Objectives. Pediatric Definitions. "Insulin Resistance Disorders in Children: Obesity, Metabolic Syndrome (MetS), and Type 2 Diabetes (T2D)

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1 "Insulin Resistance Disorders in Children: Obesity, Metabolic Syndrome (MetS), and Type 2 Diabetes (T2D) Kristen Nadeau MD University of Colorado Denver Objectives Describe the pathophysiology of insulin resistance (IR) and identify the factors associated with the epidemic of T2D and MetS in children and adolescents. Describe the approach to screening and diagnosis of T2D and MetS. Discuss alternative approaches to the treatment of IR related disorders. Pediatric Definitions BMI= kg/m2 Obese = BMI>95% Overweight = BMI>85% Requires BMI charts (pediatric BMI percentile calculator available on CDC website

2 Pediatric Obesity is Common: Prevalence of Obesity in U.S. Youth yr yr * Gender & age specific BMI > 95 th percentile [Ogden et al, JAMA 01/10] Ethnic Minority Youth are at Higher Risk for Severe Obesity [Ogden et al, JAMA, 2010] Risk of Adult Obesity with Childhood Obesity: Prevention must be done before puberty AJCN 70S:145S,1999.

3 Why is Pediatric Obesity Concerning: 40 Year Follow-Up of Overweight Children 30 * CVD HTN DM Death * Study Reference Mossberg HO Lancet 2:491,1989 (8/26) What Does Insulin Resistance (IR) Mean? Insulin Tissue Level (Fed state, Storage) Muscle: glucose uptake, glycogen storage Liver: glycogen storage, blocks gluconegenesis, glycogenolysis and ketogenesis Adipose: storage (blocks lipolysis) Beta Cell: increased insulin output Brain: decreases appetite (fed state) Vessels: Smooth muscle quiescence

4 Tissue Level (acts like fasting) Muscle: decreased glucose uptake»hyperglycemia Liver: increased gluconegenesis, glycogenolysis»hyperglycemia and ketogenesis»dka Adipose: increased lipolysis»high TG s Beta Cell: decreased insulin output Brain: Increased appetite Vessels: Smooth muscle proliferation»cvd All Tissues are not IR: Potential Excess Insulin Effects Ovary: increased androgen production, anovluation Kidney: salt and water retention Skin: acanthosis, skin tags (?cross reactivity with IGF s) Muscle and Liver: lipid accumulation Why care about IR more than Obesity Alone? Obesity worsens IR, but obesity not=ir BMI or waist circ vs IR r=0.6 At any given BMI, if IR TG s 2x higher, HDL 10x lower, Insulin 3x higher If IS and obese, fewer risk factors so weight loss doesn t impact, NNT too high with obesity alone Hypertensive and IS, no more CVD than normotensive

5 Causes of Insulin Resistance IR Syndromes Leprechaunism: IUGR, fasting hypogly (no glycogen), die by 1 Rabson-Mendenhall: similar, abnl teeth and nails, pineal hyperplasia Type A IR: Insulin receptor defect Type B IR: Anti-insulin receptor antibodies Lipodystrophy: (no adipocyte depot) Metabolic Syndrome (mixed bag) Our Obesity promoting Culture Dietary changes fast food snacking high caloric density cheap increased portion size Cultural changes never hungry advertising assault energy saving automobiles vs. pedestrians Activity Changes decreased school PE time decreased play time at home expense and transportation problems associated with sports emphasis on excellence lack of supervision Increased Sedentary Time computers video games 64 channel TV lack of supervision

