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Type 1 and Type 2 Diabetes in Children and Youth: What’s New and What’s True

Type 1 and Type 2 Diabetes in Children and Youth: What’s New and What’s True

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Type 1 and Type 2 Diabetes in Children and Youth: What’s New and What’s True

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  1. Prepared for your next patient. Type 1 and Type 2 Diabetesin Children and Youth:What’s New and What’s True Francine Ratner Kaufman, MD, FAAP Distinguished Professor Emerita of Pediatrics and Communications, The Keck School of Medicine of the University of Southern California Center for Diabetes and Endocrinology, Childrens Hospital Los Angeles Chief Medical Officer of Medtronic Diabetes Los Angeles, CA

  2. Disclaimer I am the Chief Medical Officer for Medtronic Diabetes.

  3. Disclaimers continued • Statements and opinions expressed are those of the authors and not necessarily those of the American Academy of Pediatrics. • Mead Johnson sponsors programs such as this to give healthcare professionals access to scientific and educational information provided by experts. The presenter has complete and independent control over the planning and content of the presentation, and is not receiving any compensation from Mead Johnson for this presentation. The presenter’s comments and opinions are not necessarily those of Mead Johnson. In the event that the presentation contains statements about uses of drugs that are not within the drugs' approved indications, Mead Johnson does not promote the use of any drug for indications outside the FDA-approved product label.

  4. Outline of Presentation 1. Presentation, Diagnostic Criteria, Screening 2. Rates, Causes – Genes/Environment 3. Treatment 4. Co-morbidities and Complications 5. Prevention

  5. 11 8/12-Year-Old Female Patients Type 2 Diabetes (T2) • Chief complaint: Urinates 2 to 3 times at night times 2 months • A1C 8.2% at outside clinic • Weight 78 kg, BMI >95th percentile for age/gender • Reported 30 lb weight gain last year, recent loss • BP 128/83 • Menses at age 10 years – irregular • Prenatal – excessive maternal weight gain, ? diabetes, • Family history • Mother from Arizona, AI/HA, + for obesity • Father is non-Hispanic White, hypertension Type 1 Diabetes (T1) • Chief complaint: Urinates 2 to 3 times at night times 2 weeks • A1C 8.2% at outside clinic • Weight 63 kg, body mass index (BMI) >85th percentile for age/gender • Reported 15 lb weight gain last year, recent loss • Blood pressure (BP) 92/65 • Menses at 10 years – irregular • Prenatal – excessive maternal weight gain, no diabetes • Family history • Mother from Arizona, HA, + for obesity • Father non-Hispanic White, hypertension

  6. Presentation, Diagnostic Criteria, Screening • Presentation • T1 rapid onset, severe hyperglycemia, acidosis, diabetic ketoacidosis (DKA) • Results of TrialNet show T1 can be indolent • T2 indolent, mild hyperglycemia, rare acidosis, no DKA • AA high rate of mild DKA, higher glucose/A1C, symptomatic at presentation • Diagnostic criteria is the same for T1 and T2 • Symptoms of diabetes plus casual glucose ≥200 mg/dL • Fasting plasma glucose ≥126 mg/dL • 2-hour postload glucose ≥200 mg/dL during oral glucose tolerance test (OGTT) • ?A1C >6.5% • Used in adults but not established in children

  7. Presentation, Diagnostic Criteria, Screening • Evidence of insulin resistance, hypertension, dyslipidemia, NASH • Presentation during or after puberty • T2 in first-degree relative • Acanthosisnigricans, sleep apnea, polycystic ovary syndrome (PCOS), candidiasis • Evidence of insulin deficiency – hyperglycemia and acidosis, DKA mistaken for flu • Hardest diagnosis in infants/toddlers • No other family member • Other autoimmune diseases Zeitler P. Approach to the obese adolescent with new-onset diabetes. J ClinEndocrinolMetab. 2010;95(12):5163–5170

