Insulin Resistance and Type 2 Diabetes in Children

Brandon Nathan, MDAssistant Professor

Disclosures

• I have no relevant financial relationships with the manufacturers of any commercial products and/or provider of commercial services discussed in this CME activity.

• I do intend to discuss an unapproved/investigative use of a commercial product/device in my presentation.– Thiazolidenedione and GLP-1 agonist classes

of pharmaceuticals in pediatric type 2 diabetes

Objectives1. Recall the relative differences in prevalence rates

for type 1 vs. type 2 diabetes among children of different ethnic backgrounds in the United States

2. Discuss the risk factors that lead to the development of type 2 diabetes in children

3. List the appropriate diagnostic tests to screen an at risk child for type 2 diabetes and the associated metabolic co morbidities of insulin resistance/obesity.

Diabetes Etiology: Insulin Supply, Secretion, Demand

Normal Type 2Pre-type 2Type 1

Slide courtesy of Toni Moran, MD

Acanthosis Nigricans: A Sign of Insulin Resistance

Criteria for the Diagnosis of Diabetes

Test Criteria (x2) Fasting plasma glucose ≥ 126 mg/dl

Casual glucose ≥ 200 mg/dl with symptoms

Hemoglobin A1c ≥ 6.5%

or

or

Prediabetes: HbA1c 5.7-6.4% IFG: impaired fasting glucose (Fasting

glucose 100-125) IGT: impaired glucose tolerance (2 hr

glucose reading of 140-199 on OGTT)

The Trend in Diabetes is Alarming

• 25.8 million people in the US have diabetes (8.3% of population)– Additional 79 million have prediabetes

• Overall risk of death twice that of people without diabetes of similar age

• Leading cause of blindness, end stage renal disease, non-traumatic leg amputation

• 2-4 fold increased risk for cardiovascular disease

• Estimated costs in 2007: $174 billion

• 1 in 3 children born in the US in 2000 will develop diabetes (CDC) – 50% of African American and Latino children may develop

T2DM

Rates of New Cases of Diabetes in US from 2002-2005

Mayer-Davis EJ, et.al. Diabetes Care, 2009

Is Pediatric T2DM a global epidemic?

• Cohort of 535 obese Italian childrenIFG (7.6%), IGT (3.2%), T2DM (0.18%)

Cambuli, VM, et.al. Diab Metab Res Rev, 2009

• Prevalence of T2DM among 0-20 year old German children estimated at 2.3 cases per 100,000.

Neu A, et.al. Pediatric Diabetes, 2009

• Highest risk populations (obese, Latino, positive fam hx) from Los Angeles from 2000-2007 showed prevalence of

1.3% on OGTT Goran MI, et.al. J Pediatr, 2008

• Taiwanese children aged 6-18 taking part in screening program found diabetes prevalence of 9 (♂) and 15.3 (♀) per 100,000 children. After 3 years, 54% of cases identified as type 2.

Wei JN, et.al. JAMA, 2003

NHANES suggests an increase in prediabetes and diabetes over

past 10 years

May AL, et.al. Pediatrics, 2012

How did we get here?

Caglecartoons.com

Visceral Adiposity

U.S. childhood obesity rates have tripled over the past 40

years

Source: CDC (NHANES data)

Obesity: BMI > 95%

Obesity rates are highest among adolescents of ethnic

backgroundsPrevalence of obesity among

boys aged 12-19 yearsPrevalence of obesity among

girls aged 12-19 years

Source: CDC (NHANES data)

Popular Teen-Age/Pediatric Grand Rounds Lunch Items…

• Chipotle– Chicken Burrito – rice, black beans, cheese, salsa,

grilled chicken– 1154 calories

• Dominos: Slice of Pizza– Cheese/Veggie: 290 calories, 9 grams fat– Sausage/Pepperoni: 330 calories, 12 grams fat

