6.24, p = 0.01) and established or advanced nephropathy (OR 5.72, 95% CI 1.62, 22.03, p = 0.007), and with
the incidence of renal events, which were defined as new cases of microalbuminuria or progression to a
more severe stage of nephropathy during follow-up (HR 1.82, 95% CI 1.13, 2.81, p = 0.01) in SURGENE
participants. The same risk allele was associated with incipient nephropathy (OR 3.13, 95% CI 1.42,
7.24, p = 0.004) and with the incidence of end-stage renal disease (ESRD) (HR 2.11, 95% CI 1.23,
3.60, p = 0.008) in GENEDIAB participants. In both cohorts, the risk allele was associated with lower
catalase activity. Associations with incipient and established or advanced nephropathy were confirmed in
the replication cohort.
Conclusions/interpretation
CAT variants were associated with the prevalence and incidence of diabetic nephropathy and ESRD in type
1 diabetic patients. Our results confirm the protective role of catalase against oxidative stress in the kidney.
Celebrating 30 Years of Research Accomplishments of the Diabetes Control and
Complications Trial/Epidemiology of Diabetes Interventions and Complications Study
21 Nov 2013 08:01 pm
Central Diabetes Insipidus in Children and Young Adults: Etiological Diagnosis and Long Term Outcome of Idiopathic Cases
25 Nov 2013 05:52 pm
Context:
Central diabetes insipidus (CDI) is considered idiopathic in 20 to 50% of affected subjects.
Objective:
To determine whether systematic diagnostic work-up could allow achieving better etiologic diagnosis in
children and adolescents presenting with polyuria and polydipsia.
Design and Setting:
This is a prospective study conducted at a tertiary referral center. Patients underwent clinical and endocrine
evaluations every 6 months and neuroimaging every 6 months for 2 years, yearly for 3 years. Endocrine
function and neuroimaging were also reassessed after adult height achievement.
Participants:
Eighty-five consecutive patients with CDI were enrolled at a median age of 7.5 years; those with idiopathic
CDI were stratified based on pituitary stalk thickness.
Main Outcome Measures:
To establish the etiology of CDI; the time-lag between its onset and the specific diagnosis; the long-term
impact on pituitary function and the overall long-term outcomes.
Results:
Twenty-four (28.2%) subjects received an etiologic diagnosis at presentation, 11 (13%) within 2.5 years
(n=7 germinomas, n=4 Langherans-cell histiocytosis), 7 (8.2%) were lost to follow-up and 43 (50.6%) were
considered idiopathic and followed till the median age of 17.3 years. Neuroimaging identified 40 out of 43
patients with self-limited inflammatory/autoimmune pituitary stalk thickness within the first 6 months, the
severity of which was significantly correlated to pituitary dysfunction. The probability of more than 10-yearsurvival without anterior pituitary defect was related to the severity of pituitary stalk thickness and 53%
showed permanent anterior pituitary defects. Three developed Langherans-cell histiocytosis and one
Hodgkin's lymphoma after a median of 9 and 13 years, respectively.
Conclusions:
A diagnostic etiology was achieved in 96% of patients with CDI. Risk stratification based on the degree of
pituitary stalk thickness is of prognostic value for long-term outcomes including permanent pituitary
dysfunction. New guidance is provided for the management of these patients.
Ceramide accumulation in L6 skeletal muscle cells due to increased activity of ceramide
synthase isoforms has opposing effects on insulin action to those caused by palmitate
treatment
01 Dec 2013 12:00 am
Abstract
Aims/hypothesis
An accumulation of ceramides has been implicated in the generation of insulin resistance in skeletal muscle
upon an oversupply of fatty acid. Different ceramide species are generated through the actions of ceramide
synthases (CerSs), which incorporate specific acyl side chains. We tested whether particular CerS isoforms
promoted insulin resistance through the generation of more inhibitory ceramide species, thus representing
potential targets for intervention.
Methods
CerS isoforms CerS1, CerS2, CerS4, CerS5 and CerS6 were overexpressed in L6 myotubes using
adenovirus, and cells were treated with palmitate and stimulated with insulin. Alternatively, CerS isoforms
were knocked down using siRNAs. Sphingolipids were examined by mass spectrometry and tracer
incorporation. Phosphorylation of IRS1 and Akt was measured by immunoblotting, while glucose disposal
was assessed by measuring GLUT4 translocation and the incorporation of [ 14C]glucose into glycogen.
Results
Palmitate treatment increased the levels of several ceramides but reduced the levels of sphingomyelins,
while insulin had no effect. The fatty acid also inhibited insulin-stimulated Akt phosphorylation and glycogen
synthesis. Overexpression of CerS isoforms increased specific ceramides. Unexpectedly, the
overexpression of CerS1 and CerS6 promoted insulin action, while no isoform had inhibitory effects. CerS6
knockdown had effects reciprocal to those of CerS6 overexpression.
Conclusions/interpretation
Palmitate may increase intracellular ceramide levels through sphingomyelin hydrolysis as well as de novo
synthesis, but no particular species were implicated in the generation of insulin resistance. The modulation
of ceramides through an alteration of CerS expression does not affect the action of insulin in the same way
as ceramide generation by palmitate treatment. Conversely, certain isoforms promote insulin action,
indicating the importance of ceramides in cell function.