  8. Immune Tolerance Network Screening for T1 The reason to screen and intervene early in T1D: • Common, serious in terms of morbidity and mortality • Latency period without symptoms • Screening test with sensitivity and specificity • Intervention early is more effective, preservesC-peptide • In the context of research trials • TrialNet, Immune Tolerance Network,TEDDY, etc. • Screen with antibodies,? genes • Reason • Prevention studies • Oral insulin, omegas, vitamin D, anti-CD3 • Natural history study

  9. Screening for T2 American Diabetes Association (ADA) / American Academy of Pediatrics (AAP) ConsensusStatement, 2000 • Criteria*: Overweight (BMI 85th percentile for age and sex, weight for height 85th percentile, or weight 120% of ideal for height) PLUS: any 2 of the following risk factors: • Family history of diabetes mellitus (DM) 2 in first- or second-degree relative • Race/ethnicity • Signs of insulin resistance • Age of Initiation: Age 10 or at onset of puberty • Frequency: Every 2 years in the context of health visit • Test: Fasting plasma glucose preferred * Clinical judgment should be used. American Diabetic Association. Type 2 diabetes in children and adolescents. Diabetes Care. 2000;23(3):381–389

  10. Screening for T2 Results of the HEALTHY Study and Pilot – Diabetes Not Found *n=6 of which only 1 confirmed on follow-up testing**n=7 Baranowski T, Cooper DM, Harrel J, et al. Presence of diabetes in a U.S. eighth-grade cohort. Diabetes Care. 2006;29(2):212–217; HEALTHY Study Group; Kaufman FR, Hirst K, Linder B, et al. Risk factors for type 2 diabetes in a sixth-grade multiracial cohort: the HEATHLY study. Diabetes Care. 2009;32(5):953–955

  11. Causes: Genes and the Environment • 3–5% increase in T1 consistently • T2 from <2–25% of new onset diabetes SEARCH for Diabetes in Youth Study Group; Liese AD, D’Agostino RB Jr, Hamman RF, et al. The burden of diabetes mellitus among US youth: prevalence estimate from the SEARCH for Diabetes in Youth Study. Pediatrics. 2006;118(4):1510–1518

  12. Causes: Obesity as a Risk Factor BMI >85th Percentile at Diagnosis • Type 2 • 100% African American • 95% non-Hispanic • 91% Hispanic • Type 1 • 44% BMI >85th percentile • 30% BMI >95th percentile • Greater than the general population rates Search Data SEARCH for Diabetes in Youth Study Group; Liese AD, D’Agostino RB Jr, Hamman RF, et al. The burden of diabetes mellitus among US youth: prevalence estimate from the SEARCH for Diabetes in Youth Study. Pediatrics. 2006;118(4):1510–1518

  13. NEWLY DIAGNOSED DIABETES Causes T1 ENVIRONMENTAL TRIGGERS CELLULAR (T CELL) AUTOIMMUNITY HUMORAL AUTOANTIBODIES (ICA, IAA, GAD65A, ICA512A) LOSS OF INSULIN BETA CELL MASS GLUCOSE STARTS TO INCREASE Honeymoon GENETICS BETA CELL INJURY “PRE” DIABETES DIABETES TIME

  14. Causes T1: Genes and Antibodies • 4 antibodies: glutamic acid decarboxylase (GADA), islet tyrosine phosphatase (IA2), zinc transporter 8 A (ZnT8A), insulin autoantibodies (IAA) • >90% newly diagnosed +Abs; 3.5–4% of unaffected first-degree relatives • 40–50% of genetic predisposition on short arm of chromosome 6, Class II HLA region of the major histocompatibility complex (MHC) • Whites HLA-DR3 or HLA-DR4, Blacks HLA-DR7, Japanese HLA-DR9 • ~11 other loci, insulin gene chromosome 11 (INS-VNTR), T-cell activation and regulation genes (CTLA-4), protein tyrosine phosphatase N22 (PTPN22), genes in interleukin pathway (IL-2R) • HLA, CTLA-4, and PTPN22 are associated with other autoimmune diseases

