Type 2 Diabetes in Children

Transcription

1 Type 2 Diabetes in Children February 19, 2005 Brandon Nathan, MD Endocrinology Department of Pediatrics University of Minnesota Medical School University of Minnesota Masonic Children s Hospital

2 Agenda 1. Discuss the cellular factors that lead to insulin resistance, prediabetes, and eventually type 2 diabetes in children 2. Recall differences in prevalence rates of type 2 diabetes among children of different ethnic backgrounds in the United States 3. Understand the appropriate diagnostic tests to screen an at risk child for type 2 diabetes 4. Recall suggested tests to screen for the metabolic comorbidities of insulin resistance/obesity.

3 Type 2 Diabetes is a continuum of progressive, pathologic changes in insulin supply, secretion, and demand Normal Insulin Resistant Prediabetes Type 2 Slide courtesy of Toni Moran, MD

4 Beta-cell secretory abnormalities accompany progression to T2DM Bacha F, et.al. Diabetes Care, 2009

5 ADA/ISPAD Criteria for the Diagnosis of Diabetes in Children 1. Fasting glucose >126 mg/dl 2. Random/casual glucose>200 mg/dl (with symptoms) 3. Oral glucose tolerance test, 2 hour sample> 200 mg/dl 4. HbA1c 6.5** (controversial does not correlate well with FPG or OGTT, poor sensitivity but highly specific, affected by race, Hgb) Prediabetes : HbA1c %** (some advocating for 6-6.4%) IFG: impaired fasting glucose (Fasting glucose ) IGT: impaired glucose tolerance (2 hr glucose reading of on OGTT)

6 Alarming Diabetes Statistics 25.8 million people in the US have diabetes (9.3% of adult 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 2012: $245 billion (41% increase from 2007) 1 in 3 children born in the US in 2000 will develop diabetes (CDC) 50% of African American and Latino children may develop T2DM Assuming 2.3% annual increase in T2D in <20 years, a four fold increase in prevalence will occur over next 40 years. Worldwide, an estimated 366 million people will have T2D by 2030

7 Rates of New Cases of Diabetes in US from Mayer-Davis EJ, et.al. Diabetes Care, 2009

8 NHANES suggests an increase in prediabetes and diabetes over past 10 years May AL, et.al. Pediatrics, 2012

9 How did we get here?

10 Caglecartoons.com Visceral Adiposity

11 U.S. childhood obesity rates have tripled over the past 40 years Obesity: BMI > 95% Source: CDC (NHANES data)

12 Obesity rates are highest among adolescents of ethnic backgrounds Prevalence of obesity among boys aged years Prevalence of obesity among girls aged years Source: CDC (NHANES data)

13 BMI in childhood further defines risk for T2DM, HTN, and CHD as an adult Park MH, et.al. PLOS One, 2013; 8(7): e70684

14

15 Risks of obesity increases with sedentary activity Gortmaker S., et.al. Arch Pediatr Adol Med, 1996; 150:

16 Intrauterine environment plays important role in contributing future risk for T2DM Wei JN, et.al. Diabetes Care, 2003

17 Primary Factors Contributing to Development of T2DM in Children OTHER GENES ETHNIC BACKGROUND FAMILY HISTORY T2DM ACCELERATED BETA CELL FAILURE IFG/IGT INSULIN RESISTANCE OBESITY visceral PRENATAL ENVT. SEDENTARY LIFESTYLE PUBERTY

18 Acute, Chronic and Future Complication Risks

19 Acute, Life-Threatening Complications of T2DM in Children Diabetic ketoacidosis (DKA) May occur in up to 40% of patients Non-ketotic hyperosmolar coma : 35 cases reported; : 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

20 Adolescents with T2DM are at greater risk for rapid deterioration in glycemic control Katz LL, et.al. J Pediatr, 2010

21 Co-morbid metabolic conditions are present at high rate in children with T2DM TODAY Cohort (n = 704) Co-morbidity Present at Baseline Low HDL ( <50, <40) 80% High TG (> 200) 10% Hypertension 14% ALT > ULN [>2.5 excluded] 3% Microalbuminuria 13% Copeland KC, et.al. J Clin Endocrinol Metab, 2011

22 Atherosclerosis begins in Childhood Berenson GS, et.al. N Engl J Med, 1998

23 T2DM in childhood predisposes for earlier onset of nephropathic disease ESRD IN PIMA INDIANS Pavkov ME, et.al. JAMA, 2006

