Type 2 Diabetes in Children and Adolescents

1. Type 2 Diabetes in Children and Adolescents By: Jennifer Harris November 17, 2005

2. Outline • Pediatric Obesity – How big is the problem, and why should we care? • How does DM2 develop? • Clinical Heterogeneity in DM2 – What are the implications? • What can we do to stop the epidemic? • Conclusions

3. Pediatric Obesity

4. How big a problem is pediatric obesity? 1999-2002 NHANES (National Health and Nutrition Examination Survey): • 22.6% of 2-5 year olds are “at risk for overweight” (BMI 85-95%) • 31% of 6-19 year olds are “at risk for overweight” • 10.3% of 2-5 year olds are “overweight” (BMI >95%) • 16% of 16-19 year olds are “overweight” This is not just an American trend. Other countries, like Japan, New Zealand, and Thailand, are also seeing increases in childhood development of DM2.

5. Why should we care? Annual obesity-related hospital costs in 6-17 year olds = $127 million/year, a 3-fold increase in the past 20 years Wang and Dietz, Pediatrics. 109;E81

6. Metabolic Syndrome in Kids Must have at least 3 to diagnose (in children, all adjusted for age and sex): • BMI >97th percentile • Triglycerides >95th percentile • HDL <5th percentile • Systolic or diastolic BP >95th percentile • Impaired glucose tolerance test (IGTT)

7. The link between obesity, insulin resistance, and metabolic syndrome • The prevalence of metabolic syndrome in children increases directly with increased insulin resistance. This was seen in Hispanics > Caucasians > African-Americans. • The percentage of children with IGTT increased directly with the severity of obesity, even after adjusting for sex, race, and Tanner stage. • The CARDIA study of 4576 young adults showed that there is a weight-independent association between fasting insulin and HTN. (Manolio et al. Arteriosclerosis. 1990;10:430-36) • The AHA released a scientific statement in 2003 stating that increased LV mass, an independent risk factor for CVD, can already be seen in childhood in obese children. Weiss, et al. NEJM. 2004;350:2362-74.

8. How Fatty Acids Interfere with Insulin-Mediated Glucose Uptake McGarry, J.D. “Dysregulation of Fatty Acid Metabolism in the Etiology of Type 2 Diabetes.” Diabetes. 51:7-18, 2002.

9. How does DM2 develop?

10. Factors Contributing to Insulin Resistance 1. Obesity/sedentary lifestyle 2. Race/ethnicity 3. Family history a. The Bogalusa Heart Study (Srinivasan, et al. Metabolism. 2003; 52:443-450.) looked at >6500 kids age 4-17, with and without parental DM, from childhood to adulthood. b. In kids with parental DM: 1. Increased BMI and SBP starting in childhood. 2. Increased fasting insulin, glucose, and insulin resistance index starting in puberty. 3. Increased TGs and LDL, decreased HDL starting in adulthood.

11. Factors (continued) 4. Puberty: increased GH/IGF-1 levels cause insulin resistance a. Insulin-mediated glucose disposal decreased 30% in Tanner Stages 2-4 compared to Stage 1 in some hyperinsulinemic euglycemic clamp studies. b. Caprio et al. (Journal of Pediatrics. June 1989: 963-967) showed, via a hyperglycemic clamp study, that both early and late responses to hyperglycemia were enhanced during puberty (leading to hyperinsulinemia). This differs from the hyperinsulinemia seen in early DM2, where the early phase release of insulin is impaired, and late phases exhibit a compensatory increased insulin release.

12. Factors (continued) 5. PCOS 6. Intrauterine factors (GDM, low birth weight, small head circumference) a. A study in Pima Indians showed that intrauterine factors were separate from family history. Kids born after mom developed DM2 were more likely to get DM than siblings born before mom developed DM2. (Pettitt, et al. Diabetes Care. 1993;16:310-14) b. LBW: thrifty gene hypothesis. Associated with increased fasting insulin and decreased beta cell function.

13. How DM2 develops – traditional thinking Insulin resistance  pancreatic insulin secretion increases  beta cell failure  decompensation  clinical DM. This way of thinking may underemphasize the role of beta cell dysfunction.

