insulin resistance and type 2 diabetes in children brandon nathan, md assistant professor
TRANSCRIPT
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Insulin Resistance and Type 2 Diabetes in Children
Brandon Nathan, MDAssistant Professor
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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
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Objectives
1. 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.
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Diabetes Etiology: Insulin Supply, Secretion, Demand
Normal Type 2Pre-type 2Type 1
Slide courtesy of Toni Moran, MD
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Acanthosis Nigricans: A Sign of Insulin Resistance
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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)
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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
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Rates of New Cases of Diabetes in US from 2002-2005
Mayer-Davis EJ, et.al. Diabetes Care, 2009
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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
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NHANES suggests an increase in prediabetes and diabetes over
past 10 years
May AL, et.al. Pediatrics, 2012
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How did we get here?
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Caglecartoons.com
Visceral Adiposity
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U.S. childhood obesity rates have tripled over the past 40
years
Source: CDC (NHANES data)
Obesity: BMI > 95%
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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)
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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
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Risks of obesity increases with sedentary activity
Gortmaker S., et.al. Arch Pediatr Adol Med, 1996; 150: 356-62
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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
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Intrauterine environment plays important role in contributing
future risk for T2DM
Wei JN, et.al. Diabetes Care, 2003
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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
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Beta-cell secretory abnormalities accompany progression to T2DM
Bacha F, et.al. Diabetes Care, 2009
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Acute, Chronic and Future Complication Risks
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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
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T2DM in childhood predisposes for earlier onset
of nephropathic disease ESRD IN PIMA INDIANS
Pavkov ME, et.al. JAMA, 2006
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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
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Adolescents with T2DM are at greater risk for rapid
deterioration in glycemic control
Katz LL, et.al. J Pediatr, 2010
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Atherosclerosis begins in Childhood
Berenson GS, et.al. N Engl J Med, 1998
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Children with T2DM are at increased risk for premature
cardiovascular disease
1. 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
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Screening and Management of Pediatric Type 2
Diabetes
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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
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OGTT may help identify youth at greatest
risk
MonophasicBiphasic
Kim JY, et. al. Diabetes Care, 2012
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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
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Cumulative Incidence of Diabetes in the Diabetes Prevention Program
Risk reduction31% by metformin58% by lifestyle
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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)
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Complementary 2nd line therapies are not approved for Pediatric T2DM Management
1. AGENTS THAT INCREASE INSULIN SENSITIVITYThiazolidinediones: PPARγ activators
rosiglitazone, pioglitazone
α-Glucosidase inhibitors: Inhibit carbohydrate absorption
acarbose, miglitol
2. AGENTS THAT INCREASE INSULIN SECRETIONSulfonylureas: Stimulate SUR receptor
glyburide, glipizide, gliclazide, glimepiride
Meglitinides
repaglinide, nateglinide
3. AGENTS THAT MIMIC INCRETIN PEPTIDESGLP-1 agonists
Exenitide, liraglutide
DPP-4 inhibitors
Sitagliptin
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• 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
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Primary TODAY Results
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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.
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Known and undiagnosed cases of pediatric T2D
Undiagnosed cases of pediatric pre-T2D (IGT/metabolic syndrome)
“Pre-pre” T2D: insulin resistance with risk factors
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