1. Type 2 Diabetes in Youth Francine Ratner Kaufman, M.D.
Distinguished Professor of Pediatrics
The Keck School of Medicine of USC
Head, Center for Diabetes and Endocrinology
Childrens Hospital Los Angeles

2. What Do We Know About Type 2 Diabetes in Youth?
Question
What Do We Know About Type 2 Diabetes in Youth?

3. Prevalence of Diabetes and IFG in US Adolescents – NHANES 1999-2002
Type 2 Diabetes
0.5% of adolescents have diabetes
71% type 1 and 29% type 2
Determined by insulin use vs no insulin use
39,005 US teens with T2D
Impaired Fasting Glucose
11% had IFG
2,769,736 teens with IFG
Diabetes Increased 41% from 4.9 to 6.9/1000 from 1997 to adults
Duncan, Arch Pediatr Adolesc Med 2006;160:523; Geiss, Am J Prevent Med 2006;30:371

4. Is it an epidemic?
The incidence is increasing and probably underestimated
Population based estimates indicate an ~10-fold increase in incident cases over the past years
8% to 43% of all new cases of diabetes in the United States depending on ethnicity
The SEARCH Trial
What about prevalence??
Bloomgarden ZT. Diabetes Care. 2004;27: Centers for Disease Control. Diabetes Fact Sheet. 2005

5. Controversies as to the Nature of this Epidemic
Difficult to recruit for the TODAY trial
13 centers across the country
Presence of antibodies
The SEARCH Trial
19,000 new patients with T1D
4,100 new patients with T2D
Type 1a
+ Ab
FCP < 0.8 ng/ml
Type 2
- Ab
FCP > 2.9 ng/ml
Hybrid

6. Diabetes Trends Among Adults in the US BRFSS 1990, 1995 and 2001

7. Is Type 2 Diabetes An Epidemic? Little Rock, Cincinnati, San Antonio35 30 25 20
% with type 2 15 10 5 87 88 89 90 91 92 93 94 95 96
Ten-fold increase 0.7 vs 7.2/100000
8% to 43% of all new cases of diabetes in youth in US depending on ethnicity
J Pediatr 136: , 2000

8. Question Is the Presentation the Same as in Adults?
Does not appear to be preceded by long asymptomatic period
Do not find undiagnosed cases on screening

9. Natural History of Type 2 Diabetes
Complications
Genetic susceptibility
Environmental factors
Onset of diabetes
Disability
PRE
Obesity Insulin resistance
Ongoing hyperglycemia
Death
Risk for
Disease
Metabolic
Syndrome
Blindness Renal failure CHD Amputation
Atherosclerosis Hyperglycemia Hypertension
Retinopathy Nephropathy Neuropathy

10. Pre-diabetes (IGT) and T2D
Overweight Sample
IGT
T2D
Paulsen et al, 1968
66 multi-ethnic youth (4-16 years)
17% 6%
Weninger et al, 1980
15 subjects
33% 0%
Sinha et al, 2002
55 multi-ethnic youth (>95th %ile)
25%
112 multi-ethnic teens (>95th %ile)
21% 4%
Goran et al, 2004
150 Hispanic +FH
(8-13 years >85th %ile)
28%
IGT = Impaired Glucose Tolerance

13. OGTT Feasibility Study Pre-diabetes and Diabetes by ADA Cut-offs
Fasting glucose
2-hour glucose
Normal
(< 140)
Pre-diabetes
( )
Diabetes
( 200)
(< 100)
57.6%
0.2%
0.0%
( )
39.7%
2.0%
0.1%
( 126)
0.4%

14. Type 2 Diabetes ? Curve for Youth B-cell Function (%)
Progressive Pancreatic B-cell Failure
Prevention and Early Treatment
UKPDS Data
B-cell Function (%)
? Curve for Youth
Years from Clinical Diagnosis

15. Occurs at the time of intense insulin resistance due to puberty
Question
Is the Pathophysiology the Same as in Adults?
Associated with significant ß-cell failure as well as insulin resistance
Occurs at the time of intense insulin resistance due to puberty

16. Polycystic ovary syndrome
Type 2 Diabetes
Prediabetes
Beta Cell Defect
Beta Cell Defect
Age
Puberty
Obesity
BP,
Lipids
Insulin Resistance
Genetics
Ethnicity
Sedentary Lifestyle
Gender – Girls
Polycystic ovary syndrome

17. Insulin Resistance Beta Cell Defect Type 2 Diabetes Prediabetes
Autoimmunity
Genetic Defect
Beta Cell Defect
Fat cell
toxicity
Intrauterine
IUGR, DM
Glucose
toxicity
Insulin Resistance

18. What distinguishes type 1 from type 2 diabetes in youth?
Question
What distinguishes type 1 from type 2 diabetes in youth?