14. A new paradigm There is some evidence that there is beta cell dysfunction present before the onset of impaired glucose tolerance. It is important to note that just because insulin secretion increases in the early stages of DM2, this doesn’t necessarily mean the beta cells are functioning properly. Late hyperinsulinemia may in fact be a result of inadequate beta cell response to hyperglycemia that is itself a result of early impaired insulin release. Gerich, J.E. Endocrine Reviews. 1998;19(4): 491-503.

15. Clinical Heterogeneity in DM2

16. What do all DM2 patients have in common? • Both genetic and environmental components are involved. • Has polygenic inheritance. 1. Diabetogenic genes: Genes that, if inherited, will cause most people to develop DM. Essential and specific to the development of DM, but may not be enough by themselves to cause DM. Example: mutation in insulin receptor gene that leads to insulin resistance. 2. Diabetes-related genes: Not specific. By themselves, not enough to cause DM. Genetically-determined risk factors. Example: genes that regulate appetite and energy expenditure. • Both insulin sensitivity and insulin secretion are impaired. • Most patients are obese. Obesity, especially intra-abdominal, is believed to cause insulin resistance.

17. Differentiating DM1 from DM2 (Not always as easy as it may seem!) DM1 1. Increased incidence of other autoimmune disorders 2. Ususally low insulin/c-peptide levels (may be normal during “honeymoon phase”) 3. Usually non-obese DM2 1. Increased c-peptide levels (may be normal at time of diagnosis) 2. Usually no auto-antibodies (can sometimes see these, however, and this is usually prognostic for a more severe clinical picture/rapid progression) 3. Strong family history of diabetes 4. Usually obese 5. Signs of insulin resistance (HTN, acanthosis, PCOS)

19. Acanthosis nigricans Currently thought to be an effect of IGF-1. At one point was thought to be a result of skin folds rubbing together. One study cited in The Journal of Pediatrics (2001;138:453-4) showed acanthosis was directly associated with: 1. Increased fasting insulin levels 2. Increased insulin/glucose ratio 3. Increased insulin responses and decreased glucose disposal rates during hyperglycemic clamps 4. These effects seen in patients with acanthosis more than in overweight patients without acanthosis. (However, after adjusting for differences in total body fat, there was no significant difference between overweight patients with and without acanthosis.)

20. How does DM2 differ from patient to patient? • Not all people with DM2 are insulin resistant. Several studies (cited in Gerich, J.E. Endocrine Reviews. 1998;19(4): 491-503), demonstrate that certain subgroups of type 2 diabetics have impaired insulin secretion, but not insulin resistance. So why wouldn’t you call these patients type 1? Because they are not ketosis-prone and won’t die without insulin. • Compensatory responses to insulin resistance are different in different ethnic groups. 1. AA: decreased hepatic extraction of insulin 2. Hispanic: increased 2nd phase secretion of insulin

21. How does DM2 differ from patient to patient? (continued) HHNK (hyperglycemic hyperosmolar non-ketosis) is a common presentation of DM2 in kids. Fourtner, et al. (Pediatric Diabetes. 2005;6:129-135) conducted a chart review at CHOP, and found that 7/190 patients diagnosed with DM2 presented with HHNK, one of whom subsequently died. HHNK doesn’t seem to be associated with concurrent infections/stresses like commonly seen in adult HHNK. African American children appear to be more likely to present in DKA than other races/ethnicities, for reasons not fully understood.

22. How does DM2 differ from patient to patient? (continued) MODY (maturity-onset diabetes of the young) • An AD-inherited, heterogeneous group of disorders. • Characterized by: 1. nonketotic DM 2. onset usually <25 years old 3. primary defect of beta cell function 4. at least 6 different genes have been implicated 5. can be affected/precipitated by factors affecting insulin sensitivity (puberty, pregnancy, infection) • Typical presentation: Mild, asymptomatic hyperglycemia in nonobese young person with prominent family history of diabetes. • May account for up to 5% of all DM in the US and other industrialized countries. • Similar to DM2 in that beta cell experiences a decline in function.

