Objectives. "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 Pediatric Metabolic syndrome is becoming more common Metabolic Syndrome usually becomes apparent first at puberty; must use pediatric-specific criteria in general, but if a component would be considered abnormal in adults, is definitely abnormal in youth Testing for insulin resistance per se is not usually clinically useful Screening for co-morbidities is essential Lifestyle is still the main recommended approach, but this is difficult in families with few resources Risk of Adult Obesity with Childhood Obesity: Prevention must be done before puberty AJCN 70S:145S,1999.

2 Why is Pediatric Obesity Concerning: 40 Year Follow-Up of Overweight Children * CVD HTN DM Death * Study Reference Mossberg HO Lancet 2:491,1989 (8/26) 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 (pediatric BMI percentile calculator Metabolic Syndrome Prevalence Adolescents years (2430 subjects)

3 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: Effect of diabetes and metabolic syndrome on cardiovascular disease Alexander et al. Diabetes 52: , 2003 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

4 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 Screening Obese youth for MS 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, prediabetes, 5.8 diabetes Acanthosis, striae, buffalo hump: nonspecific, seen with obesity CUSHINGS: height growth!!!!!!!!

5 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 Insulin Resistance Testing 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

6 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 between labs, 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 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

7 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 Example Normal IR T2DM T2DM T1DM Glucose Insulin /Insulin G/I HOMA IR

8 TG/HDL 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 May not work in T1D Reaven GM, Nov 2004 Metabolic Syndrome Conference Treatment of IR 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

9 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, chocolate milk, soda machines at school, fast food Lobby Government to increase school funding for exercise, higher quality food 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 Fitness/exercise/activity Life long exercise habits, activities the child likes, family/peer involvement Decreased sedentary activities Electronics, Homework, Vacation, no TV under age 2, no TV in bedrooms, timed passwords for computers Identification of barriers Spandexophobia, Cult of excellence Money, transportation Intrinsic cardiovascular or endothelial defect

10 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 or 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 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 Binge eating, violence depression limits options for interaction outside the family

11 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,?cancer 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

12 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 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 Liraglutide?

13 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 More aggressive with FH early MI like in case Total-C 126 mg/dl Tg 280 mg/dl HDL-C 34 mg/dl LDL-C 118 mg/dl Lifestyle and Fish Oil Case Blood Pressure Goals Goal < 95%ile for age Confirm, echo to rule out coarct, RUS, BUN, Cr to r/o kidney disease, 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 142/88 in case- Ace inhibitor

14 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 NAFLD very common in obese IR youth: AST 55, ALT 142 R/O ETOH abuse (AST predominance), meds First line: lifestyle 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 W/U: 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) Conclusions Comprehensive care of the adolescent with MS 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

15 THE OBESE CHILD 16 y/o boy comes in for a well child check. PMH: obesity Medications: none Social Hx: denies alcohol intake, poor diet, sedentary lifestyle Family Hx: father had an MI in his 50s, mother has GDM while pregnant with him Exam: BP-142/88 BMI-32 THE OBESE CHILD Fasting Labs: Total-C 126 mg/dl Glucose 98 mg/dl Tg 280 mg/dl AST 55 U/L HDL-C 34 mg/dl ALT 142 U/L LDL-C 118 mg/dl

16 THE OBESE CHILD What is a good marker of insulin resistance to assess in this patient? a. Fasting insulin b. HOMA-IR c. Fasting lipid panel d. Acanthosis e. a or b