  15. Causes T1 Number of Antibodies P-value <0.001 (Log Rank Test) 1.0 0.9 0.8 0.7 0.6 0.5 Survival Distribution Function 0.4 Number at Risk 0.3 61 59 89 66 41 46 58 52 30 33 40 35 22 19 19 19 7 8 2 10 0.2 72 70 113 84 0.1 1 0.0 0 1 2 3 4 5 6 7 Years Followed 1 Ab (ICA Only) 2 Abs STRATA: 3 Abs 4 Abs

  16. Causes T2: THE HEALTHY MIDDLE SCHOOL STUDY 6th Grade Students—Predominately Minority Baranowski T, Cooper DM, Harrel J, et al. Presence of diabetes in a U.S. eighth-grade cohort. Diabetes Care. 2006;29(2):212–217; HEALTHY Study Group; Kaufman FR, Hirst K, Linder B, et al. Risk factors for type 2 diabetes in a sixth-grade multiracial cohort: the HEATHLY study. Diabetes Care. 2009;32(5):953–955

  17. Causes T2 Baseline and outcome glucose tolerance classification T2DM, type 2 diabetes NGT N=76 (90.5%) NGT N=84 IGT N=8 (9.5%) 117 obese children and adolescents NGT N=15 (45.5%) IGT N=10 (30.3%) IGT N=33 T2DM N = 8 (24.2%) Mean follow-up of 20.4 + 10.3 months Weiss R, Taksali SE, Tamborlane WV, et al. Predictors of changes in glucose tolerance status in obese youth. Diabetes Care. 2005;28(4):902–909

  18. Causes T2 Comparison of Subjects with Impaired Glucose Tolerance (IGT) Who Developed Type 2 Diabetes and Who Reverted to Normal Glucose Tolerance (NGT) IGT to NGT IGT to T2D BMI 33 versus 44 BMI z-score 2.27 versus 2.76 Weight Δ kg 6.1 versus 27 BMI Δ1.06 versus 6.8 Weiss R, Taksali SE, Tamborlane WV, et al. Predictors of changes in glucose tolerance status in obese youth. Diabetes Care. 2005;28(4):902–909

  19. Causes T2: Gestational Diabetes as a Driver of T2 Diabetes in pregnancy can lead to a cycle of diabetes affecting future generations. Dabalea D, Hanson RL, Bennett PH, et al. Increasing prevalence of Type II diabetes in American Indian children. Diabetologia. 1998;41(8):904–910

  20. Insulin sensitivity 50% Diabetes Beta-cell 75% Insulin sensitivity 75% Impaired glucose tolerance Beta-cell 50% Insulin sensitivity 75% Normal glucose tolerance Beta-cell function 2Xs Causes T2: Progression from Pre-diabetes to Diabetes Pre-diabetes A1C 5.8–<6.4% 15% IFG, FPG >100 mg/dL 25% IGT in obese, 2h OGTT PG >140 mg/dL Diabetes A1C >6.4% FPG >126 mg/dL, RPG >200 mg/dL 3,700/ year (TIDM 16,000) 6% W, 67% AI 1/3 AA, HA, API 31.3% BMI>85th percentile 16.9% obese Family History Environmental Factors Genetic Susceptibility Beginning in Utero Maternal Obesity Breast Feeding Obesity Metabolic Syndrome Risk Factors Gunger N, Bacha F, Saad R, et al. Youth type 2 diabetes: insulin resistance, beta-cell failure, or both? Diabetes Care. 2005;28(3):638–644; Arslanian SA, Lewy VD, Danadian K. Glucose intolerance in obese adolescents with polycystic ovary syndrome: roles of insulin resistance and beta-cell dysfunction and risk of cardiovascular disease. J ClinEndocrinolMetab. 2001;86(1):66–71; and Bacha F, Saad R, Gungor N, et al. Adiponectin in youth: relationship to visceral adiposity, insulin sensitivity, and beta-cell function. Diabetes Care. 2004;27(2):547–552

