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Type 1 and Type 2 Diabetes
in Children and Youth:
What’s New and What’s True
Francine Ratner Kaufman, MD, FAAP
Distinguished Professor Emerita of Pediatrics and Communications,
The Keck School of Medicine of the University of Southern California
Center for Diabetes and Endocrinology, Childrens Hospital Los Angeles
Chief Medical Officer of Medtronic Diabetes
Los Angeles, CA
Disclaimer
I am the Chief Medical Officer
for Medtronic Diabetes.
Disclaimers continued
• Statements and opinions expressed are those of the authors and not
necessarily those of the American Academy of Pediatrics.
• Mead Johnson sponsors programs such as this to give healthcare
professionals access to scientific and educational information provided by
experts. The presenter has complete and independent control over the
planning and content of the presentation, and is not receiving any
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Outline of Presentation
1. Presentation, Diagnostic Criteria, Screening
2. Rates, Causes – Genes/Environment
3. Treatment
4. Co-morbidities and Complications
5. Prevention
11 8/12-Year-Old Female Patients
Type 1 Diabetes (T1)
• Chief complaint: Urinates 2 to 3 times
at night times 2 weeks
– A1C 8.2% at outside clinic
• Weight 63 kg, body mass index (BMI)
>85th percentile for age/gender
– Reported 15 lb weight gain last
year, recent loss
• Blood pressure (BP) 92/65
• Menses at 10 years – irregular
• Prenatal – excessive maternal weight
gain, no diabetes
• Family history
– Mother from Arizona, HA, + for
obesity
– Father non-Hispanic White,
hypertension
Type 2 Diabetes (T2)
• Chief complaint: Urinates 2 to 3 times
at night times 2 months
– A1C 8.2% at outside clinic
• Weight 78 kg, BMI >95th percentile
for age/gender
– Reported 30 lb weight gain last
year, recent loss
• BP 128/83
• Menses at age 10 years – irregular
• Prenatal – excessive maternal weight
gain, ? diabetes,
• Family history
– Mother from Arizona, AI/HA, + for
obesity
– Father is non-Hispanic White,
hypertension
Presentation, Diagnostic Criteria, Screening
• Presentation
– T1 rapid onset, severe hyperglycemia, acidosis, diabetic
ketoacidosis (DKA)
• Results of TrialNet show T1 can be indolent
– T2 indolent, mild hyperglycemia, rare acidosis, no DKA
• AA high rate of mild DKA, higher glucose/A1C, symptomatic
at presentation
• Diagnostic criteria is the same for T1 and T2
– Symptoms of diabetes plus casual glucose ≥200 mg/dL
– Fasting plasma glucose ≥126 mg/dL
– 2-hour postload glucose ≥200 mg/dL during oral glucose
tolerance test (OGTT)
• ?A1C >6.5%
– Used in adults but not established in children
Presentation, Diagnostic Criteria, Screening
• Evidence of insulin
deficiency – hyperglycemia
and acidosis, DKA
mistaken for flu
• Hardest diagnosis in
infants/toddlers
• No other family member
• Other autoimmune
diseases
• Evidence of insulin
resistance, hypertension,
dyslipidemia, NASH
• Presentation during or
after puberty
• T2 in first-degree relative
• Acanthosis nigricans,
sleep apnea, polycystic
ovary syndrome (PCOS),
candidiasis
Zeitler P. Approach to the obese adolescent with new-onset diabetes. J Clin Endocrinol Metab. 2010;95(12):5163–5170
Screening for T1
The reason to screen and
intervene early in T1D:
• Common, serious in terms
of morbidity and mortality
• Latency period without
symptoms
• Screening test with
sensitivity and specificity
• Intervention early is more
effective, preserves
C-peptide
Immune Tolerance Network
• In the context of research
trials
– TrialNet, Immune
Tolerance Network,
TEDDY, etc.
• Screen with antibodies,
? genes
• Reason
– Prevention studies
• Oral insulin, omegas,
vitamin D, anti-CD3
– Natural history study
Screening for T2
American Diabetes Association (ADA) / American Academy of
Pediatrics (AAP) Consensus Statement, 2000
 Criteria*: Overweight (BMI 85th percentile for age and sex,
weight for height 85th percentile, or weight 120% of ideal for
height)
PLUS: any 2 of the following risk factors:
 Family history of diabetes mellitus (DM) 2 in first- or second-degree relative
 Race/ethnicity
 Signs of insulin resistance



Age of Initiation: Age 10 or at onset of puberty
Frequency: Every 2 years in the context of health visit
Test: Fasting plasma glucose preferred
* Clinical judgment should be used.