6 Metabolic Syndrome: Clustering of IR-related risk factors, increase risk of CVD, T2D, Mortality, IR Related Disorders Criterion Adults Adolescents (Modified ATP3 Criteria) Triglycerides 150 mg/dl 110 mg/dl HDL Males <40 mg/dl Females < 50 mg/dl Abdominal Obesity Glucose WC Males > 102 cm Females > 88 cm Fasting 100 mg/dl 2 hour 140 mg/dl 40 mg/dl BMI or WC 90 th %ile for age Fasting 100 mg/dl 2 hour 140 mg/dl Blood pressure 130/85 90 th %ile for age modified Cook et al, Arch Pediatr Adolesc Med 157:821, 2003 Metabolic Syndrome Criteria as a Screening Tool 1-2 MS criteria N = MS criteria N = 47 P value BMI NS IGT 0/36 (0%) 10/47 (21%).004* GGT > 55 1/34 (3%) 9/43 (21%).036* ALT > 40 8/21 (39%) 19/30 (63%).08 Hepatic steatosis on US 8/17 (47%) 19/20 (95%).001* Love-Osborne et al, unpublished data Mortality Associated With Metabolic Syndrome Mortality (% of patients) POWERSEARCH PLUG-IN 2.0 Copyright Accent Graphics, Inc. All-cause mortality* CVD mortality* CHD mortality* *Adjusted for known CHD risk Slide Number: factors PPS 3 Metabolic syndrome No metabolic syndrome Slide Source: "R:\NDEI-2\2004 Grant\T108\ARS\T095 ARS Case 2 FINAL-Baton Rouge ppt" <OPEN> Last Modified: December 9, :17:25 PM Lakka H - M et al. JAMA. 2002;288:

7 Effect of diabetes and metabolic syndrome on cardiovascular disease Alexander et al. Diabetes 52: , 2003 Metabolic Syndrome Prevalence Adults Duncan et al, Diabetes Care 27: 2438, 2004 Metabolic Syndrome Prevalence Adolescents years (2430 subjects)

8 Differences between Adult and Youth Metabolic Syndrome/T2D More severe lifestyle abnormality (age should be protective)- More obese and sedentary, Psychiatric challenges common Insulin resistance of puberty: Potential for improvement with time Adolescents live in families Onset prior to child bearing: GDM is strong predictor of early onset T2D in offspring A Central Role for Central Obesity in Insulin Resistance Intra-abdominal Fat Waist Circumference 87% of youth (6-13) w/ BMI > 95% had WC > 90% 28% of BMI 85-95% had WC > 90% Message: measure WC in overweight to ID higher risk for MS co-morbidities Chart for 90% for age, race and sex Fernandez JR 2004 J Peds 145(4):439 Hirschler et al, Arch Ped Adol Med 2005; 159:740

9 Screening Obese youth for MS Not just for diabetes! HTN (manual BP w/ large adult or thigh cuff) Non-alcoholic fatty liver (NAFLD)-ALT, AST Dyslipidemia (fasting lipids) Hyperandrogenism (PCOS) in girls Sleep apnea Gallbladder disease Depression and other psychiatric, eating d/o QOL lower in MetS Youth with higher BMI, more MetS Criteria, Non-Hipanic white and girls Diabetes New Criteria HbA1c <5.8 normal, pre-diabetes, 5.8 diabetes Charts to determine 90% blood pressure for age, sex and height: Go to blood pressure tables LFTs in Type 2 Diabetic Children AST Mean 45, max 214, min 10, #37 SD 39 ALT Mean 71, max 357, min 8, #37 SD 71 Characteristics of Adolescents with T2DM (from various series) Most are minority (AA, AI, H) Female:Male ratio = Mean age: 13 years > 80% history of T2D in a first degree relative or GDM Obese (Average BMI > 30) > 60% have acanthosis nigricans Frequent co morbidity hypertension, elevated lipids, sleep apnea, fatty liver disease, PCOS Frequent pre-existing psychiatric medications

10 The Type 2 Family 45% of mothers and 40% of fathers with T2DM 27% both parents with T2DM 50% of the remaining fathers diagnosed with T2DM in the study Parents have poor DM control mothers A1c: 13.4 ± 1.6 % Mothers, fathers AND siblings obese The Type 2 Family Diet high in fat, low in fiber Doesn t make a a difference if mother has T2DM Binge Eating prevalent No routine exercise Most with no activity whatsoever 3-5 hours/day TV Insulin resistance prevalent among unaffected family members Insulin Resistance Testing

