1. Obesity and Type 2 Diabetes in children and adolescents Eva Tsalikian M.D. Stead family Department of Pediatrics Pediatric Endocrinology and Diabetes April 16, 2014

2. Obesity and Type 2 Diabetes in children and adolescents: outline Epidemiology and definitions Pathophysiology of Type 2 diabetes Obesity leading to metabolic syndrome and Type 2 diabetes Treatment of Type 2 Diabetes in children and adolescents Case presentations

4. Rates of Overweight and Obese Children 20052007

5. The problem in children and adolescents Approximately 17% (or 12.5 million) of children and adolescents aged 2—19 years are obese. In 2011-2012, 8.4% of 2- to 5-year-olds were obese compared with 17.7% of 6- to 11-year-olds and 20.5% of 12- to 19-year-olds. The prevalence of obesity among children aged 2 to 5 years decreased significantly from 13.9% in 2003-2004 to 8.4% in 2011-2012.

6. Identification Children (Ages 6 to 11) Prevalence (%) Adolescents (Ages 12 to 19) Prevalence (%) RaceOverweightObesityOverweightObesity Black (Non-Hispanic)35.919.540.423.6 Mexican American39.323.743.823.4 White (Non-Hispanic)26.211.826.512.7 Source: CDC, National Center for Health Statistics, National Health and Nutrition Examination Survey. Ogden et. al. JAMA. 2002;288:1728-1732.

7. Why is this a problem? Overweight children become overweight adults Risk for diabetes, cardiovascular disease and many other chronic diseases Before becoming adults: Psychological and self image problems Medical problems: hypertension, dyslipidemia, diabetes

8. DIABETES : IN CHILDREN AND ADOLESCENTS HISTORICALLY Type 1 Diabetes Prevalence 1 in 500 TYPE 1 DIABETES 95-98% OTHER TYPES OF DIABETES 2-5%

9. TYPE 2 DIABETES DEFINITION Syndrome associated with obesity, hypertension and cardiovascular disease Characterized by both peripheral resistance to insulin action and insulin secretory defects Historically rare in children and adolescents, incidence has been increasing recently

10. DIAGNOSIS OF DIABETES World Health Organization and American Diabetes Association Fasting blood glucose 126 mg/dL Post prandial glucose >200mg/dL Oral glucose Tolerance test not always necessary Elevated HgA1c

12. Type 2 Diabetes Risk Factors and Testing Criteria Who to screen? Overweight (BMI >85th percentile for age and gender; weight for height >85th percentile; or weight >120 percent of ideal for height PLUS Any two of the following risk factors --family history of type 2 diabetes in first- or second-degree relative --race/ethnicity – American Indian, African American, Hispanic/Latino, Asian American, or Pacific Islander --signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovarian syndrome, or small-for-gestational-age birth weight) -- maternal history of diabetes or GDM during the child’s gestation

13. When and how to screen Age to begin testing – 10 years old or at onset of puberty if puberty occurs earlier Frequency of testing – every 3 years Tests to use – fasting plasma glucose, A1C, 2-h oral glucose tolerance test Clinical judgment should be used to perform testing in children and adolescents who do not meet the above criteria.

14. Type 2 diabetes in children : World wide phenomenon

15. TYPE 2 DIABETES PATHOPHYSIOLOGY Failure of insulin secretion to compensate for insulin resistance associated with obesity, in most cases Evidence of both genetically limited beta-cell reserve and heritable insulin resistance In Adolescents Pubertal insulin resistance compounded by obesity results in type 2 diabetes Polycystic ovarian syndrome (PCOS) in adolescent females

16. Case presentation 11 year old boy was referred because father, who was recently diagnosed with Type 2 Diabetes, noted similar symptoms in son i.e. Polyuria, polydipsia, nocturia. Twelve lbs weight loss was noted. Child is overweight, no other abnormal findings. Fasting blood sugar 124 mg/dl. OGTT did not meet criteria for diagnosis of diabetes. Hg A1c 6% (4.2-6%)

17. Physical characteristics in children and adolescents with diabetes

18. BMI in New onset Type 2 Diabetes

19. Why Are They Obese? Endocrine disorders – Hypothyroidism – Glucocorticoid excess (iatrogenic or endogenous) – Growth hormone deficiency – All cause linear growth failure associated with short stature Genetic syndromes – Prader-Willi – Bardet-Biedl (mental retardation, hypogonadism, polydactyly, retinitis pigmentosa) – Albright’s hereditary osteodystrophy (short stature, short fourth metacarpal, mental retardation, hypocalcemia) Exogenous – usually tall above the 75th - 95th %ile – usually familial