American Diabetic Association. Type 2 diabetes in children and adolescents.
Diabetes Care. 2000;23(3):381–389
Screening for T2
Results of the HEALTHY Study and Pilot – Diabetes Not Found
6th Grade
N = 6367
8th Grade
N = 1740
22.4 (5.7)
24.3 (5.9)
50.5%
19.8%
29.7%
51.0%
19.8%
29.2%
93.4 (6.7)
84.0%
14.7%
98.2 (8.5)
59.5%
34.3%
110–125
≥126
1.2%
0.1%*
5.8%
0.4%**
≥30
6.2%
36.2%
Measurement
BMI (kg/m2)
BMI percentile (adjusted
for age and gender)
Fasting glucose (mg/dL)
Mean (SD)
<85
85–94
≥95
Mean (SD)
<100
100–109
Fasting insulin (µU/mL)
*n=6 of which only 1 confirmed on follow-up testing
**n=7
Baranowski T, Cooper DM, Harrel J, et al. Presence of diabetes in a U.S. eighth-grade cohort. Diabetes Care. 2006;29(2):212–
217; HEALTHY Study Group; Kaufman FR, Hirst K, Linder B, et al. Risk factors for type 2 diabetes in a sixth-grade multiracial
cohort: the HEATHLY study. Diabetes Care. 2009;32(5):953–955
Causes: Genes and the Environment
• 3–5% increase in T1 consistently
• T2 from <2–25% of new onset diabetes
SEARCH for Diabetes in Youth Study Group; Liese AD, D’Agostino RB Jr, Hamman RF, et al. The burden of diabetes mellitus among US youth:
prevalence estimate from the SEARCH for Diabetes in Youth Study. Pediatrics. 2006;118(4):1510–1518
Causes: Obesity as a Risk Factor
BMI >85th Percentile at Diagnosis
• Type 2
– 100% African American
– 95% non-Hispanic
– 91% Hispanic
• Type 1
– 44% BMI >85th percentile
– 30% BMI >95th percentile
– Greater than the general population rates
Search Data
SEARCH for Diabetes in Youth Study Group; Liese AD, D’Agostino RB Jr, Hamman RF, et al. The burden of diabetes mellitus among US youth:
prevalence estimate from the SEARCH for Diabetes in Youth Study. Pediatrics. 2006;118(4):1510–1518
Causes T1
ENVIRONMENTAL
TRIGGERS
CELLULAR (T CELL) AUTOIMMUNITY
HUMORAL AUTOANTIBODIES
BETA CELL MASS
(ICA, IAA, GAD65A, ICA512A)
LOSS OF INSULIN
GLUCOSE STARTS TO INCREASE
Honeymoon
GENETICS
BETA CELL INJURY
TIME
“PRE”
DIABETES
DIABETES
NEWLY DIAGNOSED DIABETES
Causes T1: Genes and Antibodies
• 4 antibodies: glutamic acid decarboxylase (GADA), islet
tyrosine phosphatase (IA2), zinc transporter 8 A (ZnT8A),
insulin autoantibodies (IAA)
– >90% newly diagnosed +Abs; 3.5–4% of unaffected first-degree
relatives
• 40–50% of genetic predisposition on short arm of
chromosome 6, Class II HLA region of the major
histocompatibility complex (MHC)
– Whites HLA-DR3 or HLA-DR4, Blacks HLA-DR7, Japanese HLA-DR9
• ~11 other loci, insulin gene chromosome 11 (INS-VNTR), T-cell
activation and regulation genes (CTLA-4), protein tyrosine
phosphatase N22 (PTPN22), genes in interleukin pathway (IL2R)
– HLA, CTLA-4, and PTPN22 are associated with other autoimmune
diseases
Causes T1 Number of Antibodies
P-value <0.001
(Log Rank Test)
1.0
Survival Distribution Function
0.9
0.8
0.7
0.6
0.5
0.4
Number at Risk
0.3
0.2
72
70
0.1 113
0.0 84
0
61
59
89
66
41
46
58
52
30
33
40
35
22
19
19
19
7
8
2
10
1
1
2
3
4
5
6
Years Followed
STRATA:
1 Ab (ICA Only)
3 Abs
2 Abs
4 Abs
7
Causes T2: THE HEALTHY MIDDLE SCHOOL STUDY
6th Grade Students—Predominately Minority
Distribution of Glycemic Risk Factors by BMI Percentile
<85
(N=3221)
85–94
(N=1255)
95
(N=1882)
Fasting glucose
(mg/dL)
92.8 (6.7)
93.3 (6.8)
94.5 (6.6)
Fasting glucose ≥100
13.5%
15.5%
20.8%
p <.0001§
Fasting insulin (μU/mL)
8.4 (5.2)
12.8 (7.5)
22.1 (15.8)
Fasting insulin ≥30
0.8%
3.0%
19.6%
p <.0001§
Baranowski T, Cooper DM, Harrel J, et al. Presence of diabetes in a U.S. eighth-grade cohort. Diabetes Care. 2006;29(2):212–217; HEALTHY Study
Group; Kaufman FR, Hirst K, Linder B, et al. Risk factors for type 2 diabetes in a sixth-grade multiracial cohort: the HEATHLY study. Diabetes Care.
