Type 2 Diabetes Mellitus and Insulin resistance syndrome in Children

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1 Type 2 Diabetes Mellitus and Insulin resistance syndrome in Children Anil R Kumar MD Pediatric Endocrinology MCV/VCU, Richmond VA Introduction Type 2 diabetes mellitus (T2 DM) has increased in children since 1990s. This rise is linked to rise in childhood obesity. It is important for us to understand pathogenesis, comorbidities and complications of T2 DM. Get familiar with diagnosing and treating this condition. Why Type 2 diabetes in children? Linked to rise In obesity in children T2 DM in Children and Adolescents - An Epidemic 1994: 16% of new cases - urban areas 1999: 8-45% of all new cases 2001: % all new cases Pinhas-Hamiel,96; Scott,97; Neufeld,98; Hale,98; Willi,98; Langher,98 Epidemiology of T2 DM in Children The rise in T2 DM is occurring worldwide. In US (Cincinnati), T2 DM in children between years rose from 0.7 (1982) to 7.2 (1994) cases per 100, 000. Increased incidence of T2 DM has been reported from Asia, Africa, Australia and Europe. Pathophysiology of T2 DM Glucose is in a tight range in fasting as well as in fed state. This delicate balance is maintained between insulin secretion (pancreas) and insulin sensitivity (uptake from muscle, liver and adipose tissue).

2 Pathophysiology of T2DM Insulin sensitivity Insulin secretion lipogenesis Pathophysiology of T2 DM Product of insulin secretion and sensitivity: Glucose disposition index (GDI): GDI is a accurate reflection of pancreatic beta cell function. Glycogenesis/ prevent gluconeogenesis Glucose uptake Pathophysiology of T2DM Insulin resistance FFA Resistin/TNF/IL6 FFA Beta cell dysfunction No compensation Insulin resistance Compensated Hyperinsulinemia Hyperglycemia GLUCONEOGENESIS Euglycemia IGT/ Type 2 diabetes DECREASE GLUCOSE UPTAKE IGT: impaired glucose tolerance/ prediabetes Insulin secretion increase to maintain euglycemia Pathophysiology of T2DM Lipid abnormalities in insulin resistance Impaired insulin resistance with compensatory hyperinsulinemia is the earliest abnormality. FFA Insulin resistance This hyperinsulinemia can cause metabolic changes even well before patient develops diabetes (PCOS, lipid abnormalities and hypertension) FFA Small Dense LDL More Atherogenic. 3.6 fold CAD Triglyceride LOW HDL

3 Pediatric studies INSULIN RESISTANCE AND HIGH BLOOD PRESSURE Bogalusa Heart study: 4136 subjects, 5-30 years: measured BMI insulin levels, lipid levels. Strong correlation insulin levels l with lipoprotein was observed in obese than lean subjects. Salomaa et al demonstrated that increased fasting insulin levels predict arterial stiffness Liao et al demonstrated that increased arterial stiffness was associated with development of hypertension. Pediatric studies Bogalusa Heart study Fasting insulin significantly correlated with systolic BP after controlling for glucose levels, BMI, skin fold thickness. Prediabetic state Hyperinsulinemia and insulin resistance lead to development of lipid abnormalities and hypertension. Patients may have well compensated high insulin secretion to maintain euglycemia. Thus Prediabetic state carries increase cardiovascular morbidity. Pre-Diabetes Impaired Fasting Glucose (IFG): FPG > 100 and <125 mg/dl Impaired Glucose Tolerance (IGT): 2h PG > 140 and <200 mg/dl Intermediate between normal glucose homeostasis and diabetes Increased risk for Type 2 diabetes Higher morbidity / mortality Pathophysiology of T2DM Factors affecting GDI i.e. insulin sensitivity and insulin secretion. Risk factors for T2 DM

4 Family History of T2 DM Family History of T2 DM Ethnicity 40-80% of adolescents with T2DM have at least one affected parent. Offspring risk: 40%-- 1 parent 60%--- both parents RISK FACTORS T2DM RISK FACTORS T2DM Obesity & Sedentary Life Style Insulin resistance phenotype Ethnicity Obesity & Sedentary Life Style RISK FACTORS T2DM RISK FACTORS T2DM Pima Indian adolescents: 51/ 1000 North America: 4.5/1000 African Americans Hispanics Asiansi Obesity in particular abdominal obesity Increases insulin resistance Identify the risk factors RISK FACTORS T2DM Insulin resistance phenotype Puberty: insulin sensitivity decrease by 30% (GH/ IGF1). PCOS Acanthosis nigricans IUGR Exposure to Gestational diabetes 12 year old obese, African American girl in mid puberty, with family history of diabetes presenting with dark circles around the neck. Obese Race: African American Family history Puberty Acanthosis nigricans