23. Case Presentation(from Gassner, et al. Clinical Diabetes. 2003; 21,3, 140-1) • 17 YO AAF with new-onset DM. • History and Physical HPI: polyuria, polydipsia, weight loss FH: + family history of DM, no family history of autoimmune diseases VS: 103/53, 79, 37C Weight=60kg, height=61in; BMI=25 (85th percentile) PE: + acanthosis, Tanner stage 5 • Labs: UA: glucose >1000 mg/dl, ketones=40 mg/dl Serum glucose=726, bicarbonate=21, venous pH=7.37 A1C=8.6%, c-peptide=1.0 ng/ml (nl=0.6-3.2) Type 1 or Type 2??

24. Case Presentation (continued) • She was admitted, given insulin and fluids, and diagnosed with Type 2 DM based on her race, family history, acanthosis, elevated BMI, normal c-peptide level, and lack of ketoacidosis. • She was started on metformin and insulin, and counseled about a diabetic diet. • However, at her 1 month follow-up visit, her labs came back positive for islet cell antibodies (ICAs), glutamic acid decarboxylase (GAD) antibodies, and ICA-512 antibodies. • Her A1C had decreased at this point, and her glucose was WNL on 0.4u/kg/day of insulin. Metformin was stopped given the patient’s antibody status.

25. “Double Diabetes” or “Type 1.5 DM” • This patient represents a type of DM in which the patient has characteristics of both Type 1 and Type 2. • As of 2003, there were tests for 4 different antibodies commercially available. 90% of DM1 patients will test positive for at least 1 antibody, and 40-50% will test positive for 2 or more. • Interestingly, AA adolescents with DM1 are four times more likely to have no antibodies at time of diagnosis. • This is dangerous, because if you had assumed that this patient was DM2 without sending antibody tests, you might have sent her home on metformin only. Then, when the honeymoon period was over, she could decompensate and end up in DKA. • Moral of the story: Always send antibody tests in children and adolescents, no matter how clear-cut you think the diagnosis is!

26. What can we do to stop the epidemic?

27. Current Treatment Recommendations • Per American Academy of Pediatrics: 1. Glucose 126-200 and A1C <8.5  lifestyle modifications +/- metformin 2. Glucose >200 and A1C >8.5, +/- ketosis  insulin 3. Do NOT give metformin if patient is ketotic, because this increases the risk of lactic acidosis. • Per ADA: 1. Start with diet and exercise. 2. If goals not met, start monotherapy (usually metformin). 3. If goals still not met, add a second oral agent (sulfonylurea, meglitinide, or a TZD). 4. If goals still not met, start insulin. You should start insulin immediately if the patient presents with DKA. • Metformin is currently the only oral hypoglycemic that has been approved for use in children.

28. Lifestyle Modifications • Lifestyle modifications are most efficacious, but metformin decreases rate of progression to DM. • Robinson (JAMA. 1999;282:1561-1567) started a 6 month curriculum in 3rd and 4th graders in San Jose, CA to see what effect decreasing TV watching/video games would have on obesity, and found that there was a significant decrease in BMI, triceps skinfold thickness, waist circumference, and waist-hip ratio. • Programs to eliminate coke and candy machines from schools and serve healthier lunches are in place now throughout the country, but how efficacious are these?

29. Role of insulin • Early insulin therapy in adults is thought to possibly reverse some of the glucotoxicity that damages beta cells and other insulin-sensitive tissues. • There is some evidence suggesting that DM2 may be more aggressive in young people, so early insulin therapy should be strongly considered.

30. Upcoming Trials There are trials currently looking at rosiglitazone, meglitinide, and glucovance in kids. One example is the STOPP-T2D trial (Studies to Treat of Prevent Pediatric Type 2 Diabetes), sponsored by National Institutes of Diabetes, Digestive, and Kidney Diseases Kids with diagnosis for <2 years are randomized to one of 3 arms: 1. Metformin 2. Metformin + Rosiglitazone 3. Metformin + intensive lifestyle program Failure = A1C >8% for 6 months  start glargine insulin Secondary outcomes to be studied: beta cell function, insulin resistance, body composition, nutrition, physical activity/fitness, CV risk factors, microvascular complications, quality of life, and psychological outcomes.