2009;32(5):953–955
Causes T2
Baseline and outcome glucose tolerance
classification T2DM, type 2 diabetes
• NGT
• N=84
• 117 obese
children and
adolescents
• NGT
• N=76 (90.5%)
• IGT
• N=8 (9.5%)
• NGT
• N=15 (45.5%)
• IGT
• N=10 (30.3%)
• IGT
• N=33
• T2DM
• N = 8 (24.2%)
Mean follow-up of 20.4 + 10.3 months
Weiss R, Taksali SE, Tamborlane WV, et al. Predictors of changes in glucose tolerance status in obese youth. Diabetes Care. 2005;28(4):902–909
Causes T2
Comparison of Subjects with Impaired Glucose Tolerance (IGT) Who Developed
Type 2 Diabetes and Who Reverted to Normal Glucose Tolerance (NGT)
IGT to NGT
IGT to T2D
BMI
33
versus
44
BMI z-score
2.27
versus
2.76
6.1
versus
27
1.06
versus
6.8
Weight Δ
BMI Δ
kg
Weiss R, Taksali SE, Tamborlane WV, et al. Predictors of changes in glucose tolerance status in obese youth. Diabetes Care. 2005;28(4):902–909
Causes T2: Gestational Diabetes as a Driver of T2
Diabetes in pregnancy can lead to a cycle
of diabetes affecting future generations.
Dabalea D, Hanson RL, Bennett PH, et al. Increasing prevalence of Type II
diabetes in American Indian children. Diabetologia. 1998;41(8):904–910
Causes T2: Progression from Pre-diabetes to Diabetes
31.3% BMI
>85th percentile
16.9% obese
•
•
•
•
•
•
Obesity
Diabetes
A1C >6.4%
Pre-diabetes
A1C 5.8–<6.4%
15% IFG, FPG >100 mg/dL
25% IGT in obese,
2h OGTT PG >140 mg/dL
Family History
Environmental Factors
Genetic Susceptibility
Beginning in Utero
Maternal Obesity
Breast Feeding
Insulin sensitivity 75%
Normal glucose tolerance
Beta-cell function 2Xs
FPG >126 mg/dL, RPG >200 mg/dL
3,700/ year (TIDM 16,000)
6% W, 67% AI
1/3 AA, HA, API
Insulin sensitivity 75%
Impaired glucose tolerance
Beta-cell 50%
Metabolic Syndrome
Risk Factors
Gunger N, Bacha F, Saad R, et al. Youth type 2 diabetes: insulin resistance,
beta-cell failure, or both? Diabetes Care. 2005;28(3):638–644; Arslanian
SA, Lewy VD, Danadian K. Glucose intolerance in obese adolescents with
polycystic ovary syndrome: roles of insulin resistance and beta-cell
dysfunction and risk of cardiovascular disease. J Clin Endocrinol Metab.