11 Hyperinsulinemic Euglycemic Clamp Gold Standard Directly measures metabolic actions of insulin under steady state conditions Concept: Clamp off pancreas, infuse fixed dose of insulin and see how much dextrose required to keep glucose constant The more dextrose required, the more IS you are (M) FSIVGTT (Si) and variations Fasting Insulin Obese 8-16 yo r= with Si (Conwell Diabetes Care 2004) Prepubertal girls with premature adrenarche r=0.75 with Si (Vuguin JCEM ) Problem- insulin assay variable, often not really fasting Falls apart if insulin secretion defect FGIR Fasting glucose/fasting insulin Obese 8-16 yo r= with Si (Conwell Diabetes Care 2004) Prepubertal girls with premature adrenarche r=0.76 with Si (Vuguin JCEM ) Falls apart if insulin secretion defect or high glucose

12 HOMA IR HOMA IR: fasting insulin x fasting glucose /22.5 insulin in microunits/ml, glucose in millimoles/l Ideal=1 (normal weight adult under 35); higher =IR Computer based model sss.dtu.ox.ac.uk/homa Obese 8-18yo, r=-0.57 w/m (Caprio JCEM March 2004); Obese 8-16yo r= w/si (Conwell Diabetes Care 2004) Obese/nl 6-12yo, r= to 0.56 w/m (Uwaifo) Problem if low insulin secretion QUICKI 1/log 10 [fasting glucose] + [log 10 [fasting insulin] 1/log 10 [fasting glucose] + [log 10 [fasting insulin] Insulin in microunits/ml, glucose in mg/dl Obese 8-16 yo r= with Si (Conwell Diabetes Care 2004) Obese/nl 6-12yo r= to 0.69 w/m (Uwaifo) Problem if low insulin secretion WBISI Whole body insulin sensitivity index from OGTT (Matsuda and DeFronzo in adults Diabetes Care 22, 1999) Insulin in microunits/ml, glucose in mg/dl WBISI=10,000/sqrt(fasting glucose x fasting insulin/mean glucose x mean insulin) Obese kids best corr with clamp of OGTT IR tests, r = 0.78 (by Caprio JCEM March 2004) and r=-0.74 w/ IMCL

13 Example Normal IR T2DM T2DM T1DM Glucose Insulin /Insulin G/I HOMA IR HDL/TG ratio Correlations with IR (r): LDL 0.18, non HDL 0.35, HDL 0.4, TG 0.57 TG/HDL r=0.6, better assay than insulin and gives lipid info too TG/HDL >3, only 3% are insulin sensitive Reaven GM, Nov 2004 Metabolic Syndrome Conference May not work in T1D Treatment of IR

14 Intervention Prevention is ideal Target overweight parents before/during pregnancy Reinforce healthy eating at well child checks Limit juice (4 oz/day), bottle at 12 mo Encourage family physical activity Limit Screen Time No TV under age 2, get TV s out of bedrooms! Weight Management Cessation of weight gain with linear growth or achieve and maintain BMI < 95%ile (? 85%ile) for age 5-10% sufficient to improve metabolic profile Small changes Monitor/log Set realistic goals not ideal body weight Diet

15 Fitness/exercise/activity Increased routine physical activity, life long exercise habits, activities the child likes, family/ peer involvement Decreased sedentary activities Electronics, Homework, Vacations Identification of barriers Spandexophobia, Cult of excellence Money, transportation Intrinsic cardiovascular and/or endothelial defect Effects of Exercise Training effect requires change in body composition over time Decreases BP, TG, T Chol, crp, variable on HDL (better if w/wt loss) Minimal wt loss unless one hour at 50% VO 2 Max 5x week Helps maintain wt loss Teen Readiness for change Ask how would you rate your diet/exercise 1-10? What keeps it from being a 10? How interested are you in changing this behavior? (1-10) Focus on the problems they identify rather than nagging

16 Specific Psychological barriers Psychiatric challenges common and critical to lifestyle change Depression common in obese children, females>males Severe psychiatric diagnoses (15-25%) Medication-induced obesity Domestic violence/sexual abuse as inciting factors Binge eating in patient and/or family members General adolescent issues Search for independence will limit ability of family to motivate resistance to outside advice, including from team Peer pressure pressure to conform with lifestyle habits of peers outside influences on self-image and selfesteem are potent Social isolation common in obese and type 2 adolescents limits options for interaction outside the family Metformin Mechanism of action suppression of HGO Secondary decrease in insulin levels May have peripheral effects? Well-studied in adults and children effective, safe, and (relatively) inexpensive Approved for pediatric use in diabetes Slight weight loss Mild improvement in lipids Improvement in menstrual irregularities/hirsutism Improvement in hepatic steatosis

