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Francine Ratner Kaufman, M.D. Distinguished Professor of Pediatrics The Keck School of Medicine of USC Head, Center for Diabetes and Endocrinology Childrens.

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Presentation on theme: "Francine Ratner Kaufman, M.D. Distinguished Professor of Pediatrics The Keck School of Medicine of USC Head, Center for Diabetes and Endocrinology Childrens."— Presentation transcript:

1 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 Type 2 Diabetes in Youth

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

3 Prevalence of Diabetes and IFG in US Adolescents – NHANES 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+ AbFCP < 0.8 ng/ml Type 2- AbFCP > 2.9 ng/ml Hybrid+ AbFCP > 2.9 ng/ml

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 % with type J Pediatr 136: , 2000 Ten-fold increase 0.7 vs 7.2/ % to 43% of all new cases of diabetes in youth in US depending on ethnicity

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 Genetic susceptibility Environmental factors Atherosclerosis Hyperglycemia Hypertension Retinopathy Nephropathy Neuropathy Blindness Renal failure CHD Amputation Onset of diabetes Complications Disability Death Ongoing hyperglycemia PREPRE Obesity Insulin resistance Risk for Disease Metabolic Syndrome

10 Pre-diabetes (IGT) and T2D Overweight SampleIGTT2D Paulsen et al, multi-ethnic youth (4- 16 years) 17%6% Weninger et al, subjects33%0% Sinha et al, multi-ethnic youth (>95 th %ile) 25%0% Sinha et al, multi-ethnic teens (>95 th %ile) 21%4% Goran et al, Hispanic +FH (8-13 years >85 th %ile) 28%0%



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

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

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 Insulin Resistance AgePuberty Type 2 Diabetes Prediabetes Beta Cell Defect ObesityBP, Lipids Lipids Gender – Girls Polycystic ovary syndrome GeneticsEthnicity Sedentary Lifestyle Beta Cell Defect

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

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

19 T1DMT2DM 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 DKA35%-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% - 1 st – 2 nd degree with T2DM ComorbidThyroid, adrenal, vitiligo, celiac Increase in polycystic ovary syndrome Acanthosis nigricans C-peptideC-peptide can be preserved at DXNormal or increased Antibody Ethnicity 85% Whites predominate 15% (reported as high as 30%) NA, AA, HA, Asian, Pacific Islander Type 1 Versus type 2 Diabetes in youth? 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, 1 st degree relative, BMI>24, +C-peptide, acanthosis Type 2Type 1 DKA33%53% C-peptide ug/l ug/l Abs8.1% 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 > Boys1.7:1 Obese BMI >85 th % Minority Groups 94% Strong Family History % Acanthosis Nigricans56-92% Diagnosis made by Symptoms, not Screening HbA1c 10-13% Weight loss 19-62% Glucose in urine95% Ketosis 16-79% DKA5-10%

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 Goals (Diabetes Care, 2000) FG PP Bed A1c <7.0

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 outcomes 1 Lifestyle Coaching Preconception counseling Immunizations Dental care Smoking and alcohol counseling 1. Bradshaw, J Pediatr Endocrinol Meta 15, Pediatrics 112:2003 Prevention and treatment of type 2 diabetes in children with special emphasis on Native American Youth

26 Question What are the Treatment Regimens for Youth?

27 GLP

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

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

31 *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: Intensive Therapy for Diabetes: Reduction in Incidence of Complications T1DM DCCT T2DM Kumamoto T2DM UKPDS A1C 9% 7% 8% 7% Retinopathy63%69%17%–21% Nephropathy54%70%24%–33% Neuropathy60%58%– Cardiovascular disease 41%*52*16%* T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.

32 Long term outcome Arslanian S. Hormone Res 2002; 57 Suppl 1: Dean., Diabetes 2002;51(Suppl 2):A24. 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

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

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

37 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

38 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

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 85 th 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 Programs Tip Sheets for Kids with Type 2 What is Diabetes?What is Diabetes? Be ActiveBe Active Stay at a Healthy WeightStay at a Healthy Weight Eat Healthy FoodsEat Healthy Foods

42 Helping the Student with Diabetes Succeed

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

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