2001;86(1):66–71; and Bacha F, Saad R, Gungor N, et al. Adiponectin in
youth: relationship to visceral adiposity, insulin sensitivity, and beta-cell
function. Diabetes Care. 2004;27(2):547–552
Insulin sensitivity 50%
Diabetes
Beta-cell 75%
11 8/12-Year-Old Female Patients
• Obtain the following workup:
– Random plasma glucose,
247 mg/dL, repeat A1C 8.5%
– CO2 16 meq/L, venous pH 7.32,
LDL 165 mg/dL, triglycerides
200 mg/dL
• ANTIBODIES GADA+
• Treatment: In- or out-patient?
• What kind of insulin treatment?
– Intensive?
• All patients and families receive
diabetes and lifestyle education.
• Obtain the following work up:
– Random plasma glucose 247 mg/dL,
repeat A1C 8.5%
– CO2 20 meq/L, venous pH 7.38, LDL
178 mg/dL, triglycerides 215 mg/dL
• ANTIBODIES ALL NEGATIVE
• Treatment: In- or out-patient?
– Do you start insulin?
– Metformin alone is first-line therapy
when glucose level is <250 mg/dL
and patient is non-ketotic
– All patients and families receive
diabetes and lifestyle education.
Treatment: Determining Diabetes Type in Youth
with BMI >85th Percentile
New onset of diabetes
BMI >85th percentile
Positive
Consider MODY;
if not obese,
NHW
Pancreatic
autoantibodies
Negative
Likely Type 2
Monitor course
Type 1
Insulin
requirement
No
Yes
C-peptide normal/elevated
• Type 2 ?adherence
• Severe resistance/deficiency
Zeitler P. Approach to the obese adolescent with new-onset diabetes.
J Clin Endocrinol Metab. 2010;95(12):5163–5170
Type 2
Treatment: Diabetes is Hard to Manage
Early and Persistent Glucose Control is Important.
Age
Pre-Meal BG
HS/Night BG
A1c
Toddler
(0–5 years)
100–180
110–200
≥7.5 & ≤8.5%
90–180
School-age
(6–11 years)
<8%
Adolescent
(12–19 years)
90–130
90–150
<7.5%
Type 2
80–130
90–150
<7.0%
Silverstein J, Klingensmith G, Copeland K, et al. Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes
Association. Diabetes Care. 2005;28(1):186–212
Treatment
Early and Persistent Glucose Control is Important.
• Glucose monitoring
– Self-monitoring glucose, continuous glucose
monitoring, understanding glucose targets,
A1C quarterly
• Medications
– Insulin therapy: Multiple injections, pens,
pumps, changing dosages prn
• Medical nutrition therapy
– Balancing food: Managing carbs, weight
• Psychosocial support
• Assess, treat co-morbidities, complications
– BP, cholesterol, thyroid, celiac, eye exams,
microalbuminuria, disordered eating
• Visits to health care team
– Routine pediatric care, flu shots, hepatitis B
immunization, transition planning
– Sick day management
• Glucose monitoring
– Self-monitoring glucose, understanding
glucose targets, A1C quarterly
• Medications
– Glucose lowering agents
 Metformin, insulin therapy
 Others not approved
• Medical nutrition therapy
– Weight reduction, lifestyle counseling
• Psychosocial support
• Assess, treat co-morbidities, complications
– BP, cholesterol, disordered eating, PCOS,
NASH, microalbuminuria, eye exams
• Visits to health care team
– Routine pediatric care, flu shots, hepatitis B
immunization, transition planning
– Sick day management
Silverstein J, Klingensmith G, Copeland K, et al. Care of children and
adolescents with type 1 diabetes: a statement of the American Diabetes
Association. Diabetes Care. 2005;28(1):186–212
Treatment: DCCT Results, EDIC Results and Rate of
Severe Hypoglycemia
DCCT Results
15
13
Retinop
11
9
Neph
7
Neurop
5
3
1
6
7
8
0.5
9
10
11
12
EDIC Results
0.4
0.3
0.2
0.1
0
0
1
2
3
4
5
Years in EDIC
6
7
Reduction in Severe Hypoglycemia
Treatment T1: Insulin Pump Therapy Improves Control
Compared with MDI, insulin pumps are more effective at reducing A1C.
(Insulin Pump)
52 studies show that CSII is significantly more effective in lowering A1C
compared to MDI and conventional insulin therapy.
Bruttomesso D, Pianta A, Crazzolare D, et al. Continuous subcutaneous insulin infusion (CSII) in the Veneto region: efficacy, acceptability and quality of life. Diabet Med.