17 Metformin and Prediabetes/ Metabolic syndrome Not a weight-loss medication May delay onset of diabetes in patients with IGT Not yet studied in adolescents What is the treatment target? Appropriate for patients with PCOS Fatty liver disease? Weight Loss Meds: orlistat (Xenical) Blocks 1/3 of fat uptake, lowers lipids 120 mg t.i.d dosing (skip if skip meal) Side effects oily stools, incontinence, need vitamins ADEK Recent OTC approval; $120/mo Study of 539 teens: 26% with a 5% BMI decrease; intense lifestyle piece Those losing weight in the first 12 weeks had the best results Chanoine et al JAMA 2005; 293:2873 Weight Loss Meds: sibutramine (Meridia) Serotonin and norepi reuptake inhibitor related to fenfluramine; 10-15mg qd 1 year of sibutramine 10 mg vs. placebo and behavioral therapy in 498 teens dose increased to 15 mg at 6 months if BMI not decreased by 10% BMI decreased by 3.1 kg/m2 in sibutramine,.3 in placebo. Improved TG, HDL and insulin (but not glucose, TC or LDL) SE s: tachycardia, BP, HA, dry mouth, insomnia Expensive ($ /mo), not covered by insurance Berkowitz et al; Annals IM :81-90

18 Weight Loss Meds: phentermine (Adipex) Stimulant, increases norepi (related to amphetamine) 5-8% weight loss Only approved for 3 month use Side effects: HTN, tachycardia, insomnia Less expensive ($22-32/mo) Some have used dexedrine 5-10mg TID 30 min before meals or 5-15mg ER; HTN, tachycardia, dependency, psychosis, insomnia, tics, etc Other Weight Loss Meds bupropion (Wellbutrin, Xyban): Good choice if need an antidepressant or smoking cessation, not worth it alone (HTN, tachycardia, sucidality, etc) Octreotide: decreases GH and causes gallstones accomplia (Rimonibant):Cannabanoid antagonist; 5-8% weight loss, 5-20mg (Nausea at 20mg), increase in anxiety and depression fluoxetine (Prozac): need 3 x the dose (60mg) compared with depression (10-20mg) therefore unclear if safe, and lose effect over first year; >$300/month Topamax or zonisamide- severe neurologic SE, >$300/ month Lipid Goals LDL < 160 mg/dl (< 130 with other risk factors or < 100 with DM) LDL > goal: diet therapy (7% sat fat, < 200 mg chol) LDL > 160 mg/dl: Statin; titrate to < 90 th percentile TG < 150 mg/dl fasting TG > 400, statin/fibrate to avoid postprandial > 1000 mg/dl, fish oil for range HDL > 35 mg/dl

19 Blood Pressure Goals Goal < 95%ile for age Consider pharmacologic therapy if > 95%ile AND No improvement with lifestyle modification ACE or ARB first line drug Titrate ACE until BP < 90 th %ile Charts to determine 90% blood pressure for age, sex and height: Go to blood pressure tables PCOS and Hyperandrogenism Metformin first line Oral Contraceptive pills help with androgens and regulate periods but adverse CV effects- thus add on or use second line- Ovcon or Orthocyclen Spironolactone Watch girls with premature adrendarche Hepatocellular work-up R/O ETOH abuse, meds ft4/tsh, PT, HepC Ab, HepB SAg, Fe, TIBC, ferritin (hemochromatosis) Less commonly ceruloplasmin, and serum copper(wilson s) ANA, anti-sm ab, anti LKM ab, (autoimmune hepatitis), alpha-1 anittrypsin phenotype, antimitochondrial ab (primary biliary cirrhosis) Refer to GI Refer to GI if initial ALT>200 or predominately abnl GGT,AP and bili, (cholestasis or infiltration) or if 6 months of exercise/5% wt loss doesn t improve at s

20 Conclusions Comprehensive care of the adolescent with MS or Type 2 diabetes requires management of Traditional targets Glycemia lipids blood pressure weight Adolescent targets barriers to exercise, activity, and diet change social pressures enabling family behavior Stage-specific developmental challenges psychiatric and psychological challenges