Francine Ratner Kaufman, M.D. Distinguished Professor of Pediatrics

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. 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 2003 - 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 10-15 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;27:998-1010 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

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

7. Is Type 2 Diabetes An Epidemic? Little Rock, Cincinnati, San Antonio 35 30 25 20 % with type 2 15 10 5 0 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 136:664-672, 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 Geneticsusceptibility Environmentalfactors Onset ofdiabetes Disability PRE Ongoing hyperglycemia Obesity Insulin resistance Death Risk for Disease Metabolic Syndrome BlindnessRenal failureCHDAmputation RetinopathyNephropathyNeuropathy AtherosclerosisHyperglycemiaHypertension

10. Pre-diabetes (IGT) and T2D

13. OGTT Feasibility StudyPre-diabetes and Diabetes by ADA Cut-offs

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

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

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

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

19. Type 1 Versus type 2 Diabetes in youth? Kaufman,Endocrinol Meta Clinics N Am, 34;659-676: 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 • 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 2Fagot-Campagna et al J Pediatr 2000 • Mean Age 12-14 years • Girls > Boys 1.7:1 • Obese BMI >85th % • Minority Groups 94% • Strong Family History 74-100% • Acanthosis Nigricans 56-92% • Diagnosis made by Symptoms, not Screening • HbA1c 10-13% • Weight loss 19-62% • Glucose in urine 95% • Ketosis 16-79% • DKA 5-10%

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% • Eliminate symptoms of hyperglycemia • Maintenance of reasonable body weight • Improve cardiovascular risk factors • Reduce microvascular complications • Improvement in physical and emotional well-being

25. Question What are the Treatment Regimens for Youth?

26. GLP

27. 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 6:1406-1409.

28. LWPES Survey130 Clinical Practices • 48% treated with insulin alone • 2 injections • 44% with oral agents • 71% metformin • 46% sulfonylurea • 9% TZD • 4% meglitinide • 8% lifestyle

29. A1c at CHLA 2005

30. Intensive Therapy for Diabetes:Reduction in Incidence of Complications 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;329:977-986; Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117; UKPDS 33: Lancet. 1998;352: 837-853; Stratton IM, et al. Brit Med J. 2000;321:405-412.

31. Long term outcome • Pima Indians - diagnosed < 20 years of age • 22% had microalbuminuria at diagnosis • Increased to 60% at 20-29 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: 19-28Dean., Diabetes 2002;51(Suppl 2):A24.

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

33. An Answer The Today Trial?

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

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

36. Primary Outcomes • Treatment goal • 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

37. Outcome Measures • Glycemia • 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

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

39. 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

40. National Diabetes Education Program’s Tip Sheets for Kids with Type 2 • What is Diabetes? • Be Active • Stay at a Healthy Weight • Eat Healthy Foods

41. Helping the Student with Diabetes Succeed

42. 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

43. Thank you Fkaufman@chla.usc.edu