2002;19(8):628–634; Bell DSH, Ovalle F. Improved glycemic control with use of continuous subcutaneous insulin infusion compared with multiple insulin injection
therapy. Endocr Pract. 2000;6(5):357–360; Rudolph JW, Hirsch IB. Assessment of therapy with continuous subcutaneous insulin infusion in an academic diabetes clinic.
Endocr Pract. 2002;8(6):401–405; Chantelau E, Spraul M, Mühlhauser I, et al. Long-term safety, efficacy and side effects of continuous subcutaneous insulin infusion
treatment for type 1 (insulin dependent) diabetes mellitus: a one centre experience. Diabetologia. 1989;32(7):421–426; Boland EA, Grey M, Oesterle A, et al.
Continuous subscutaneous insulin infusion. A new way to lower risk of severe hypoglycemia, improve metabolic control, and enhance coping in adolescence with type
1 diabetes. Diabetes Care. 1999;22(11):1779–1784; Maniatis AK, Klingensmith GJ, Slover RH, et al. Continuous subcutaneous insulin infusion therapy for children and
adolescents: an option for routine diabetes care. Pediatrics. 2001;107(2):351–356; Litton J, Rice A, Friedman N, et al. Insulin pump therapy in toddlers and preschool
children with type 1 diabetes mellitus. J Pediatr. 2002;141(4):490–495; and Weissberg-Benchell J, Lomaglio JA, Seshadri R. Insulin pump therapy: a meta-analysis.
Diabetes Care. 2003;26(4):1079–1087
Treatment T1: CSII Reduces Incidents of
Severe Hypoglycemia
Severe hypoglycemic episodes MDI vs CSII
Rudolph JW, Hirsch IB. Assessment of therapy with continuous subcutaneous insulin infusion in an academic diabetes clinic. Endocr Pract. 2002;8(6):401–405;
Bode BW, Steed RD, Davidson PC. Reduction in severe hypoglycemia with long-term continuous subcutaneous insulin infusion in type 1 diabetes. Diabetes
Care. 1996;19(4):324–327; and Boland EA, Grey M, Oesterle A, et al. Continuous subscutaneous insulin infusion. A new way to lower risk of severe
hypoglycemia, improve metabolic control, and enhance coping in adolescence with type 1 diabetes. Diabetes Care. 1999;22(11):1779–1784
Treatment T1: Meta-analysis for Mean
Difference in A1C between CSII and MDI
In 22 studies, severe hypoglycemia was reduced with CSII by a rate ratio of 2.89
for RCTs and 4.34 for before/after studies. The mean difference in A1C was 0.21%
for RCTs and 0.72% for before/after studies, related to initial A1C (p<0.001).
Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in Type 1
diabetes: meta-analysis of multiple daily injections compared with continuous
subcutaneous insulin infusion. Diabet Med. 2008;25(7):765–774
Treatment T1: Continuous Glucose
Monitoring
Multiple RCTs have been performed
• Across the spectrum of glucose
control
• Adults and children
• Starting therapy MDI and CSII
• All show relationship between
sensor use and decrease in A1C
Starting
Therapy
and A1C
Study
Groups
Change in
A1C
SAP vs
Control
RealTrend
N=132
MDI
>8.0
SAP v CSII
~.5
Eurythmics
N=83
MDI
8.2
SAP v MDI
1.23
Onset
N=154
New onset
children
11.2
SAP v CSII
.2
Outcome
C-peptide
JDRF
N=322
CSII or MDI
7.6 and <7.0
CSII or MDI
+ CGM
Adults .5
STAR 3
N=495
MDI
>7.4, <9.5
SAP v MDI
Adults and
Children .6
Bergenstal RM, Tamborlane WV, Ahmana A, et al. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. New Eng J Med. 2010;363(4):311–
320; Misso ML, Egberts KJ, Page M, et al. Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus. Cochrane
Database of Systematic Reviews 2010, Issue 1. Art. No.: CD005103; Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group; Beck RW,
Buckingham B, Miller K, et al. Factors predictive of use and of benefit from continuous glucose monitoring in type 1 diabetes. Diabetes Care. 2009;32(11):1947–
1953; and Raccah D, Sulmont V, Reznik Y, et al. Incremental value of continuous glucose monitoring when starting pump therapy in patients with controlled type 1
diabetes: the REALTrend study. Diabetes Care. 2009;32(12):2245–2250
Treatment T1: Glycemic Control During Real-time CGM
Meta-analysis of Randomized Controlled Trials Using Individual Patient Data
Pickup JC, Freeman SC, Sutton AJ.