Cerebral Blood Flow and Glucose Metabolism in Appetite-Related Brain Regions in Type 1
Diabetic Patients After Treatment With Insulin Detemir and NPH Insulin: A randomized
controlled crossover trial
21 Nov 2013 08:01 pm
OBJECTIVE
To test the hypothesis that insulin detemir, which is associated with less weight gain than other basal insulin
formulations, exerts its weight-modulating effects by acting on brain regions involved in appetite regulation,
as represented by altered cerebral blood flow (CBF) or cerebral glucose metabolism (CMRglu).
RESEARCH DESIGN AND METHODS
Twenty-eight male type 1 diabetic patients (age 36.9 ± 9.7 years, BMI 24.9 ± 2.7 kg/m 2, A1C 7.5 ± 0.6%)
successfully completed a randomized crossover study, consisting of two periods of 12-week treatment with
either insulin detemir or NPH insulin, both in combination with prandial insulin aspart. After each treatment
period, patients underwent positron emission tomography scans to measure regional CBF and CMR glu.
RESULTS
After 12 weeks, A1C, daily insulin doses, fasting insulin, and blood glucose levels were similar between
treatments. Insulin detemir resulted in body weight loss, whereas NPH insulin induced weight gain
(between-treatment difference 1.3 kg; P = 0.02). After treatment with insulin detemir relative to NPH insulin,
CBF was higher in brain regions involved in appetite regulation, whereas no significant difference in
CMRglu was observed.
CONCLUSIONS
Treatment with insulin detemir versus NPH insulin resulted in weight loss, paralleled by increased CBF in
appetite-related brain regions in the resting state, in men with well-controlled type 1 diabetes. These
findings lend support to the hypothesis that a differential effect on the brain may contribute to the
consistently observed weight-sparing effect of insulin detemir.
Cerebral white matter integrity and resting-state functional connectivity in middle-aged
patients with type 2 diabetes
07 Nov 2013 09:12 pm
Early detection of brain abnormalities at the pre-clinical stage can be useful for developing preventive
interventions to abate cognitive decline. We examined whether middle-aged type 2 diabetic patients show
reduced white matter integrity in fiber tracts important for cognition, and whether this abnormality is related
to pre-established altered resting-state functional connectivity in the default-mode network. Diabetic and
non-diabetic participants underwent fMRI and cognitive assessment. Multiple diffusion measures were
calculated using streamline tractography, and correlations with default-mode network functional connectivity
were determined. Diabetic patients showed lower fractional anisotropy (a measure of white matter integrity)
in the cingulum bundle and uncinate fasciculus -- fiber tracts that connect frontal, temporal, and parietal
regions. Controls showed stronger functional connectivity than patients between the posterior cingulate and
both left fusiform and medial frontal gyri. Fractional anisotropy of the cingulum bundle was correlated with
functional connectivity between the posterior cingulate and medial frontal gyrus for combined groups. Thus,
middle-aged patients with type 2 diabetes show white matter abnormalities that correlate with disrupted
functional connectivity in the default-mode network, suggesting that common mechanisms may underlie
both structural and functional connectivity. Detecting brain abnormalities in middle age enables
implementation of therapies to slow progression of neuropathology.
Changing Impact of Modifiable Risk Factors on the Incidence of Major Outcomes of Type 1
Diabetes: The Pittsburgh Epidemiology of Diabetes Complications Study
21 Nov 2013 08:01 pm
OBJECTIVE
The incidence of type 1 diabetes complications appears to be decreasing, but relative contributions of risk
factors are unclear. We thus estimated the effect of modifiable risk factors on the incidence of a composite
end point, major outcomes of diabetes (MOD).
RESEARCH DESIGN AND METHODS
The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study was used to derive two cohorts based
on diabetes diagnosis year (1960–1969 and 1970–1980). Baseline exam data in the current analysis for the
1960s group were collected in 1986–1988 and for the 1970s in 1996–1998. Each group was followed for 8
years for MOD incidence (diabetes-related death, myocardial infarction, revascularization
procedure/blockage ≥50%, stroke, end-stage renal disease, blindness, and amputation). Assessed risk
factors include the following: HbA1c, hypertension, microalbuminuria, BMI, hypercholesterolemia, and
smoking. Accelerated failure time models were used to estimate the acceleration factor.
RESULTS
MOD incidence decreased in the 1970s cohort (15.8% [95% CI 11.6–21.4]) compared with the 1960s
(22.6% [17.0–29.1]) over the 8-year follow-up (P = 0.06). Hypertension and microalbuminuria were
associated with significantly accelerated MOD incidence in both cohorts (P < 0.01 for both). High HbA1c (P =
0.0005), hypercholesterolemia (P = 0.01), and current smoking (P = 0.003) significantly accelerated the
incidence of MOD in the 1960s but not 1970s cohort. BMI was not associated with MOD in either cohort.
CONCLUSIONS
These results suggest that hypertension and microalbuminuria remain important predictors of complications
that are not being adequately addressed.