• Popular Beverages (Pop, Monster Energy, etc.)– 16 oz: 200 calories

• Starbucks– Venti (20 oz) Caramel Macchiato– 300 Calories

Risks of obesity increases with sedentary activity

Gortmaker S., et.al. Arch Pediatr Adol Med, 1996; 150: 356-62

Energy Excess

Adipocyte Hepatocyte-cellLipogenesis

Steatohepatitis

Insulin Resistance

Oxidative Stress

Impaired Insulin Secretion

Hypertrophy & Hyperplasia

Oxidative Stress/ROS

CarbohydratesCarbohydrates Fats

Inflammatory Mediators

Adipokines Free Fatty Acids

•Peripheral Insulin Resistance•Lipid accumulation in peripheral tissues•Endothelial Dysfunction

Diet & ActivityGenetic Influences

Frohnert B, et.al. Rev Endocr Metab Disord, 2008

Intrauterine environment plays important role in contributing

future risk for T2DM

Wei JN, et.al. Diabetes Care, 2003

Primary Factors Contributing to Development of T2DM in

Children

INSULIN RESISTANCE

PRENATAL ENVT.

FEMALE GENDER

ETHNIC BACKGROUND

T2DM

SEDENTARY LIFESTYLE

OBESITY

• visceral

ACCELERATED BETA CELL

FAILURE

IFG/IGT

Beta-cell secretory abnormalities accompany progression to T2DM

Bacha F, et.al. Diabetes Care, 2009

Acute, Chronic and Future Complication Risks

Acute, Life-Threatening Complications of T2DM in Children

• Diabetic ketoacidosis (DKA)– May occur in up to 40% of patients

• Non-ketotic hyperosmolar coma– 1966-2001: 35 cases reported; 2001-2010: 65 cases– More typical in African-American boys before T2D

dx– Characterized by shock, non-acidosis, stupor/coma– Fatality rates ~ 40% (BMI-SDS > 2.9)

Rosenbloom A, J Pediatr, 2009

– CHOP: 4.2% of patients over 5.7 year period Fourtner SH, et.al. Pediatr Diab, 2005

T2DM in childhood predisposes for earlier onset

of nephropathic disease ESRD IN PIMA INDIANS

Pavkov ME, et.al. JAMA, 2006

Co-morbid metabolic conditions are present at high rate in children with

T2DMTODAY Cohort (n = 704)Co-morbidity Present at

BaselineLow HDL (♀<50, ♂ <40) 80%High TG (> 200) 10%Hypertension 14%ALT 1.5-2.5 > ULN [>2.5 excluded] 3%Microalbuminuria 13%

Copeland KC, et.al. J Clin Endocrinol Metab, 2011

Adolescents with T2DM are at greater risk for rapid

deterioration in glycemic control

Katz LL, et.al. J Pediatr, 2010

Atherosclerosis begins in Childhood

Berenson GS, et.al. N Engl J Med, 1998

Children with T2DM are at increased risk for premature

cardiovascular disease1. Fasting glucose ≥ 110 mg/dl2. Waist circumference ≥ 90th %3. Triglycerides ≥ 110 mg/dl4. HDL-C ≤ 40 mg/dl5. Blood pressure ≥ 90%

• Pediatric Criteria for Metabolic Syndrome (three of five)

• Other Evidence for Premature Cardiovascular Disease• Increased vascular stiffness• Higher aortic pulse wave pressure• Inflammatory cytokines

Screening and Management of Pediatric Type 2

Diabetes

Who Should be Screened for T2DM? ADA 20131. Overweight Children ≥ 10 years or at puberty:

• BMI >85th percentile for age and sex

• weight for height >85th percentile

• weight >120% of ideal for height

2. Plus any two other risk factors• Signs of insulin resistance: acanthosis nigricans,

hypertension, dyslipidemia, PCOS, hx for SGA

• Race: American Indian, African American, Latino, Asian American, Pacific Islander