  21. 11 8/12-Year-Old Female Patients • Obtain the following work up: • Random plasma glucose 247 mg/dL, repeat A1C 8.5% • CO2 20 meq/L, venous pH 7.38, LDL 178 mg/dL, triglycerides 215 mg/dL • ANTIBODIES ALL NEGATIVE • Treatment: In- or out-patient? • Do you start insulin? • Metformin alone is first-line therapy when glucose level is <250 mg/dL and patient is non-ketotic • All patients and families receive diabetes and lifestyle education. • Obtain the following workup: • Random plasma glucose,247 mg/dL, repeat A1C 8.5% • CO2 16 meq/L, venous pH 7.32, LDL 165 mg/dL, triglycerides200 mg/dL • ANTIBODIES GADA+ • Treatment: In- or out-patient? • What kind of insulin treatment? • Intensive? • All patients and families receive diabetes and lifestyle education.

  22. Treatment: Determining Diabetes Type in Youth with BMI >85th Percentile New onset of diabetes BMI >85th percentile Consider MODY; if not obese, NHW Negative Pancreatic autoantibodies Likely Type 2 Positive Monitor course Type 1 No Insulin requirement Type 2 Yes C-peptide normal/elevated • Type 2 ?adherence • Severe resistance/deficiency Zeitler P. Approach to the obese adolescent with new-onset diabetes.J ClinEndocrinolMetab. 2010;95(12):5163–5170

  23. Treatment: Diabetes is Hard to Manage Early and Persistent Glucose Control is Important. Silverstein J, Klingensmith G, Copeland K, et al. Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care. 2005;28(1):186–212

  24. Treatment Early and Persistent Glucose Control is Important. • Glucose monitoring • Self-monitoring glucose, continuous glucose monitoring, understanding glucose targets, A1C quarterly • Medications • Insulin therapy: Multiple injections, pens, pumps, changing dosages prn • Medical nutrition therapy • Balancing food: Managing carbs, weight • Psychosocial support • Assess, treat co-morbidities, complications • BP, cholesterol, thyroid, celiac, eye exams, microalbuminuria, disordered eating • Visits to health care team • Routine pediatric care, flu shots, hepatitis B immunization, transition planning • Sick day management • Glucose monitoring • Self-monitoring glucose, understanding glucose targets, A1C quarterly • Medications • Glucose lowering agents • Metformin, insulin therapy • Others not approved • Medical nutrition therapy • Weight reduction, lifestyle counseling • Psychosocial support • Assess, treat co-morbidities, complications • BP, cholesterol, disordered eating, PCOS, NASH, microalbuminuria, eye exams • Visits to health care team • Routine pediatric care, flu shots, hepatitis B immunization, transition planning • Sick day management Silverstein J, Klingensmith G, Copeland K, et al. Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care. 2005;28(1):186–212

  25. Treatment: DCCT Results, EDIC Results and Rate of Severe Hypoglycemia DCCT Results Reduction in Severe Hypoglycemia EDIC Results