Cinacalcet Monotherapy in Neonatal Severe Hyperparathyroidism: a Case Study and
Review
07 Nov 2013 05:15 pm
Context:
Neonatal Severe Hyperparathyroidism (NSHPT) is a severe form of Familial Hypocalciuric Hypercalcemia
(FHH) characterized by severe hypercalcemia and skeletal demineralization. In most cases, NSHPT is due
to biallelic loss-of-function mutations in the CASR gene encoding the calcium sensing receptor (CaSR), but
some patients have heterozygous mutations. Conventional treatment consists of intravenous saline,
bisphosphonates and parathyroidectomy.
Objective:
To characterize the molecular basis for NSHPT in an affected newborn and to describe the response to
monotherapy with cinacalcet.
Methods:
Clinical and biochemical features were monitored as cinacalcet therapy was initiated and maintained.
Genomic DNA was obtained from the proband and parents. TheCASR gene was amplified by PCR and
sequenced directly.
Results:
The patient was a full term male who developed hypotonia and respiratory failure soon after birth. He was
found to have multiple fractures and diffuse bone demineralization, with a marked elevation in serum
ionized calcium (1.99 mmol/L) and elevated serum levels of intact PTH (1154 pg/mL); serum 25hydroxyvitamin D was low and fractional excretion of calcium was reduced. The serum calcium level was
not reduced by intravenous saline infusion. Based on an extensive family history of autosomal dominant
hypercalcemia, a diagnosis of NSHPT was made and cinacalcet therapy was initiated with a robust and
durable effect. Molecular studies revealed a heterozygous R185Q missense mutation in the CASR in the
patient and his father, while normal sequences for the CASR gene were present in the patient's mother.
Conclusions:
We describe the first use of cinacalcet as monotherapy for severe hypercalcemia in a newborn with
NSHPT. The rapid and durable response to cinacalcet suggests that a trial of calcimimetic therapy should
be considered early in the course of NSHPT.
Circadian Clock Characteristics Are Altered in Human Thyroid Malignant Nodules
05 Nov 2013 06:01 pm
Context:
The circadian clock represents the body's molecular time-keeping system. Recent findings revealed strong
changes of clock gene expression in various types of human cancers.
Objective:
Due to emerging evidence on the connection between the circadian oscillator, cell cycle, and oncogenic
transformation, we aimed to characterize the circadian clockwork in human benign and malignant thyroid
nodules.
Design:
Clock transcript levels were assessed by quantitative RT-PCR in thyroid tissues. To provide molecular
characteristics of human thyroid clockwork, primary thyrocytes established from normal or nodular thyroid
tissue biopsies were subjected to in vitro synchronization with subsequent clock gene expression analysis
by circadian bioluminescence reporter assay and by quantitative RT-PCR.
Results:
The expression levels of the Bmal1 were up-regulated in tissue samples of follicular thyroid carcinoma
(FTC), and in papillary thyroid carcinoma (PTC), as compared with normal thyroid and benign nodules,
whereas Cry2 was down-regulated in FTC and PTC. Human thyrocytes derived from normal thyroid tissue
exhibited high-amplitude circadian oscillations of Bmal1-luciferase reporter expression and endogenous
clock transcripts. Thyrocytes established from FTC and PTC exhibited clock transcript oscillations similar to
those of normal thyroid tissue and benign nodules (except forPer2 altered in PTC), whereas cells derived
from poorly differentiated thyroid carcinoma exhibited altered circadian oscillations.
Conclusions:
This is the first study demonstrating a molecular makeup of the human thyroid circadian clock.
Characterization of the thyroid clock machinery alterations upon thyroid nodule malignant transformation
contributes to understanding the connections between circadian clocks and oncogenic transformation.
Moreover, it might help in improving the thyroid nodule preoperative diagnostics.
Circulating Inflammatory Markers and The Risk of Vascular Complications and Mortality in
People With Type 2 Diabetes Mellitus and Cardiovascular Disease or Risk Factors: The
Advance Study
12 Nov 2013 07:31 pm
C-reactive protein (CRP), fibrinogen, and interleukin-6 (IL-6), are associated with cardiovascular disease
and death in general populations. However, studies in type 2 diabetes are limited. We studied their
associations with risk of major macrovascular events, microvascular complications and mortality in patients
with type 2 diabetes who participated in the ADVANCE trial. Plasma CRP, fibrinogen and IL-6 levels were
determined in a case-cohort study (n=3,865) nested within the 11,140 men and women with type 2 diabetes
and baseline cardiovascular disease or risk factors in the ADVANCE trial. All three biomarkers of
inflammation were associated with an increased risk of macrovascular events and death in analyses
adjusting for age, sex and treatment groups. After further adjustment, only IL-6 was an independent
predictor of macrovascular events (hazard ratio [HR] per SD increase 1.37, 95% confidence interval [CI]
1.24-1.51); and death (HR 1.35, 95% CI 1.23-1.49). IL-6 significantly improved the prediction of
macrovascular events and death. After adjustment, none of the markers predicted microvascular
complications. We conclude that IL-6 levels, but not CRP or fibrinogen levels, add significantly to the
prediction of macrovascular events and mortality in individuals with type 2 diabetes who have baseline
cardiovascular disease or risk factors.
