Obesity and Pre-diabetes in Pediatrics David Olson, MD PhD Assistant Professor of Pediatrics University of Michigan Medical School MAPA Fall CME Conference

Obesity and Pre-diabetes in Pediatrics David Olson, MD PhD Assistant Professor of Pediatrics University of Michigan Medical School MAPA Fall CME Conference October 11, 2013

Address the link between obesity, insulin resistance and the development of diabetes Review the pathophysiology of Insulin resistance and T2DM Review the diagnostic criteria for diabetes Explore the treatment options for insulin resistance, pre-diabetes and diabetes in children

Case Presentation HPI: 12 year 6 month old Latino male with a concern about increasing weight gain. He is in good health. PMH: Entirely healthy Meds: none FH: Parents: Father 510, Mother 52: Type 2 DM, HTN, obesity ROS: negative for polyuria, polydipsia Physical Exam: Ht 62, Wt 189.2 lb (85.8 kg), P 90, BP 118/67 BMI 34.6 kg/m2 (>99%ile) Diffuse adiposity Skin: acanthosis nigricans on the neck and in the axillae No thyromegaly Chest clear, no murmur Abdominal exam: unreliable Tanner 3 genitalia

Acanthosis Nigricans

Category Former Terminology Recommended 95 th % Overweight Obese PEDIATRICS Volume 120, Supplement 4, December 2007, p. S167. Body Mass Index (BMI=kg/m 2 ) Categories

Trends in US Childhood Obesity Since 1980, obesity prevalence has nearly tripled to 16.9%, with no difference between 2007-2008 and 2009-2010 for ages 2-19. Racial and ethnic disparities in obesity prevalence: increased in African Americans, Hispanics, American Indians/Alaska Natives. The prevalence of extreme obesity among low income preschoolers: From 2003 through 2010, decreased slightly from 2.22% to 2.07% From 1998 through 2003, increased from 1.75% to 2.22% The prevalence of obesity among low income preschoolers: From 2003 through 2010, decreased slightly from 15.21% to 14.94% From 1998 through 2003, increased from 13.05% to 15.21% Sources: cdc.gov/obesity/childhood/index.html Ogden et al. JAMA 301(5): 483

Prevalence of obesity across racial groups (2009-2010) Children (Age 6-11) Adolescents (Age 12-19) % Prevalence % Prevalence RaceOverwt Obese Overwt Obese Black ( Non-Hispanic ) 42.7 28.6 41.2 23.7 Mexican American 39.0 22.1 43.4 23.9 White ( Non-Hispanic ) 27.613.9 30.0 16.1 Source: Ogden et. al. JAMA. 2012;307:483-490.

Co-morbidities associated with Obesity Stroke Hypertension Vascular disease Hypertension Asthma Cancer Gestational Diabetes Fetal Programming Orthopedic/Arthritis Depression Insulin Resistance Hyperlipidemia Prediabetes Type 2 Diabetes NAFLD

National Diabetes Statistics, 2011 http://diabetes.niddk.nih.gov/dm/pubs/statistics

Cheng, et.al Nat. Review Endocrinol. 8:228-236 (2012) Predicted Burden of Prediabetes and Diabetes

Important Definitions Pre-diabetes Impaired fasting glucose IFG) of 100-125 mg/dl, OR Impaired glucose tolerance (IGT), with plasma glucose of 140-199 mg/dl 2 hours after a standard OGTT (75 grams of glucola) Diabetes (in asymptomatic patients) Fasting venous plasma sugar > 126 mg/dl or, Oral GTT with BG> 200 mg/dL at 2hr (**must be repeated) Metabolic syndrome Combination of abnormalities predisposing individuals to diabetes and cardiovascular disease. Pediatric definitions are debated, incidence increasing Insulin resistance is the principal metabolic abnormality

What is the Metabolic Syndrome? At least 3 of 5 following criteria: Abdominal obesity (> 90 th percentile waist circumference) Elevated blood pressure (>90 th percentile) Fasting glucose > or = 110 mg/dl Fasting triglycerides >/= 110 mg/dl HDL Cholesterol

Links Between Obesity and Insulin Resistance Hyperinsulinemia is critical, risk factors include: Genetically at-risk children Simple carbohydrates in the diet Inactivity Obesity Leads to reduction in fatty acid oxidation and hypertriglyceridemia Triglycerides accumulate in liver and muscle->decreased glucose uptake.

The Path from Insulin Resistance to Pre-diabetes to Type 2 Diabetes 1)Insulin Resistance, normal glucose tolerance 2) Insulin Resistance, increased post-prandial glucose (PPG), decreased first phase insulin release, abnormal GTT(IGT-pre-diabetes) 3) Insulin Resistance, Increased fasting (IFG) and PPG (IFG=pre-diabetes) 4) Diabetes, Insulin Resistance (IR) 5) Diabetes, IR, Severe Insulinopenia Most people with pre-diabetes develop type 2 diabetes within 10 years, unless they lose 5 to 7 percent of their body weight making changes in their diet and level of physical activity. http://diabetes.niddk.nih.gov/DM/pubs/insulinresistance/

DeFronzo RA. Diabetes. 2009;58:773-795

Hyperglycemia results from a combination of: Pancreatic -cell dysfunction with impaired insulin secretion Increased hepatic glucose production due to excessive glucagon Decreased peripheral glucose uptake due to insulin resistance Path to Hyperglycemia and T2DM

Type 2 Diabetes in Children (T2DM)- Rationale for Prevention The pre-diabetic stage is definable and lengthy Clear risk factors Proven interventions successful in adults T2DM is difficult to treat Early complications are common at diagnosis, and likely to occur with time, leading to a huge healthcare burden Insulin deficiency is progressive