  26. Treatment T1: Insulin Pump Therapy Improves Control Compared with MDI, insulin pumps are more effective at reducing A1C. (Insulin Pump) 52 studies show that CSII is significantly more effective in lowering A1C compared to MDI and conventional insulin therapy. Bruttomesso D, Pianta A, Crazzolare D, et al. Continuous subcutaneous insulin infusion (CSII) in the Veneto region: efficacy, acceptability and quality of life. DiabetMed. 2002;19(8):628–634; Bell DSH, Ovalle F. Improved glycemic control with use of continuous subcutaneous insulin infusion compared with multiple insulin injection therapy. EndocrPract. 2000;6(5):357–360; Rudolph JW, Hirsch IB. Assessment of therapy with continuous subcutaneous insulin infusion in an academic diabetes clinic. EndocrPract. 2002;8(6):401–405;Chantelau E, Spraul M, Mühlhauser I, et al. Long-term safety, efficacy and side effects of continuous subcutaneous insulin infusion treatment for type 1 (insulin dependent) diabetes mellitus: a one centre experience. Diabetologia. 1989;32(7):421–426; Boland EA, Grey M, Oesterle A, et al. Continuous subscutaneous insulin infusion. A new way to lower risk of severe hypoglycemia, improve metabolic control, and enhance coping in adolescence with type 1 diabetes. Diabetes Care. 1999;22(11):1779–1784; Maniatis AK, Klingensmith GJ, Slover RH, et al. Continuous subcutaneous insulin infusion therapy for children and adolescents: an option for routine diabetes care. Pediatrics. 2001;107(2):351–356; Litton J, Rice A, Friedman N, et al. Insulin pump therapy in toddlers and preschool children with type 1 diabetes mellitus. J Pediatr. 2002;141(4):490–495; and Weissberg-Benchell J, Lomaglio JA, Seshadri R. Insulin pump therapy: a meta-analysis. Diabetes Care.2003;26(4):1079–1087

  27. Treatment T1: CSII Reduces Incidents of Severe Hypoglycemia Severe hypoglycemic episodes MDI vs CSII Rudolph JW, Hirsch IB. Assessment of therapy with continuous subcutaneous insulin infusion in an academic diabetes clinic. EndocrPract. 2002;8(6):401–405; Bode BW, Steed RD, Davidson PC. Reduction in severe hypoglycemia with long-term continuous subcutaneous insulin infusion in type 1 diabetes. Diabetes Care. 1996;19(4):324–327; and Boland EA, Grey M, Oesterle A, et al. Continuous subscutaneous insulin infusion. A new way to lower risk of severe hypoglycemia, improve metabolic control, and enhance coping in adolescence with type 1 diabetes. Diabetes Care. 1999;22(11):1779–1784

  28. Treatment T1: Meta-analysis for Mean Difference in A1C between CSII and MDI In 22 studies, severe hypoglycemia was reduced with CSII by a rate ratio of 2.89 for RCTs and 4.34 for before/after studies. The mean difference in A1C was 0.21% for RCTs and 0.72% for before/after studies, related to initial A1C (p<0.001). Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in Type 1 diabetes: meta-analysis of multiple daily injections compared with continuous subcutaneous insulin infusion. Diabet Med. 2008;25(7):765–774

  29. Treatment T1: Continuous GlucoseMonitoring Multiple RCTs have been performed • Across the spectrum of glucose control • Adults and children • Starting therapy MDI and CSII • All show relationship between sensor use and decrease in A1C Bergenstal RM, Tamborlane WV, Ahmana A, et al. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. New Eng J Med. 2010;363(4):311–320; Misso ML, Egberts KJ, Page M, et al. Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD005103; Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group; Beck RW, Buckingham B, Miller K, et al. Factors predictive of use and of benefit from continuous glucose monitoring in type 1 diabetes. Diabetes Care. 2009;32(11):1947–1953; and Raccah D, Sulmont V, Reznik Y, et al. Incremental value of continuous glucose monitoring when starting pump therapy in patients with controlled type 1 diabetes: the REALTrend study. Diabetes Care. 2009;32(12):2245–2250

  30. Treatment T1: Glycemic Control During Real-time CGM Meta-analysis of Randomized Controlled Trials Using Individual Patient Data Pickup JC, Freeman SC, Sutton AJ. Glycemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta analysis of randomized controlled trials using individual patient data. BMJ. 2011;343:d3805

  31. Treatment T1: STAR 3 Study A1C at 3, 6, 9, and 12 Months: All Patients Sensor Augmented Pump A1C 8.3% n=244 Adults=166, Pediatrics=78 Multiple Injections A1C 8.3% n=241 Adults=163, Pediatrics=78 8.1% 8.1% 8.0% 8.0% 7.5% 7.5% 7.5% 7.3% Bergenstal RM, Tamborlane WV, Ahmana A, et al. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. New Eng J Med. 2010;363(4):311–320