19. Type 1 Versus type 2 Diabetes in youth?
T1DM
T2DM
Weight
20% may be overweight / obese
Virtually all BMI > 85%th percentile
Course
Rapid
From DPT-1 can be indolent
Indolent
Virtually none found on screening
DKA
35%-40%
Ketonuria (33%)
Mild DKA (5%-25%)
Relative with DM
5% with T1DM
Up to 30% may have with T2DM
FH of T2 2-3Xs in person with T1
74%-100% - 1st –2nd degree with T2DM
Comorbid
Thyroid, adrenal, vitiligo, celiac
Increase in polycystic ovary syndrome
Acanthosis nigricans
C-peptide
C-peptide can be preserved at DX
Normal or increased
Antibody
Ethnicity
85%
Whites predominate
15% (reported as high as 30%)
NA, AA, HA, Asian, Pacific Islander
Kaufman,Endocrinol Meta Clinics N Am, 34; : 2005

20. Differentiation Between Type 1 and 2
48 with type 2 vs 39 with type 1
Type 2
Ethnicity, 1st degree relative, BMI>24, +C-peptide, acanthosis
Type 2
Type 1
DKA
33%
53%
C-peptide
ug/l
ug/l
Abs
8.1% ICA
30% GAD 35%IAA
85% have islet autoimmunity
Hathout et al Pediatrics 107e102,June,2001

21. Question How Does Type 2 Present in Youth?
Is it asymptomatic or symptomatic in youth?

22. Diagnosis with Type 2 Fagot-Campagna et al J Pediatr 2000
Mean Age years
Girls > Boys :1
Obese BMI >85th %
Minority Groups 94%
Strong Family History %
Acanthosis Nigricans %
Diagnosis made by Symptoms, not Screening
HbA1c %
Weight loss %
Glucose in urine 95%
Ketosis %
DKA %

23. Question What Are Treatment Targets in Youth with Type 2 Diabetes?
Are they the same as in adults?

24. TREATMENT GOALS Glucose control, HbA1c <7%
Goals (Diabetes Care, 2000) FG PP
Bed
A1c <7.0
TREATMENT GOALS
Glucose control, HbA1c <7%
Eliminate symptoms of hyperglycemia
Maintenance of reasonable body weight
Improve cardiovascular risk factors
Reduce microvascular complications
Improvement in physical and emotional well-being

25. Treatment Issues Self-monitoring of blood glucose
Fasting and postprandial
Frequency depends on regimen
Medical Nutrition Therapy
Diabetes Education
Involves family
Direct family supervision produces better glycemic control outcomes1
Lifestyle Coaching
Preconception counseling
Immunizations
Dental care
Smoking and alcohol counseling
1. Bradshaw, J Pediatr Endocrinol Meta 15, 2002
2. Pediatrics 112:2003 Prevention and treatment of type 2 diabetes in children with special emphasis on Native American Youth

26. What are the Treatment Regimens for Youth?
Question
What are the Treatment Regimens for Youth?

27. GLP

28. Start with insulin and diet, exercise
Diagnosis
BG 250 mg/dL or 12 mmol/L
Asymptomatic
Start with insulin and diet, exercise
Diet and exercise
<7%
<7%
Monthly review, A1C q3mo
Add metformin
Attempt to
wean insulin
>7%
Add metformin
>7%
Add insulin, TZD, sulfonylurea
>7%
Add 3rd agent
TZD = thiazolidinedione
Silverstein JH, Rosenbloom AL.
J Pediatr Endcrinol Metab. 2000;13 Suppl 6:

29. LWPES Survey 130 Clinical Practices
48% treated with insulin alone
2 injections
44% with oral agents
71% metformin
46% sulfonylurea
9% TZD
4% meglitinide
8% lifestyle