*May et al. Pediatrics June 2012; 129(6): 1035-1041 **Today Study Group. NEJM June 14, 2012; 366 (24): 2247-2256 Prevalence of prediabetes and diabetes has increased significantly, despite obesity stabilization (NHANES 1999- 2008*) of adolescents with T2DM fail metformin monotherapy, with rapid deterioration** The Challenge of T2DM in Children This implies a more aggressive disease and a tendency toward more severe insulin deficiency

Does Treatment of Pre-diabetes Prevent T2DM? No studies in children Diabetes Prevention Program-3234 adults with Impaired Glucose Tolerance (NEJM 2002) 58% reduction in T2DM with lifestyle 31% reduction in metformin treated In younger adults, reduction in T2DM in metformin group was similar to lifestyle

Treatment of Adolescents at High Risk for T2DM Lifestyle Change Remains the Cornerstone of Therapy: Exercise: ideal 60 minutes of aerobic exercise daily for all children Limit sedentary activites (TV, computers, video games) Weight loss via calorie restriction. However, weight maintenance in a growing child = decrease in BMI ?? some studies have suggested that a decrease in carbohydrate and/or focus on glycemic index may improve weight loss efforts

Look AHEAD: Action for Health for Diabetes Intensive Lifestyle Intervention in Adult T2DM JAMA (2012) 308: 2489

Treatment of Adolescents at High Risk for T2DM (medications) Metformin (subsequent slides) Others: no data in children for diabetes prevention

The MOCA Trial (Metformin in Obese Children and Adolescents) Prospective, randomized, double-blind, placebo-controlled trial of metformin in 151 obese children and adolescents with hyperinsulinemia and/or impaired fasting glucose or impaired glucose tolerance for 6 months 67.5% females, 65.6% postpubertal, 23.8% Asian or Afro-Caribbean age range 818 years (mean 13.7 (SD 2.3)) mean BMI-SDS was 3.4 (SD 0.5). Metformin dose: 1 g in the AM and 500 mg in the evening Results: Metformin had a beneficial treatment effect over placebo for BMI-SDS (-0.1SD), fasting glucose (-0.16 mmol/l), ALT (-19%), with changes in BMI-SDS sustained at 6 months. J Clin Endocrinol Metab 98: 322329, 2013

Metformin for insulin resistance or pre-diabetes in children Controversial Off label The benefit (extrapolated from adult studies) likely outweighs the risk in motivated patients. General approach: consider metformin (500 mg/day initial, max 1000 mg BID) in motivated patient after lifestyle intervention failure Pre-diabetes (IFG or IGT) Extreme high-risk group (PCOS or strong FHx DM in high-risk ethnic group) Precautions: stop medicine with illness, hypoxia, CHF, dehydration (including contrast agents): theoretical risk of life threatening metabolic acidosis. Check renal function yearly, daily MVI

diabetesmanager.pbworks.com

Arch Pediatr Adolesc Med. 2012;166(8):757-766. Bariatric surgery: Laparoscopic adjustable gastric banding Roux-en-Y gastric bypass Sleeve gastrectomy: Horizontal (C) or vertical (D) resection of the stomach A DC B

Arch Pediatr Adolesc Med. 2012;166(8):757-766.

Screening for T2DM in Children Who? Overweight child (BMI or wt/ht 85-94% ile), PLUS 2 risk factors: 1.Family History of T2DM (1 st or 2 nd degree relative) 2.Hispanic/ African American/ Am Indian, or Asian Pacific Islander 3.Signs of insulin resistance (acanthosis, HTN, dyslipidemia, PCOS) 4.Maternal history of diabetes or GDM during the childs gestation When? At age 10 or younger if pubertal How often? Every 3 years How to screen? Fasting plasma glucose vs. HbA1c vs. Oral GTT. American Diabetes Association. Standards of medical care in diabetes2013. Diabetes Care 2013 Jan; 36 (supplement 1): S14-15

Back to our Patient: What to Do? o Labs: Lipids: yes (universal screening at 9-11 years and 17-21 years- NHLBI Guidelines 2011) Fasting chemistry profile: yes (glucose, LFT-Screen for non alcoholic fatty liver disease) Consider Hemoglobin A1c, OGTT if the FBG is borderline ? TFTs: not needed-normal growth, no symptoms or goiter o Treatment: Diet and exercise intervention Consider metformin if the FBG is abnormal and does not normalize with lifestyle intervention, or if OGTT/A1c are abnormal Frequent (?) visits *PEDIATRICS Volume 120, Supplement 4, December 2007, S177.

AAP: Clinical Practice Guideline Management of Newly Diagnosed Type 2 Diabetes Mellitus in Children and Adolescents Key action statement 1: Clinicians must ensure that insulin therapy is initiated for children and adolescents with T2DM who are ketotic or in DKA and in whom the distinction between T1DM and T2DM is unclear And, insulin therapy should be initiated for patients with random BG >250mg/dL or HbA1c >9%

Key action statement 2: In all other instances, life style modifications should be initiated, including nutrition and physical activity. Metformin should be used as first-line therapy at the time of diagnosis of T2DM. AAP: Clinical Practice Guideline Management of Newly Diagnosed Type 2 Diabetes Mellitus in Children and Adolescents TODAY study: Metformin alone is not usually enough; Metformin + rosiglitazone is better but there are concerns regarding TZDs.

Key action statement 3: Clinicians should monitor HbA1c every 3 months and intensify treatment goals for BG and HbA1c (

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Obesity and Pre-diabetes in Pediatrics David Olson, MD PhD Assistant Professor of Pediatrics University of Michigan Medical School MAPA Fall CME Conference