  32. Treatment T1 A1C at 3, 6, 9, and 12 Months: Pediatrics 7–18 Years 8.6% 8.5% 8.4% 8.3% 7.9% 7.8% 7.7% 7.5% Bergenstal RM, Tamborlane WV, Ahmana A, et al. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. New Eng J Med. 2010;363(4):311–320

  33. Treatment T1 The majority of patients used sensors >60% of the time. n=27 n=46 n=108 n=56 A1C Reduction is Correlated with Increased Sensor Usebut Not an Increase in Hypoglycemia or DKA Severe hypoglycemia rate low and at lower A1C, little DKA Bergenstal RM, Tamborlane WV, Ahmana A, et al. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. New Eng J Med. 2010;363(4):311–320

  34. Treatment T1 The Evolution of a Fully-Automated Insulin Delivery System Present Past Sensor Augmented Insulin Pump Low Glucose Suspend Insulin Pump Therapy Potential Future products Predictive LGS with restart when glucose returns to normal Overnightclosed loop Intermittent closed loop Fully automated closed loop Treat to target Clips off highs

  35. Treatment: T2 ISPAD Guidelines, 2009 Rosenbloom AL, Silverstein JH, Amemiya S. Type 2 diabetes in children and adolescents. Pediatric Diabetes. 2009;10(12):17–21

  36. Funded by National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Treatment T2 • Randomized clinical trial with a pre-randomization run-in period • 704 patients at 15 clinical centers • 3 treatment regimens • Metformin + Placebo • Metformin + Rosiglitazone • Metformin + Intensive Lifestyle Program • At treatment failure: Standardized approach to insulin initiation • Primary outcome: Time to failed glycemic control • Inclusion criteria • Age 10–17 years • Duration of diabetes <2 years • BMI 85th percentile Copeland KC, Zeitler P, Geffner M, et al. Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline. J ClinEndocrinolMetab. 2011;96(1):159–167

  37. Treatment T2: The TODAY Trial Medications at Presentation • No medication 11% • Insulin only 12% • Metformin only 49% • Metformin + insulin 25% • Other medication 4% Copeland KC, Zeitler P, Geffner M, et al. Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline. J ClinEndocrinolMetab. 2011;96(1):159–167

  38. A Clinical Trial to Maintain Glycemic Control in Youth with Type 2 Diabetes TODAY Study Group; Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. New Eng J Med. 2012:1–10

  39. Treatment T2: The TODAY Trial Study Results TODAY Study Group; Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. New Eng J Med. 2012:1–10

  40. TODAY Study Group; Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. New Eng J Med. 2012:1–10

  41. Treatment: Lifestyle Tips for Teens with Diabetes Series from National Diabetes Education Program

  42. Co-morbidities and Complications: Cardiovascular Risk Factors—SEARCH Trial MetS: >2 cardiovascular disease (CVD) risk factors • 68% American Indian37% Asian, 32% African American, 35% Hispanic,16% White (p<0.0001) • At least 2 risk factors • 92% of type 2 • 14% of type 1 (p<0.0001) Rodriguez BL, Fujimoto WY, Mayer-Davis EJ, et al. Prevalence of cardiovascular disease risk factors in U.S. children and adolescents with diabetes: the SEARCH for diabetes in youth study. Diabetes Care. 2006;29(8);1891–1896

  43. Co-morbidities and Complications: Australia Eppens MC, Craig ME, Cusumano J, et al. Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes. Diabetes Care. 2006;29(6):1300–1306

  44. Complications T1: Catastrophe at Diagnosis—DKA • Severe metabolic disturbance • Insulin deficiency, secondary counter-regulatory hormone elevation • North America and Europe statistics • 30% of new cases, 20% of deaths from diabetes <20 years • 1/200 episodes result in cerebral edema • 1/3 die, 1/3 permanently impaired, 1/3 recover • Costs: >2.5 billion dollars • Risk factors for cerebral edema • Young age, poverty, no knowledge of signs and symptoms, lack of access to care • Lower pCO2 , higher BUN at DX, Rx with HCO3, smaller increase in Na • Mechanism(s) • Osmotic cellular swelling versus vasogenicprocess Glaser NS, Wooten-Gorges SL, Marcin JP, et al. Mechanism of cerebral edema in children with diabetic ketoacidosis. J Pediatr. 2004;145(2):164–171