Clinical Presentation and Management of Children With Diffuse and Focal Hyperinsulinism:
A Review of 223 Cases
05 Nov 2013 06:01 pm
Context:
Congenital hyperinsulinism (HI) occurs in two distinct histologic forms: diffuse and focal. Distinguishing
between them is essential because a pancreatectomy is curative for focal HI and palliative for diffuse HI.
Objective:
The purpose of this study was to compare the presentations, treatment, and outcomes of diffuse and focal
HI.
Design:
A retrospective chart review of children who underwent pancreatectomy for hyperinsulinism from December
2004 through September 2012 was conducted.
Results:
Based on pancreatic histology, 223 children were classified into 3 groups: diffuse (n = 97, 44%), focal (n =
114, 51%), and other (n = 12, 5%). Children with diffuse vs focal HI had significantly different mean
gestational ages (38 vs 39 weeks, P < .0005) and birth weights (3963 vs 3717 g P = .012). Children with
focal HI presented at an older age (0.3 vs 0 months, P < .0005) and more frequently with seizures (50 vs
25%, P < .0005). Children with diffuse HI had higher insulin levels during hypoglycemia (31.8 vs 12
μU/mL, P < .0005) and required higher glucose infusion rates (19.2 vs 16.1 mg/kg/min,P = .002). Children
with diffuse HI had a median percent pancreactectomy of 98%, and postoperatively 41% required treatment
for continued hypoglycemia. Children with focal HI had a median percent pancreatectomy rate of 27%, and
94% required no treatment after surgery.
Conclusions:
Focal and diffuse HI present unique challenges, but the clinical differences between the 2 are subtle.
Children with focal HI are at higher risk of delayed diagnosis and hypoglycemic seizures, but most are
cured with surgery. In contrast, children with diffuse disease may be identified earlier, but face ongoing
blood glucose abnormalities.
Clinical and genetic determinants of progression of type 2 diabetes: A DIRECT Study
01 Nov 2013 07:26 pm
Objective
The rate at which diabetes progresses following diagnosis of type 2 diabetes is highly variable between
individuals.
Research Design and Methods
We studied 5250 patients with type 2 diabetes using comprehensive electronic medical records on all
patients in Tayside, Scotland from 1992 onwards. We investigated the association of clinical, biochemical
and genetic factors with the risk of progression of type 2 diabetes from diagnosis to requirement for insulin
treatment (defined as insulin treatment or HbA1c ≥8.5%/69 mmol/mol treated with two or more non-insulin
diabetes therapies).
Results
Risk of progression was associated with both low and high BMI. In an analysis stratified by BMI and HbA1c
at diagnosis, faster progression was independently associated with younger age at diagnosis, higher log
triacylglyceride concentrations (Hazard Ratio (HR) 1.28 per mmol/L (95% CI 1.15-1.42)) and lower HDL
concentrations (HR 0.70 per mmol/L (95% CI 0.55-0.87)). A high genetic risk score derived from 61
diabetes risk variants was associated with a younger age of diagnosis, a younger age at starting insulin, but
was not associated with the progression rate from diabetes to requirement for insulin treatment.
Conclusions
Increased triacylglyceride and low HDL are independently associated with increased rate of progression of
diabetes. The genetic factors that predispose to diabetes are different from those that cause rapid
progression of diabetes suggesting a difference in biological process that needs further investigation.
Coexistence of Malignant Struma Ovarii and Cervical Papillary Thyroid Carcinoma
11 Nov 2013 05:44 pm
Context:
Struma ovarii is an uncommon monodermal teratoma in which thyroid tissue is the predominant element.
Malignant transformation of struma ovarii is an even rarer occurrence.
Case Presentation:
We describe a 42-year-old woman who underwent a total abdominal hysterectomy and bilateral salpingooophorectomy for a symptomatic left pelvic mass. Histology revealed malignant struma ovarii with classical
papillary thyroid carcinoma expression. Ultrasonography of the cervical neck showed thyroid micronodules
and a dominant 1-cm nodule in the left thyroid lobe. Because the ovarian tumor was large, the patient
underwent a total thyroidectomy with the intention of administering 131I therapy in an adjuvant setting.
Histology of the cervical thyroid gland revealed bilateral multifocal papillary thyroid carcinoma with
extrathyroidal extension and perithyroidal lymph node metastasis.
Methods:
Morphological (microscopy), immunohistochemical (Hector Battifora mesothelial cell 1, cytokeratin-19,
galectin-3), and molecular (BRAF V600E, RAS, RET-PTC) characteristics and clonality analysis of the
cervical thyroid and ovarian tumors were explored to distinguish them as separate malignancies.
Results:
The thyroid-type tumors from the cervical gland and ovary were discordant in terms of tissue histology and
level of cytokeratin-19 expression. The clinical features and tumor profile results supported the independent
existence of these two embryologically related, although topographically distinct, malignancies.
Conclusion:
Our findings provided support for synchronous, albeit distinct, primary tumors in the ovary and cervical
thyroid. "Field cancerization" and early genomic instability may explain multifocality in all thyroid-type tissue.
In this regard, patients with malignant struma ovarii should undergo imaging of their thyroid gland for
coexisting disease and thyroidectomy recommended for suspected malignancy or in preparation for
radioiodine therapy.
Cognitive Development in Congenital Hypothyroidism: Is Overtreatment a Greater Threat
Than Undertreatment?