30. A1c at CHLA 2005 Diabetes Type Type 1 n=1534 Type 2 n=276 A1c %
Age
years
Duration years
Visit Number

31. T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.
Intensive Therapy for Diabetes: Reduction in Incidence of Complications
T1DM
DCCT
T2DM
Kumamoto
UKPDS
A1C
9%  7%
8%  7%
Retinopathy
63%
69%
17%–21%
Nephropathy
54%
70%
24%–33%
Neuropathy
60%
58% –
Cardiovascular disease
41%*
52*
16%*
Review Data
T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.
*Not statistically significant due to small number of events.
†Showed statistical significance in subsequent epidemiologic analysis.
DCCT Research Group. N Engl J Med. 1993;329: ; Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28: ; UKPDS 33: Lancet. 1998;352: ; Stratton IM, et al. Brit Med J. 2000;321:

32. Long term outcome Pima Indians - diagnosed < 20 years of age
22% had microalbuminuria at diagnosis
Increased to 60% at years of age
Indigenous Canadians- mean age 23 yrs, 9 yrs duration of diabetes
HbA1c 10.9%
67% poor glycemic control
45% hypertension requiring treatment
35% microalbuminuria (6% required dialysis)
38% pregnancy loss
9% mortality
Arslanian S. Hormone Res 2002; 57 Suppl 1: Dean., Diabetes 2002;51(Suppl 2):A24.

33. Uncontrolled diabetes
Amputations
Loss of Sensations
Heart disease
and strokes
Blindness
Uncontrolled diabetes
can lead to…
Death
Kidney failure

34. An Answer
The Today Trial?

35. Studies to Treat Or Prevent Pediatric Type 2 Diabetes STOPP-T2D
Funded by
National Institute of Diabetes and Digestive
and Kidney Diseases
National Institutes of Health

36. STOPP-T2 TREATMENT PRIMARY AIM
To compare the efficacy of 3 treatment regimens
Metformin
Metformin + lifestyle
Metformin + TZD
On Time to Treatment Failure and on Glycemic Control
TODAY

37. Primary Outcomes Treatment goal Treatment failure
HbA1c < 6% (glycemic control)
Treatment failure
HbA1c  8.0% over 6 consecutive months OR
Inability to wean from temporary insulin therapy due to metabolic decompensation

38. Outcome Measures Glycemia Insulin sensitivity and secretion
HbA1c, fasting and postprandial glucose by home monitoring
Insulin sensitivity and secretion
OGTT, HOMA, QUICKI, proinsulin, C-peptide
Body composition
BMI, DEXA, waist circumference, abdominal height
Fitness and physical activity
PDPAR, PWC 170, accelerometer

39. Outcome Measures (continued)
Nutrition
food frequency questionnaire
Cardiovascular disease risk
BP, lipids, inflammatory markers, coagulation factors
Microvascular complications
microalbuminuria, neuropathy
Quality of life
Cost

40. Inclusion Criteria Age 10 to 17 years
Duration of diabetes < 2 years
BMI  85th percentile
Adult involved in the daily activities of the child agrees to participate in the intervention
Absence of pancreatic autoimmunity
Fasting C-peptide > 0.6 mmol/L
Fluency in English or Spanish

41. National Diabetes Education Program’s Tip Sheets for Kids with Type 2
                        
In terms of publications, these colorful tip sheets provide basic information about type 2 diabetes and encourage young people to take steps to manage the disease for a long and healthy life.
Written in simple language, the tip sheets are helpful for anyone who has type 2 diabetes and their loved ones. Topics include:
What is Diabetes?
Be Active.
Stay at a Healthy Weight.
Eat Healthy Foods.
These tip sheets also are available online on the NDEP website.
Additional tip sheets are in development covering dealing with diabetes and diabetes prevention.
What is Diabetes?
Be Active
Stay at a Healthy Weight
Eat Healthy Foods

42. Helping the Student with Diabetes Succeed
The school guide is called Helping the Student with Diabetes Succeed. A Guide for School Personnel.
NDEP took on this project because of reports from NDEP partner organizations and their constituents of the lack of awareness and knowledge on how to manage kids with diabetes during the school day and the discrimination against children with diabetes in the school setting.
Numerous NDEP partners joined NDEP to create and pretest the school guide.

43. Conclusion Increased incidence Difficult to distinguish from type 1
Occurs at the time of intense insulin resistance due to puberty
Does not appear to be preceded by long asymptomatic period
More insulin deficiency and requirement for exogenous insulin early
Safety and efficacy of therapeutic agents
Rapid progression of co-morbidities and complications

44. Thank you