  45. Hyperglycemic Hyperosmolar Non-KetoticSyndrome—at onset—very high glucose levels 3.7% (7/190) in Philadelphia Mortality 14.3% Currently 28 reported other cases Mortality 43% Pima Indians diagnosed at <20 years of age 22% had microalbuminuria at diagnosis Increased to 60% at 20–29 years of age Indigenous Canadians 23 years of age, 9 years duration HbA1c 10.9% 67% poor glycemic control 45% hypertension requiring treatment 35% microalbuminuria (6% required dialysis) 38% pregnancy loss 9% mortality Kaufman, Type 2 Youth Complications T2: Type 2 Diabetes is a Severe Disease Fourtner SH, Weinzimer SA, Katz LEL. Hyperglycemic hyperosmolar non-ketotic syndrome in children with type 2 diabetes. Pediatr Diabetes. 2005;6(3):129–135; Butler M, McKary RA, Popoff IJ, et al. Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice.Diabetes. 2002;51(4):1028–1034

  46. Complications and Co-Morbidities T2 TODAY Study Group; Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. New Eng J Med. 2012:1–10

  47. Prevention or Interdiction of T1 TrialNet and Immune Tolerance Network • Anti-CD3 • MycophenolateMofetil +/- Anti-CD25 • Anti-CD20 • Anti-thymocyte globulin • CTLA-4 • GAD-Alum immunization • Intense metabolic control • Oral insulin • Supplemental vitamin D • Omega fatty acids • Hydrolyzed formula compared to cow's milk • Outside TrialNet and Immune Tolerance Network • Alpha-1-antitrypsin, BCG, insulin peptide B:9-23, heat shock protein DiaPep277 Some studies have shown an initial benefit inC-peptide preservation. Has tolerance been achieved or onlyimmuno-blockade? Are multiple or sequential agents required? What are the risks/benefits overthe long term?

  48. Social Norms Subculture Sectors of Influence Behavioral Settings Individual Factors Energy Intake Energy Balance Energy Expenditure 5. Prevention Socio-ecological Model Built Environment Government Public Health Agriculture Education Media Land Use and Transportation Communities Foundations Industry Food Beverage Retail Leisure and Recreation Entertainment Home Communities Health Care Access, Adherence Schools and Child Care Worksites Age, Sex, SES, Race/Ethnicity Culture Psychosocial Factors - Stress Genes,Gene-Environment Interactions Intrauterine Environment Physical Activity Food & Beverage Intake Obesity Insulin Resistance/Deficiency Type 2 Diabetes

  49. Prevention: The HEALTHY Study • School unit of randomization • Primary outcome: Combined prevalence of overweight plus obesity • 42 schools • ≥50% minority and/or ≥50% with free/reduced lunch • Comprehensive health screening, results sent to parents Diabetes Care 29:212–217, 2006 49 • Intervention schools • Environmental changes, food service, physical education • Behavior change—curriculum based • Communications and promotional campaign

  50. Prevention: The HEALTHY Trial RESULTS • Reduction in percentage of overweight/obesity by 4% in both groups • Prevalence of obesity declined more in intervention schools (p=0.05) • Significant reduction in intervention schools (p=0.04) • BMI z-score • Prevalence of large waist circumference • Fasting insulin fell • In the overweight/obese subgroup (n=2292), intervention schools had significantly greater decreases in prevalence of: • Obesity (p=0.04) • Large waist circumference (p=0.03) • Insulin (p=0.04) HEALTHY Study Group; Foster GD, Linder B, Baranowski T, et al. A school-based intervention for diabetes risk reduction. New Eng J Med. 2010;363(5):443–453