05 Nov 2013 06:01 pm
Background:
Optimal treatment of children with congenital hypothyroidism (CHT) is still debated. Our objective was to
evaluate whether early undertreatment (UT) and overtreatment (OT) influence cognitive development at age
11 years.
Methods:
Sixty-one patients (27 severe CHT, 34 mild CHT) were psychologically tested at ages 1.8 (Mental
Development Index), 6 [intelligence quotient (IQ) 6], and 11 years (IQ11). Scores for cognitive development
were related to initial levels of TSH normalization (fast, moderate, or slow) and to total durations of the UT
and OT episodes within the first 2 years of life (no, short, or long UT/OT). UT and OT were defined as a free
T4(fT4) concentration below or above the individual fT4 steady-state concentration range (±2 SD).
Results:
Patients with fast and moderate TSH normalization had higher Mental Development Index scores than
patients with slow TSH normalization; 14.2 and 7.7 points higher, respectively (P = .001). TSH
normalization had no significant effect on IQ11. Patients with long and short overtreatment had IQ11s that
were –17.8 and –13.4 points lower, respectively, than the IQ11s of patients with no overtreatment (P =
.014). UT without OT was associated with normal development scores, but UT with OT was associated with
–14.7 points lower IQ11s than UT without OT (P = .005).
Conclusions:
Our study suggests that CHT overtreatment during the first 2 years leads to lowered cognitive outcomes at
11 years, whereas undertreatment, if not complicated by overtreatment, results in a normal cognitive
development. Fast TSH normalization at initial treatment leads to above-normal development scores at a
young age but does not affect IQ at age 11 years.
Cohort Study of Insulin Glargine and Risk of Breast, Prostate, and Colorectal Cancer
Among Patients With Diabetes
21 Nov 2013 08:01 pm
OBJECTIVE
To examine whether use of insulin glargine, compared with another long-acting insulin, is associated with
risk of breast, prostate, colorectal cancer, or all cancers combined.
RESEARCH DESIGN AND METHODS
Computerized health records from Kaiser Permanente Northern and Southern California regions starting in
2001 and ending in 2009 were used to conduct a population-based cohort study among patients with
diabetes aged ≥18 years. With use of Cox regression modeling, cancer risk in users of insulin glargine (n =
27,418) was compared with cancer risk in users of NPH (n = 100,757).
RESULTS
The cohort had a median follow-up of 3.3 years during which there was a median of 1.2 years of glargine
use and 1.4 years of NPH use. Among users of NPH at baseline, there was no clear increase in risk of
breast, prostate, colorectal, or all cancers combined associated with switching to glargine. Among those
initiating insulin, ever use or ≥2 years of glargine was not associated with increased risk of prostate or
colorectal cancer or all cancers combined. Among initiators, the hazard ratio (HR) for breast cancer
associated with ever use of glargine was 1.3 (95% CI 1.0–1.8); the HR for breast cancer associated with
use of glargine for ≥2 years was 1.6 or 1.7 depending on whether glargine users had also used NPH.
CONCLUSIONS
Results of this study should be viewed cautiously, given the relatively short duration of glargine use to date
and the large number of potential associations examined.
Combining incretin-based therapies with insulin: realizing the potential in type 2 diabetes.
Diabetes Care 2013;36(Suppl. 2):S226-S232
21 Nov 2013 08:01 pm
Comment on: Besser et al. Lessons From the Mixed-Meal Tolerance Test: Use of 90Minute and Fasting C-Peptide in Pediatric Diabetes. Diabetes Care 2013;36:195-201
21 Nov 2013 08:01 pm
Comment on: Bosi et al. Intensive Structured Self-Monitoring of Blood Glucose and
Glycemic Control in Noninsulin-Treated Type 2 Diabetes: The PRISMA Randomized Trial.
Diabetes Care 2013;36:2887-2894
21 Nov 2013 08:01 pm
Comment on: Butler et al. A Critical Analysis of the Clinical Use of Incretin-Based
Therapies: Are the GLP-1 Therapies Safe? Diabetes Care 2013;36:2118-2125
21 Nov 2013 08:01 pm
Comment on: Draznin et al. Pathways to Quality Inpatient Management of Hyperglycemia
and Diabetes: A Call to Action. Diabetes Care 2013;36:1807-1814
21 Nov 2013 08:01 pm
Comment on: Lazo et al. NH2-Terminal Pro-Brain Natriuretic Peptide and Risk of Diabetes.
Diabetes 2013;62:3189-3193
21 Nov 2013 08:01 pm
Comment on: Selvin et al. No Racial Differences in the Association of Glycated Hemoglobin
With Kidney Disease and Cardiovascular Outcomes. Diabetes Care 2013;36:2995-3001
21 Nov 2013 08:01 pm
Comment on: Sitnick et al. Skeletal Muscle Triacylglycerol Hydrolysis Does Not Influence
Metabolic Complications of Obesity. Diabetes 2013;62:3350-3361
21 Nov 2013 08:01 pm
Comment on: Sukumar et al. Nox2 NADPH Oxidase Has a Critical Role in Insulin
Resistance-Related Endothelial Cell Dysfunction. Diabetes 2013;62:2130-2134
21 Nov 2013 08:01 pm
Comment on: TODAY Study Group. Effects of Metformin, Metformin Plus Rosiglitazone,
and Metformin Plus Lifestyle on Insulin Sensitivity and {beta}-Cell Function in TODAY.