Glycemic control in type 1 diabetes during
real time continuous glucose monitoring
compared with self monitoring of blood
glucose: meta analysis of randomized
controlled trials using individual patient
data. BMJ. 2011;343:d3805
Treatment T1: STAR 3 Study
A1C at 3, 6, 9, and 12 Months: All Patients
Sensor Augmented Pump
Multiple Injections
A1C 8.3% n=244
A1C 8.3% n=241
Adults=166, Pediatrics=78
Adults=163, Pediatrics=78
8.0%
8.0%
7.5%
8.1%
8.1%
7.5%
7.5%
7.3%
Bergenstal RM, Tamborlane WV, Ahmana A, et al. Effectiveness of sensoraugmented insulin-pump therapy in type 1 diabetes. New Eng J Med.
2010;363(4):311–320
Treatment T1
A1C at 3, 6, 9, and 12 Months: Pediatrics 7–18 Years
8.6%
8.4%
8.3%
7.7%
7.8%
7.5%
Bergenstal RM, Tamborlane WV, Ahmana A, et al. Effectiveness of sensoraugmented insulin-pump therapy in type 1 diabetes. New Eng J Med.
2010;363(4):311–320
8.5%
7.9%
Treatment T1
A1C Reduction is Correlated with Increased Sensor Use
but Not an Increase in Hypoglycemia or DKA
Change in A1C at 1 Year vs Baseline
Frequency of Sensor Use (% of Time)
21-40%
41-60%
61-80%
SAP
Group
n=247
MDI
Group
n=248
P
Value
Severe
Hypoglycemia
Rate per 100
person-years
13.31
13.4
0.84
Diabetic
Ketoacidosis
Number of events
(# pts)
3 (3)
2 (1)
0.38
+2.4 kg
+1.8 kg
0.19
81-100%
0
-0.19
-0.5
-0.64
-0.79
-1
-1.21
-1.5
n=27
n=46
n=108
n=56
The majority of patients used sensors
>60% of the time.
Weight Change
Severe hypoglycemia rate low and at
lower A1C, little DKA
Bergenstal RM, Tamborlane WV, Ahmana A, et al. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. New Eng J Med.
2010;363(4):311–320
Treatment T1
The Evolution of a Fully-Automated Insulin Delivery System
Present
Past
Sensor Augmented
Insulin Pump
Insulin Pump
Therapy
Low Glucose
Suspend
Potential Future products
Predictive LGS
with restart when
glucose returns
to normal
Treat to target
Clips off highs
SG #1
280
Overnight
closed loop
SG #2
Intermittent
closed loop
SG (Control)
MBG
Da y (OL)
Night #1 (CL)
Fully automated
closed loop
Night #2 (CL)
Glucose (mg/dL)
240
200
160
120
80
40
ePID Infusion
Rate (U/h)
0
5
4
3
2
1
0
20
22
24
26
28
30
32
34
36
38
20
22
24
26
28
30
32
34
36
38
Time (h)
40
42
44
46
48
50
52
54
40
42
44
46
48
50
52
54
Treatment: T2 ISPAD Guidelines, 2009
Rosenbloom AL, Silverstein JH, Amemiya S.
Type 2 diabetes in children and adolescents.
Pediatric Diabetes. 2009;10(12):17–21
Funded by
National Institute of Diabetes and
Digestive and Kidney Diseases
National Institutes of Health
Treatment T2
• Randomized clinical trial with a prerandomization run-in period
– 704 patients at 15 clinical centers
– 3 treatment regimens
•
•
•
•
Metformin + Placebo
Metformin + Rosiglitazone
Metformin + Intensive Lifestyle Program
At treatment failure: Standardized approach to
insulin initiation
• Primary outcome: Time to failed glycemic
control
• Inclusion criteria
– Age 10–17 years
– Duration of diabetes <2 years
– BMI 85th percentile
Copeland KC, Zeitler P, Geffner M, et al. Characteristics of adolescents and
youth with recent-onset type 2 diabetes: the TODAY cohort at baseline. J Clin
Endocrinol Metab. 2011;96(1):159–167
Treatment T2: The TODAY Trial
Mean ± SD or %
14.3 ± 2.0
Age (years)
Race/Ethnicity
Native American
19.6%
37.4%
32.2%
5.5%
Other/Unknown
5.3%
White
African American
Hispanic
(kg/m2)
36.2 ± 7.9
25 - 71
BMI Z-score
+2.3 ± 0.5
BMI
Medications at Presentation
•
•
•
•
•
No medication
Insulin only
Metformin only
Metformin + insulin
Other medication
11%
12%
49%
25%
4%
Copeland KC, Zeitler P, Geffner M, et al. Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at
baseline. J Clin Endocrinol Metab. 2011;96(1):159–167
A Clinical Trial to Maintain
Glycemic Control in Youth with Type 2 Diabetes
TODAY Study Group; Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. New Eng J Med.