• Family history: T2D in 1st or 2nd degree relative

• Maternal history: Diabetes or gestational diabetes

Screen every three years: Fasting glucose, HbA1c, OGTT, random glucose + Sx

Diabetes Care 2011; 34:S11-S61

Others: Fasting lipid (Dyslipidemia), ALT (NAFLD), total and free testosterone (PCOS), blood pressure

OGTT may help identify youth at greatest

risk

MonophasicBiphasic

Kim JY, et. al. Diabetes Care, 2012

Metformin is only approved oral agent for pediatric T2DM

• Reduces hepatic glucose output (inhibits gluconeogenesis)

• Facilitates glucose transport in insulin-sensitive tissues

• May normalize ovulatory disturbances in girls with PCOS

• Safely used in children

– Metabolic effects usually apparent within 2 weeks

– May improve LDL, TG, ALT and augment weight loss

– GI side effects – improved if taken with food and lessen over time

– Rare lactic acidosis or hepatic inflammation

Cumulative Incidence of Diabetes in the Diabetes Prevention Program

Risk reduction31% by metformin58% by lifestyle

Insulin therapy in Pediatric T2DM• Necessary at time of diagnosis if marked hyperglycemia present

– Classification of diabetes may not be clear

• Adjunct to Metformin and lifestyle interventions

• Accumulating evidence that early insulin therapy for T2DM in adults is beneficial

• Many preparations and combinations– Basal Insulin such as Glargine (Lantus) or Detemir (Levemir)– Bolus Insulin such as Aspart (Novolog) or lispro (Humalog) for

hyperglycemia correction and meal coverage– Premixed Insulin (70/30 or 75/25)

Complementary 2nd line therapies are not approved for Pediatric T2DM Management

1. AGENTS THAT INCREASE INSULIN SENSITIVITYThiazolidinediones: PPARγ activators

rosiglitazone, pioglitazoneα-Glucosidase inhibitors: Inhibit carbohydrate absorption

acarbose, miglitol

2. AGENTS THAT INCREASE INSULIN SECRETIONSulfonylureas: Stimulate SUR receptor

glyburide, glipizide, gliclazide, glimepirideMeglitinides

repaglinide, nateglinide

3. AGENTS THAT MIMIC INCRETIN PEPTIDESGLP-1 agonists

Exenitide, liraglutideDPP-4 inhibitors

Sitagliptin

• TODAYs primary objective is to compare the efficacy of three treatment arms on time to treatment failure based on glycemic control in newly diagnosed children with T2DM.

The three treatment groups are: 1. Metformin (500-1000 mg bid) 2. Metformin (500-1000 mg bid) AND rosiglitazone (4

mg bid) 3. Metformin plus an intensive lifestyle intervention

called the TODAY Lifestyle Program (TLP). • The TLP program is designed to promote healthy,

moderate weight loss through changes in diet and increases in physical activity.

Intervention phase was completed in February, 2011

Primary TODAY Results

Summary1. The overall prevalence of T2DM in U.S. youth is ~ 1 in 1000

but is increasing, especially in non-Caucasians, surpassing rates of type 1.

2. Rates of diabetes and complications from diabetes in young adults will reach epidemic proportions in near future.

3. While many factors are involved, obesity (visceral) and insulin resistance are central to development of pediatric T2DM.

4. Additional important risk factors include ethnic background, family history, birth history.

5. Screening should include tests for diabetes and for other co-morbidities: − FPG, A1c, lipids, fatty liver disease, BP monitoring, PCOS

6. The most important treatment is lifestyle change. − May also include metformin, insulin and management of

co-morbidities (hypertension, dyslipidemia, etc).7. Prevention (policy and societal change, medical interventions,

identification of new pathways) is paramount to our efforts in combating diabetes now and in the future.

Known and undiagnosed cases of pediatric T2D

Undiagnosed cases of pediatric pre-T2D (IGT/metabolic syndrome)

“Pre-pre” T2D: insulin resistance with risk factors