20. Exogenous Obesity Nature versus Nurture – Appetite – Efficient metabolism – Decreased exercise – Altered body image

21. What Can We Do About Childhood Obesity? Identify medical risk factors – Blood pressure – Cholesterol levels – Sleep apnea – Diabetes Identify and treat medical causes. – Hypothyroidism, Cushing’s syndrome – Prader-Willi Syndrome

22. Prevention Lifestyle changes: Decreased caloric intake and increased physical activity extremely challenging Pharmacologic intervention to reduce weight is not yet deemed appropriate for children

23. Case Presentation Obese 11y old w boy, no symptoms Distant family history of type 2 Diabetes Fasting and random blood glucose within normal limits HgA1c 5.9% (4.2-6%) Serum insulin 687uIU/ml (5-20uIU/ml)

24. Relationship between Insulin resistance, metabolic syndrome and Diabetes Insulin resistance Hyperinsulinemia Inadequate Insulin secretion Metabolic syndrome Type 2 Diabetes

25. When should we intervene? Size of population Prevention of weight gain Overweight and obesity Insulin resistance Metabolic syndrome IGT Diabetes Hypertension Hyperlipidemia

26. Click on image to view larger version. Effects of metformin on fasting glucose and insulin levels in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes mellitus. Freemark, M et al JCEM, 88(1):3

27. TYPICAL CASE PRESENTATION 15 yr old w boy seen for routine sports physical: Asymptomatic UA: +glucose and ketones HISTORY of nocturia x1 for the last 2-6mo and 11 lbs wt loss FAMILY HISTORY positive for Type 2 Diabetes in maternal grandfather PE : HT 75th % WT >>95th % BP130/68

28. TYPICAL CASE PRESENTATION (continued) Fasting blood sugars locally on three different mornings : 208, 140, 153 mg/dl HgA1c 6.6% (4.5-6%) Fasting glucose, Insulin, c-peptide No autoimmune markers Diagnosis : Type 2 Diabetes Therapeutic Plan: Diet and Exercise Blood glucose monitoring

29. Treatment of children and adolescents with type 2 diabetes Goals of treatment are weight loss, normoglycemia and normal HgA1c. Young age at onset of type 2 diabetes means longer duration and thus more microvascular and macrovascular complications: Grave public health implications. 33% will have ketosis and 10% ketoacidosis: require insulin

30. Therapeutic options in children and adolescents with Type 2 diabetes Weight control through diet and exercise Oral hypoglycemic agents Insulin

31. TYPICAL CASE PRESENTATION (continued) 3 month follow up: Wt loss, HgA1c Further Follow up : Wt gain, HgA1c Hypoglycemic agents

32. TODAY Study 15 clinical centers funded by NIDDK 699 adolescents with Type 2 diabetes Participants randomized 1:1:1 to (i) metformin alone (ii) metformin plus rosiglitazone (iii) metformin plus an intensive lifestyle intervention called the TODAY Lifestyle Program (TLP)

33. TODAY Study

34. Effects of Metformin, Metformin Plus Rosiglitazone, and Metformin Plus Lifestyle on Insulin Sensitivity

40. Prevalence of Hypertension

41. In Summary: Testing children and adolescents for type 2 diabetes Criteria Overweight (BMI >85% for age and sex) Risk factors (any two) Family history of type 2 diabetes, Race/ ethnicity, Signs of insulin resistance: Acanthosis Nigricans, Hypertension, dyslipidemia, PCOS Age of initiation: 10 years of age Frequency: every 2-3 years Test: FPG preferred

42. In Summary: Approach to Treatment Prevention of type 2 diabetes needs to start at young ages Diet and exercise interventions should be started early in high risk individuals Delaying the onset of type 2 diabetes may also be a significant benefit Therapy might need to be individualized (e.g. boys better with Lifestyle +metformin, girls metformin +TZD, NHB vs Hispanics) Polypharmacy may be required

43. In Summary: Treatment of Type 2 diabetes in children Nonpharmacologic Rx (weight control, activity) Monotherapy Metformin Combination therapy Metformin, Rosiglitazone Severe hyperglycemia very symptomatic ketosis autoimmune markers Insulin + Metformin

44. Thank you!!!