2012:1–10
Treatment T2: The TODAY Trial Study Results
TODAY Study Group; Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain
glycemic control in youth with type 2 diabetes. New Eng J Med. 2012:1–10
TODAY Study Group; Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. New Eng J Med. 2012:1–10
Treatment: Lifestyle Tips for Teens with Diabetes Series
from National Diabetes Education Program
Co-morbidities and Complications:
Cardiovascular Risk Factors—SEARCH Trial
%
100
MetS: >2 cardiovascular disease (CVD) risk factors
Type1A
Type 2
• 68% American Indian
37% Asian, 32% African
American, 35% Hispanic,
16% White (p<0.0001)
90
80
70
60
50
• At least 2 risk factors
 92% of type 2
 14% of type 1
(p<0.0001)
40
30
20
10
0
↑BP
↑TG
↓HDL
↑Waist
MetS
Rodriguez BL, Fujimoto WY, Mayer-Davis EJ, et al. Prevalence of cardiovascular
disease risk factors in U.S. children and adolescents with diabetes: the SEARCH
for diabetes in youth study. Diabetes Care. 2006;29(8);1891–1896
Co-morbidities and Complications: Australia
Eppens MC, Craig ME, Cusumano J, et al. Prevalence of diabetes complications in adolescents with
type 2 compared with type 1 diabetes. Diabetes Care. 2006;29(6):1300–1306
Complications T1: Catastrophe at
Diagnosis—DKA
• Severe metabolic disturbance
– Insulin deficiency, secondary counter-regulatory hormone elevation
• North America and Europe statistics
– 30% of new cases, 20% of deaths from diabetes <20 years
• 1/200 episodes result in cerebral edema
– 1/3 die, 1/3 permanently impaired, 1/3 recover
• Costs: >2.5 billion dollars
• Risk factors for cerebral edema
– Young age, poverty, no knowledge of signs and symptoms, lack of access to care
– Lower pCO2 , higher BUN at DX, Rx with HCO3, smaller increase in Na
• Mechanism(s)
– Osmotic cellular swelling versus vasogenic process
Glaser NS, Wooten-Gorges SL, Marcin JP, et al. Mechanism of cerebral edema in children with diabetic ketoacidosis. J Pediatr. 2004;145(2):164–171
Kaufman, Type 2 Youth
Complications T2: Type 2 Diabetes is a
Severe Disease
• Hyperglycemic Hyperosmolar Non-Ketotic Syndrome—at onset—very high
glucose levels
– 3.7% (7/190) in Philadelphia
 Mortality 14.3%
– Currently 28 reported other cases
 Mortality 43%
• Pima Indians diagnosed at <20 years of age
– 22% had microalbuminuria at diagnosis
– Increased to 60% at 20–29 years of age
• Indigenous Canadians 23 years of age, 9 years duration
– HbA1c 10.9%
–
–
–
–
 67% poor glycemic control
45% hypertension requiring treatment
35% microalbuminuria (6% required dialysis)
38% pregnancy loss
9% mortality
Fourtner SH, Weinzimer SA, Katz LEL. Hyperglycemic hyperosmolar non-ketotic syndrome in children with type 2 diabetes. Pediatr Diabetes. 2005;6(3):129–
135; Butler M, McKary RA, Popoff IJ, et al. Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice. Diabetes. 2002;51(4):1028–1034
Complications and Co-Morbidities T2
TODAY Study Group; Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain
glycemic control in youth with type 2 diabetes. New Eng J Med. 2012:1–10
Prevention or Interdiction of T1
TrialNet and Immune Tolerance Network
•
•
•
•
•
•
•
•
•
•
•
•
Anti-CD3
Mycophenolate Mofetil +/- Anti-CD25
Anti-CD20
Anti-thymocyte globulin
CTLA-4
GAD-Alum immunization
Intense metabolic control
Oral insulin
Supplemental vitamin D
Omega fatty acids
Hydrolyzed formula compared to cow's milk
Outside TrialNet and Immune Tolerance
Network
– Alpha-1-antitrypsin, BCG, insulin peptide B:923, heat shock protein DiaPep277
Some studies have shown
an initial benefit in
C-peptide preservation.