31. Bariatric Surgery in Children and Adolescents (continued) Guidelines from American Pediatric Surgery Association Clinical Task Force on Bariatric Surgery: • Failure to lose weight after 6 months of organized attempts. • Near-mature physiologic status of Tanner Stage 3 or above. • BMI >/= 40 with major life-threatening comorbidities or >/= 50 with minor but life-altering comorbidities. • Commitment to medical and psychological evaluation pre and post-op. • Commitment to avoid pregnancy for at least 1 year post-op. • Ability and intent to adhere to post-op nutritional guidelines. • Supportive family environment. • Ability to provide informed assent (patient) and consent (family).

32. Bariatric Surgery in Children and Adolescents Potential complications: • Interference with linear growth • Ethics of informed consent • Not enough data available about future reproductive capability • Increased impact of decreased nutrient absorption when patient is still growing Bottom line: Long term effects on adolescents not known.

33. Conclusions • The more we learn about DM, the more is appears to be a continuum of disorders, evidenced by how hard it is sometimes to differentiate type 1 and type 2. Also evidenced by the variety of clinical pictures, and subtle laboratory nuances when mechanisms are studied. • Children developing DM2 may help us understand how this continuum works, and may help us explore some of the genetic differences that result in the spectrum of disorders that are classified as diabetes. • Knowing these subtle differences in mechanism, and knowing how to test patients for which mechanism(s) are causing their DM, may help us eventually tailor treatment programs on an individual basis.

34. Sources • Hannon, TS, et al. “Childhood Obesity and Type 2 Diabetes Mellitus.” Pediatrics. 2005;116:473-80. • Weiss, Ram, et al. “Obesity and the Metabolic Syndrome in Children and Adolescents.” NEJM. 2004;350:2362-74. • Kaufman, FR. “Type 2 Diabetes in Children and Youth.” Endocrinology and Metabolism Clinics of North America. 2005;34:659-76. • Fourtner, SH, et al. “Hyperglycemic hyperosmolar non-ketotic syndrome in children with type 2 diabetes.” Pediatric Diabetes. 2005;6:129-35. • Finkel, Y. “Obesity Surgery in Pediatrics.” Journal of Ped Gastroenterology and Nutrition. 2004;39:2-4. • Gerich, JE. “The Genetic Basis of Type 2 Diabetes Mellitus: Impaired Insulin Secretion versus Impaired Insulin Sensitivity.” Endocrine Reviews. 1998;19(4):491-503. • Caprio, S, et al. “Increased insulin secretion in puberty: A compensatory response to reductions in insulin sensitivity.” Journal of Pediatrics. 1989;June:963-7. • Srinivasan, SR, et al. “Longitudinal Changes in Risk Variables of Insulin Resistance Syndrome From Childhood to Young Adulthood in Offspring of Parents with Type 2 Diabetes: The Bogalusa Heart Study.” Metabolism. 2003;52(4):443-50. • Steinberger, J, and Daniels, SR. “Obesity, Insulin Resistance, Diabetes, and Cardiovascular Risk in Children.” Circulation. 2003;107:1448-53. • Fajans, SS, et al. “Molecular Mechanisms and Clinical Pathophysiology of Maturuty-Onset Diabetes of the Young.” NEJM. 2001;345:971-80. • Goran, MI, et al. “Obesity and Risk of Type 2 Diabetes and Cardiovascular Disease in Children and Adolescents.” Journal of Clinical Endocrinology and Metabolism. 2003;88(4):1417-27. • Pinhas-Hamiel, O, et al. “Diabetic Ketoacidosis Among Obese African-American Adolescents with NIDDM.” Diabetes Care. 1997;20(4):484-6. • Dietz, WH. “Overweight and precursors of type 2 diabetes mellitus in children and adolescents.” Journal of Pediatrics. 2001;138:453-4. • Gassner, HL, and Gitelman, SE. “Case Study: Type 1 and Type 2, Too?” Clinical Diabetes. 2003;21(3):140-1.

35. Thank You! Dr. Frank Franklin, UAB Dr. Amy Potter, Vanderbilt