Diabetes Care 2013;36:1749-1757
21 Nov 2013 08:01 pm
Comment on: Torres-Mejia et al. Moderate-Intensity Physical Activity Ameliorates the
Breast Cancer Risk in Diabetic Women. Diabetes Care 2012;35:2500-2502
21 Nov 2013 08:01 pm
Comment on: Wolpert et al. Dietary Fat Acutely Increases Glucose Concentrations and
Insulin Requirements in Patients With Type 1 Diabetes: Implications for CarbohydrateBased Bolus Dose Calculation and Intensive Diabetes Management. Diabetes Care
2013;36:810-816
21 Nov 2013 08:01 pm
Comparative Risk of Fracture in Men and Women with HIV
25 Nov 2013 05:52 pm
Context:
Men and women with HIV have an increased risk of fracture compared to individuals without HIV; however
it is unknown if women with HIV fracture at higher rates than men.
Objective:
Compare the incidence rate of fractures between men and women with HIV.
Design:
Cohort study, examining medical records from November 2001-August 2012.
Setting:
Two tertiary-care hospitals in Boston, MA.
Patients:
Adults with HIV; defined by diagnosis codes for HIV on two visits, at least one prescription for antiretroviral
therapy, and at least 18 years of age.
Intervention:
Incidence rates (IR) per 1,000 person-years (py) of all fractures and fractures at osteoporotic sites were
calculated. We calculated IRs within age and gender strata and estimated IR ratios (IRR) between men and
women.
Main Outcome Measure:
Fracture at any site.
Results:
We identified a cohort of 3,161 HIV-infected patients (869 women and 2,292 men) with a total of 587
fractures. The IRR of all fractures was 1.00 (95% CI 0.83 - 1.19) between men and women. The IR of
fractures at osteoporotic sites among men was 15.2 (95% CI 12.7 - 17.6) per 1,000 py compared to 12.1
(95% CI 8.6–15.6) in women, with IRR of 1.26 (95% CI 0.90 - 1.75). Men had similar or higher IRs than
women for osteoporotic site fractures across most age groups.
Conclusions:
This study found similar rates of fracture in men and women with HIV. Further studies validating these
findings are required to determine whether men with HIV should be screened for osteoporosis.
Conditional Hypovascularization and Hypoxia in Islets Do Not Overtly Influence Adult
{beta}-Cell Mass or Function
21 Nov 2013 08:01 pm
It is generally accepted that vascularization and oxygenation of pancreatic islets are essential for the
maintenance of an optimal β-cell mass and function and that signaling by vascular endothelial growth factor
(VEGF) is crucial for pancreas development, insulin gene expression/secretion, and (compensatory) β-cell
proliferation. A novel mouse model was designed to allow conditional production of human sFlt1 by β-cells
in order to trap VEGF and study the effect of time-dependent inhibition of VEGF signaling on adult β-cell
fate and metabolism. Secretion of sFlt1 by adult β-cells resulted in a rapid regression of blood vessels and
hypoxia within the islets. Besides blunted insulin release, β-cells displayed a remarkable capacity for coping
with these presumed unfavorable conditions: even after prolonged periods of blood vessel ablation, basal
and stimulated blood glucose levels were only slightly increased, while β-cell proliferation and mass
remained unaffected. Moreover, ablation of blood vessels did not prevent β-cell generation after severe
pancreas injury by partial pancreatic duct ligation or partial pancreatectomy. Our data thus argue against a
major role of blood vessels to preserve adult β-cell generation and function, restricting their importance to
facilitating rapid and adequate insulin delivery.
Corneal nerve fibre damage precedes diabetic retinopathy in patients with Type 2 diabetes
mellitus
05 Nov 2013 12:00 am
Aims To quantify the morphological alterations in corneal nerve fibres and cells in patients with Type 2
diabetes mellitus in relation to the severity of diabetic retinopathy. Methods One hundred and thirty-two
eyes of 132 patients with Type 2 diabetes and 32 eyes of 32 healthy control subjects were evaluated with in
vivo corneal confocal microscopy. Patients with diabetes were classified into three groups: patients without
diabetic retinopathy, patients with non-proliferative diabetic retinopathy and patients with proliferative
diabetic retinopathy. Anterior and posterior stromal keratocyte, endothelial cell and basal epithelial cell
densities and sub-basal nerve fibre structure were evaluated. Results Significant reductions in basal
epithelial cell, anterior stromal keratocyte and endothelial cell densities were observed only in patients with
diabetic retinopathy. However, nerve fibre density, nerve branch density and nerve fibre length were
reduced in patients without diabetic retinopathy and worsened progressively with increasing severity of
retinopathy. Conclusions Corneal cell pathology occurs in patients with diabetic retinopathy, but corneal
nerve fibre damage seems to precede the development of diabetic retinopathy.
Corrigendum
17 Nov 2013 09:20 pm
Corticotropin-releasing hormone promotes inflammation in human pregnant myometrium:
the evidence of CRH initiating parturition?