Has tolerance been
achieved or only
immuno-blockade?
Are multiple or sequential
agents required?
What are the
risks/benefits over
the long term?
5. Prevention
Socio-ecological Model
Home
Social Norms
Subculture
Communities
Health Care Access,
Adherence
Sectors of
Influence
Worksites
Education
Media
Land Use and
Transportation
Communities
Individual
Factors
Culture
Intrauterine
Environment
Agriculture
Behavioral
Settings
Age, Sex, SES,
Race/Ethnicity
Genes,
Gene-Environment
Interactions
Government
Public Health
Schools and Child Care
Psychosocial Factors Stress
Built Environment
Food &
Beverage
Intake
Energy Intake
Foundations
Physical
Activity
Industry
Energy Expenditure
Beverage
Energy Balance
Obesity
Insulin Resistance/Deficiency
Type 2 Diabetes
Food
Retail
Leisure and Recreation
Entertainment
Prevention: The HEALTHY Study
• School unit of randomization
• Intervention schools
• Primary outcome: Combined
prevalence of overweight plus
obesity
• 42 schools
– ≥50% minority and/or ≥50% with
free/reduced lunch
– Comprehensive health screening,
results sent to parents
– Environmental changes,
food service, physical education
– Behavior change—curriculum
based
– Communications and
promotional campaign
Diabetes Care 29:212–217, 2006
49
Prevention: The HEALTHY Trial RESULTS
• Reduction in percentage of
•
overweight/obesity by 4% in both groups
• Prevalence of obesity declined more in
intervention schools (p=0.05)
• Significant reduction in intervention
schools (p=0.04)
– BMI z-score
– Prevalence of large waist circumference
– Fasting insulin fell
In the overweight/obese subgroup
(n=2292), intervention schools had
significantly greater decreases in
prevalence of:
– Obesity (p=0.04)
– Large waist circumference (p=0.03)
– Insulin (p=0.04)
HEALTHY Study Group; Foster GD, Linder B, Baranowski T, et al. A school-based
intervention for diabetes risk reduction. New Eng J Med. 2010;363(5):443–453
Prevention: RWJ F as in Fat
1. All foods and beverages
served in schools meet
Dietary Guidelines for
Americans.
4. Increasing physical activity
by improving the built
environment in
communities.
2. Increasing access to highquality, affordable foods
through new or improved
grocery stores and healthier
corner stores and bodegas.
5. Using pricing strategies—
both incentives and
disincentives—to promote
the purchase of healthier
foods.
3. Increasing the time,
intensity, and duration of
physical activity during the
school day.
6. Reducing youths’ exposure
to the marketing of
unhealthy foods through
regulation, policy, and
effective industry selfregulation.
Conclusion
Type 1 diabetes
•
•
•
•
•
•
•
Genetic predisposition
and environmental triggers
cause autoimmunity,
+antibodies
Rare in family members
Screening in research
Presentation rapid, severe,
but not always
Treatment with education,
support and intensive
insulin, plus technology,
risk of hypoglycemia, A1C
main outcome measure
Complications related to
dysglycemia, occur in youth
but rare, co-morbidities
related to autoimmunity
Prevention trials with
multi-agents/approaches
Type 2 diabetes
•
Food
•
Pancreas
•
Gut
•
•
Insulin
Glucose
Muscle
•
•
Genetic predisposition and
environmental trigger of
obesity, insulin resistance and
deficiency
Common in first-, seconddegree relatives
Screening criteria but rare to
find asymptomatic
Presentation slow, mild, but
not always, and maybe less
than thought
Treatment needs to be more
aggressive than monotherapy
to maintain glycemic control
Complications common, early,
co-morbidities related to
insulin resistance
Prevention addresses the
environment to support
healthy lifestyle adoption
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