5 Who Should be Screened for T2 DM BMI > 85th% Plus any 2 other risk factors First or Second Degree Relative High risk ethnic group Gestation diabetes during child s gestation Signs of Insulin Resistance Acanthosis, HTN, PCOS, Dyslipidemia Start from age 10 / onset of puberty What should be screened? FPG preferred 2 hour post prandial A1c DIAGNOSIS OF DIABETES Symptoms of diabetes plus casual plasma glucose concentration 200 mg/dl. OR Fasting blood glucose (FPG) 126 mg/dl. OR 2-Hour plasma glucose 200 mg/dl during an Oral Glucose Tolerance Test (OGTT). OR Hemoglobin A1c >/= 6.5% Results should be confirmed on subsequent day ADA, 2003, Clinical Practice Recommendations Follow up screening Prevention and treatment Normal values : repeat every 3 years unless clinical suspicion. Intermediate values: Prediabetes: FBS: mg/dl IGT: mg/dl Hemoglobin A1c: % You can do OGTT if still in Prediabetes range repeat annually or depending on clinical course.

6 Why obesity and T2 DM in children? Link to Family Culture School Lifestyle TV Watching and Obesity Less sports participation More TV viewing Number of TV s in home Meal eating with TV TV in child s room >2 hrs / day increases risk of obesity Sebe, et al. Pediatrics, 2002; Saelens, et al. Dev Behav Pediatr, s $6 billion spent on fast food 1000 McDonalds 2000s $100 billion on fast food 23,000 McDonalds This year Americans will spend more on fast food than on higher education percent of high school students Enrollment: daily PE Surgeon General's Report on Physical Activity and Health, 1996 Annual U.S. Soft Drink Consumption 12-ounce cans per person/year Treatment goals diabetes Why keep Blood Glucose normal?

7 IMPACT OF GLYCEMIC CONTROL DCCT Kumamo UKPDS to Retinopathy 63 % 69 % Nephropathy 54 % 70 % Neuropathy 60 % Microvascular 25 % 12 % Any DM Complication Treatment options: non-pharmacologic Family involvement Diabetes education Nutrition Increase physical Activity Decrease sedentary activities Prevention Family Meals TV time Supervision Advocacy Educating children Prevention Society s role Legislation and schools Schools PE Home economics Nutrition education Cafeterias Safe play environments Business: wellness programs Diet and Exercise remain the corner stone for treatment of diabetes and also to improve insulin resistance.

8 Diabetes Prevention Program (DPP) Diabetes Prevention Program (DPP) 3234 adults with pre-diabetes (IGT) Can Type 2 be prevented or delayed? Study groups Intensive lifestyle l changes Standard diet with metformin Standard diet with placebo Decreased risk of diabetes dabetes Intensive 58 % lifestyle Metformin 31 % Knowler, W. et al. NEJM Feb 7; 346(6): Knowler, W. et al. NEJM Feb 7; 346(6): Treatment options: medications Metformin Insulin Secretagogues Sulfonylureas Meglitinides Insulin sensitizers Biguanides Glitazones Other Alpha glucosidase inhibitors Decrease glucose production Advantage: No weight gain No hypoglycemia Monitor liver and kidney functions?increase insulin sensitivity Disadvantage Decreased tolerance Lactic acidosis: rare Sulfonylureas Insulin Secretagogues Cause hypoglycemia Weight gain Insulin Started initially with high Hemoglobin A1c at diagnosis Follow up patients in poor glycemic control. No effect on insulin sensitivity

9 Thiazolidinediones Type 2: a progressive disease In type 2 diabetes there is combination of Insulin resistance and beta cell dysfunction. Beta cell dysfunction is progressive leading ultimately to total beta cell failure. Median Hb ba 1c (%) % 6.6% 8.4% 7.5% 8.7% 8.1% Conventional Intensive Years From Randomization UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352: UKPDS: Progressive Decline of β-cell Function Thiazolidinediones ction (% β) β-cell Func % decline per year We need a drug that will improve insulin sensitivity and also preserve beta cell function Years UK Prospective Diabetes Study (UKPDS) Group. Diabetes. 1995;44: Thiazolidinediones Thiazolidinediones acts through PPAR gamma receptors and helps insulin sensitivity. Thiazolidinediones when used early has shown to : improve insulin sensitivity glucose lowering effect preserve beta cell function NIH have started clinical trail to recruit patients with type 2 diabetes using these medications. (TODAY) We have already obesity program running

10 Metabolic Syndrome 47 Million Prediabetes 16 Million Obesity 39 Million Diabetes 17 Million Diabetes: Only Part of the Problem The phenotype of survival genes in an environment of plenitude JAMA, January 16, 2002 Vol. 287 (3) JAMA, September 12, 2001 Vol. 286 (10) Summary Increase In Type 2 Population In Pediatrics Risk Factors for Insulin Resistance -Role of Obesity Relative B Cell Failure - Lipotoxicity Different from Type 1 and from adults at Onset Treatment Need Guidelines Must address comorbidities Prevention A Public Health and Family Issue THANK YOU ANY?