18 Nov 2013 06:35 pm
Context:
Increasing body of evidence indicates that human labor, either term or preterm, is an inflammatory event.
Corticotropin-releasing hormone (CRH) has been implicated to be a trigger of human parturition.
Objective:
To investigate whether CRH induces the cascades of inflammation in human pregnant myometrium,
thereby leading to activation of uterus.
Design:
The myometrial tissues were obtained from pregnant women who were in labor (TL) or not in labor (TNL) at
term. The output of cytokines and prostaglandins (PGs) was determined by Multiplex and ELISA. Western
blot analysis was used to determine the levels of uterine activation proteins (UAPs).
Results:
The levels of chemokines and cytokines as well as activated NK-B were increased in TL group than TNL
group. CRH stimulated production of a number of chemokines and cytokines in cultured uterine smooth
muscle cells (USMCs), which induced chemotaxis of monocytes. These effects were mediated by CRHR1
and dependent on adenylyl cyclase(AC) /PKA and NF-B signaling. Cocultures of CRH-treated USMCs with
monocytes greatly enhanced output of cytokines and chemokines as well as PGs in cultures and increased
the expression of UAPs in USMCs. Interleukin-1β(IL-1β), IL-6 and tumor necrosis factor α stimulated the
expression of UAPs and output of PGs in USMCs.
Conclusions:
CRH induces the production of chemokines and cytokines in myometrium at term, subsequently results in
the cascades of inflammation in uterus. The inflammation induced by CRH can lead to activation of uterus.
Cost-Effectiveness of Alternative Thresholds of the Fasting Plasma Glucose Test to Identify
the Target Population for Type 2 Diabetes Prevention in Adults Aged >=45 Years
21 Nov 2013 08:01 pm
OBJECTIVE
The study objective was to evaluate the cost-effectiveness of alternative fasting plasma glucose (FPG)
thresholds to identify adults at high risk for type 2 diabetes for diabetes preventive intervention.
RESEARCH DESIGN AND METHODS
We used a validated simulation model to examine the change in lifetime quality-adjusted life years (QALYs)
and medical costs when the FPG threshold was progressively lowered in 5-mg/dL decrements from 120 to
90 mg/dL. The study sample includes nondiabetic adults aged ≥45 years in the United States using 2006–
2010 data from the National Health and Nutrition Examination Survey. High-risk individuals were assumed
to receive a lifestyle intervention, as that used in the Diabetes Prevention Program. We calculated cost per
QALY by dividing the incremental cost by incremental QALY when lowering the threshold to the next
consecutive level. Medical costs were assessed from a health care system perspective. We conducted
univariate and probabilistic sensitivity analyses to assess the robustness of the results using different
simulation scenarios and parameters.
RESULTS
Progressively lowering the FPG threshold would monotonically increase QALYs, cost, and cost per QALY.
Reducing (in 5-mg/dL decrements) the threshold from 120 to 90 mg/dL cost $30,100, $32,900, $42,300,
$60,700, $81,800, and $115,800 per QALY gained, respectively. The costs per QALY gained were lower for
all thresholds under a lower-cost and less-effective intervention scenario.
CONCLUSIONS
Lowering the FPG threshold leads to a greater health benefit of diabetes prevention but reduces the costeffectiveness. Using the conventional benchmark of $50,000 per QALY, a threshold of 105 mg/dL or higher
would be cost effective. A lower threshold could be selected if the intervention cost could be lowered.
Cromolyn Sodium for Insulin-Induced Lipoatrophy: Old Drug, New Use
21 Nov 2013 08:01 pm
Cystatin C- and creatinine-based estimated glomerular filtration rate, vascular disease, and
mortality in persons with diabetes in the United States
22 Nov 2013 06:34 pm
Introduction:
Serum cystatin C is an alternative to serum creatinine for estimating glomerular filtration rate (GFR) since
cystatin C is less influenced by age and muscle mass. Among persons with diabetes, we compared the
performance of GFR estimated using cystatin C (eGFRcys) with that using creatinine (eGFRcr) for the
identification of reduced kidney function and its association with diabetic complications.
Research Design & Methods:
We analyzed data from adult participants from the 1999-2002 National Health and Nutrition Examination
Survey with available cystatin C (N=4457). Kidney function was dichotomized as preserved (eGFR ≥ 60
ml/min/1.73 m2) or reduced (eGFR < 60 ml/min/1.73 m 2) using the 2012 CKD-EPI cystatin C and the 2009
CKD-EPI creatinine equations.
Results:
Among 778 persons with diabetes, the prevalence of reduced kidney function was 16.5% using eGFRcr and
22.0% using eGFRcys. More persons with diabetes were reclassified from preserved kidney function by
eGFRcr to reduced kidney function by eGFRcys than persons without diabetes (OR 3.1, 95% CI: 1.9-4.9,
p<0.001). The associations between lower eGFR and higher prevalence of albuminuria, retinopathy,
peripheral arterial disease, and coronary artery disease were robust regardless of filtration marker.
Similarly, the risk of all-cause mortality increased with lower eGFRcrand eGFRcys. Only lower eGFRcys was
significantly associated with cardiovascular mortality.