24 Screening and Management of Pediatric Type 2 Diabetes What Should I Do?

25 Should I screen for insulin resistance? Research methods: Euglycemic hyperinsulinemic clamp the gold standard Frequently sampled IV glucose tolerance test (FSIVGTT) No accurate, reliable and easily applicable method of measurement in the clinic Measures of OGTT derived indices (Disposition Index [DI]) has shown strong correlation with clamps but not yet routinely used in clinical practice Fasting Insulin correlates highly with BMI, not IR Screening for insulin resistance alone is not warranted

26 Acanthosis Nigricans: A Sign of Insulin Resistance

27 Who Should be Screened for T2DM? ADA 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: T2D during pregnancy or gestational diabetes Screen every three years: Fasting glucose, HbA1c, OGTT, random glucose + Sx Diabetes Care 2014; 37(1):S11-S61 Other Screens: Fasting lipid (Dyslipidemia), ALT (NAFLD), total and free testosterone (PCOS), blood pressure

28 OGTT may help identify youth at greatest risk Monophasic Biphasic Monophasic associated with: Higher A1c Decreased measures of beta cell secretion Higher insulin resistance No difference in HOMA Kim JY, et. al. Diabetes Care, 2012

29 The 1 hour time point on OGTT may predict progression on T2DM spectrum Significantly greater deterioration in beta cell function over time in those children >155 mg/dl at 1 hour time frame. Of those with NGT at start, those with a 1 hour value > 155 were 2.5 times more likely to develop prediabetes (p= 0.004) Only 3 participants developed T2DM

30 Prediabetes A1c predicts impaired beta cell response Sjaarda LA, et.al. Diabetes Care, 2012

31 Cumulative Incidence of Diabetes in the Diabetes Prevention Program Risk reduction 31% by metformin 58% by lifestyle

32 Insulin Lifestyle Modification program including moderate to vigorous activity for 60 minutes daily Metformin Family centered diabetes care

33 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

34 Insulin therapy in Pediatric T2DM Necessary at time of diagnosis if marked hyperglycemia (BG > 250 mg/dl) or DKA present Classification of diabetes may not be clear HbA1c >9% Adjunct to Metformin and lifestyle interventions Accumulating evidence that early insulin therapy for T2DM in adults has long term beneficial effects 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)

35 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 ( mg bid) 2. Metformin ( 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.

36 Primary TODAY Results

37 Complementary 2 nd line therapies that are not approved for Pediatric T2DM Management 1. AGENTS THAT INCREASE INSULIN SENSITIVITY Thiazolidinediones: PPARγ activators rosiglitazone, pioglitazone α-glucosidase inhibitors: Inhibit carbohydrate absorption acarbose, miglitol 2. AGENTS THAT INCREASE INSULIN SECRETION Sulfonylureas: Stimulate SUR receptor glyburide, glipizide, gliclazide, glimepiride Meglitinides repaglinide, nateglinide 3. AGENTS THAT MIMIC OR INCREASE INCRETIN PEPTIDES GLP-1 agonists Exenitide, liraglutide DPP-4 inhibitors Sitagliptin, saxagliptin, linagliptin, alogliptin

38 Bariatric Surgery Reverses T2D Rapid resolution of diabetes in patients suggests there are hormonal mechanism involved in improvement other than just weight loss.

39 What to Watch for Improvements in our ability to identify highest risk children OGTT with insulin timepoints, adiponectin:leptin, radiologic evaluation of visceral fat Additions to the armamentarium for type 2 therapies in children (difficult to enroll) Sustained efforts in public health efforts to stem further increases in pediatric obesity, t2dm, metabolic syndrome

40

41 Summary 1. The overall prevalence of T2DM in U.S. youth is ~ 1 in 1000 but is increasing, especially in non-caucasians, surpassing rates of type While many factors are involved, obesity (visceral) and insulin resistance are central to development of pediatric T2DM. 3. Additional important risk factors include ethnic background, family history, birth history. 4. Screening should include tests for diabetes and for other comorbidities: FPG, HbA1c, lipids, ALT (fatty liver), BP monitoring, PCOS Consider OGTT Do not perform fasting or random insulin levels. 5. The most important treatment is lifestyle change. May also include metformin, insulin and management of comorbidities (hypertension, dyslipidemia, etc). 6. Prevention (policy and societal change, medical interventions, identification of new pathways) is paramount to our efforts in combating diabetes now and in the future.

42