Conclusions:
More persons with diabetes had reduced kidney function by eGFRcys than by eGFRcr, and lower
eGFRcys was strongly associated with diabetic complications. Whether eGFRcys is superior to eGFRcr in
approximating true kidney function in a diabetic population requires additional study.
Day and Night Closed-Loop Control in Adults With Type 1 Diabetes: A comparison of two
closed-loop algorithms driving continuous subcutaneous insulin infusion versus patient selfmanagement
21 Nov 2013 08:01 pm
OBJECTIVE
To compare two validated closed-loop (CL) algorithms versus patient self-control with CSII in terms of
glycemic control.
RESEARCH DESIGN AND METHODS
This study was a multicenter, randomized, three-way crossover, open-label trial in 48 patients with type 1
diabetes mellitus for at least 6 months, treated with continuous subcutaneous insulin infusion. Blood
glucose was controlled for 23 h by the algorithm of the Universities of Pavia and Padova with a Safety
Supervision Module developed at the Universities of Virginia and California at Santa Barbara (international
artificial pancreas [iAP]), by the algorithm of University of Cambridge (CAM), or by patients themselves in
open loop (OL) during three hospital admissions including meals and exercise. The main analysis was on
an intention-to-treat basis. Main outcome measures included time spent in target (glucose levels between
3.9 and 8.0 mmol/L or between 3.9 and 10.0 mmol/L after meals).
RESULTS
Time spent in the target range was similar in CL and OL: 62.6% for OL, 59.2% for iAP, and 58.3% for CAM.
While mean glucose level was significantly lower in OL (7.19, 8.15, and 8.26 mmol/L, respectively)
(overall P = 0.001), percentage of time spent in hypoglycemia (<3.9 mmol/L) was almost threefold reduced
during CL (6.4%, 2.1%, and 2.0%) (overall P = 0.001) with less time ≤2.8 mmol/L (overall P = 0.038). There
were no significant differences in outcomes between algorithms.
CONCLUSIONS
Both CAM and iAP algorithms provide safe glycemic control.
Decreased Circulatory Response to Hypovolemic Stress in Young Women With Type 1
Diabetes
21 Nov 2013 08:01 pm
OBJECTIVE
Diabetes is associated with hemodynamic instability during different situations involving acute circulatory
stress in daily life. Young men with type 1 diabetes have been shown to have impaired circulatory response
to hypovolemic stress. The effect of type 1 diabetes on cardiovascular response to hypovolemia in young
women is unknown, however.
RESEARCH DESIGN AND METHODS
Lower body negative pressure of 30 cm H2O was used to create rapid hypovolemic stress in 15 young
women with type 1 diabetes (DW) and 16 healthy women (control subjects [C]). Compensatory mobilization
of venous capacitance blood (capacitance response) and net fluid absorption from tissue to blood were
measured with a volumetric technique. Overall cardiovascular responses and plasma norepinephrine levels
were measured.
RESULTS
Capacitance response was reduced (DW, 0.67 ± 0.05; C, 0.92 ± 0.06) and developed slower in DW (P <
0.01). Capacitance response was further reduced with increasing levels of HbA1c. Fluid absorption was
almost halved in DW (P < 0.01). The initial vasoconstrictor response was reduced and developed slower in
DW (P < 0.05). Arterial vasoconstriction was further reduced in the presence of microvascular complications
(P < 0.05).
CONCLUSIONS
DW present with decreased and slower mobilization of venous capacitance blood and decreased net fluid
absorption from tissue to blood during hypovolemic circulatory stress. Collectively, this indicates that DW
are prone to hemodynamic instability, especially in the presence of microvascular complications and poor
glycemic control.
Deliberate Total Parathyroidectomy: A Potentially Novel Therapy for Tumor-Induced
Hypophosphatemic Osteomalacia
05 Nov 2013 06:01 pm
Background:
Tumor-induced osteomalacia (TIO) is an acquired hypophosphatemic metabolic bone disorder that can be
cured by removing or ablating the offending tumor. However, when the tumor cannot be localized, lifelong
therapy with oral phosphate and calcitriol or cinacalcet with close monitoring is required.
Case Report:
A 56-year-old man was diagnosed with TIO in 1990. Initial therapy consisted of oral phosphate and calcitriol
with symptomatic and biochemical improvement and healing of osteomalacia. Eight years later,
hypercalcemic hyperparathyroidism developed, requiring subtotal parathyroidectomy with a transient
increase in serum phosphate and normalization of serum calcium and PTH. Recurrent hypercalcemic
hyperparathyroidism developed after 10 years of medical therapy. A deliberate total parathyroidectomy
produced a prompt rise in serum phosphate into the normal range > 3.0 mg/dL and remained normal during
the next 4 years of follow-up, despite continued very high serum fibroblast growth factor-23 levels
throughout the 23-year follow-up.
Conclusion:
We report an unusual case of a TIO patient with long-term follow-up who developed recurrent
hypercalcemic hyperparathyroidism on long-term oral phosphate therapy. Deliberate total
parathyroidectomy normalized serum phosphate despite persistently elevated fibroblast growth factor-23
levels. Total parathyroidectomy offers a potentially novel therapy in some patients with TIO in whom
medical therapy is not feasible or the tumor is unresectable.
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