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Diabetes Mellitus: How Genetics Informs Research, Patient Care, and Prevention

Diabetes Mellitus: How Genetics Informs Research, Patient Care, and Prevention. Fredric E. Wondisford, M.D. Metabolism Division Departments of Pediatrics, Medicine and Physiology Director, JHU-UMD Diabetes Research and Training Center Johns Hopkins University School of Medicine.

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Diabetes Mellitus: How Genetics Informs Research, Patient Care, and Prevention

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  1. Diabetes Mellitus: How Genetics Informs Research, Patient Care, and Prevention Fredric E. Wondisford, M.D.Metabolism DivisionDepartments of Pediatrics, Medicine and Physiology Director, JHU-UMD Diabetes Research and Training CenterJohns Hopkins University School of Medicine

  2. Diabetes DefinitionsThe CostsNew findings from the JHU-UMD DRTC Latest Genetic FindingsObesityHealth Disparities Outline

  3. The Insulin Hormone is Made in the Islets of Langerhans

  4. Normal Metabolism Liver Pancreas insulin Muscle Fat

  5. Type 1 Diabetes Mellitus Liver Pancreas insulin Muscle Fat

  6. Type 2 Diabetes Mellitus Liver Pancreas insulin Muscle Fat

  7. T1 DMT2DMInsulin Sensitive ResistantBMI Low HighHeritability Low High Comparison of Diabetes Types

  8. County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2004 Percent

  9. County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2005 Percent

  10. County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2006 Percent

  11. County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2007 Percent www.cdc.gov/diabetes

  12. County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2008 Percent

  13. Prevalence of Diabetes in the U.S. by Cause (%) 40- Prediabetes 30- 20- T2 DM 10- T1 DM 0- 2007 2010 2020 (est) ADA data 2007

  14. Health Care Spending on Diabetes and Related Diseases • Approximately 12% of health care spending in 2009 was used for the care of patients with diabetes. • Approximately 8% of health care spending in 2009 was used for the care of patients with end-stage kidney disease of which most is caused by diabetes. • Diabetes has a central role in other expensive to care for chronic conditions such as stroke, heart disease, and cancer.

  15. Current estimates are that up to 40% of current U.S. health care costs are related to diabetes

  16. JHU-UMD DRTC The NIH Funds Diabetes Centers 10 DERCs U WA U Penn U Mass Joslin Yale U Colorado Mass General Columbia, NY UCLA/UCSD Baylor 7 DRTCs Albert Einstein U Michigan Wash U U Chicago Vanderbilt UAB JHU-UMD 17 Centers across the US

  17. The JHU-UMD DRTC is Unique • A joint effort with another major medical center (Johns Hopkins University and the University of Maryland) • A strong focus on childhood obesity and diabetes-where the disease is now starting • A large representation of minority populations in research studies of patients with diabetes and obesity

  18. Type 2 Diabetes Mellitus Liver Pancreas Glucose insulin Muscle Fat

  19. A Better Way to Screen for T2 DM

  20. Type 2 Diabetes Mellitus Pancreas Glucose X Metformin insulin Muscle Fat

  21. A New Blood Test to See if a Common Anti-Diabetic Drug Will Work in T2 DM Patients

  22. How Diabetes and Obesity Cause Infertility: Implications for Patients with PCOS

  23. The Genetics of Diabetes • Candidate Gene Approach uses knowledge about biological pathways to screen for potentially defective genes in patients with diabetes. • Genome-Wide Association Studies (GWAS) rapidly scan markers across the complete human genomes of many people to find gene variations associated with a diabetes.

  24. Science 2007 Vol 316

  25. GWAS and Diabetes: The Good • Most genes do or are predicted to affect the function of the pancreatic beta cell. Some of these genes were already identified by the candidate approach. • Novel pathways in insulin secretion were discovered, which were not found by the candidate approach. • Certain uncommon gene variants may predict which patients will respond to common anti-diabetic drugs-pharmacogenetic trials underway Florez 2010 Ann NY Acad Sci

  26. GWAS and Diabetes: The Bad • Common genetic variants are not useful in clinical care-personalized medicine. • At best, only 10% of the heritability of T2 DM can be explained by genetic variation based on the studies performed to date-problems in study design • The prime candidate for “Missing Heritability” is a gene-environment interaction. Florez 2010 Ann NY Acad Sci

  27. Genetics and Environment 60 Years 2.5 Million Years Evolved to avoid starvation

  28. County-level Estimates of Obesity among Adults aged ≥ 20 years: United States 2004 Percent

  29. County-level Estimates of Obesity among Adults aged ≥ 20 years: United States 2005 Percent

  30. County-level Estimates of Obesity among Adults aged ≥ 20 years: United States 2006 Percent

  31. County-level Estimates of Obesity among Adults aged ≥ 20 years: United States 2007 Percent

  32. County-level Estimates of Obesity among Adults aged ≥ 20 years: United States 2008 Percent

  33. Michelangelo’s David: Effect of Environment BMI=22 kg/m2 BMI=38 kg/m2 2011 1504

  34. Hypothesis Obesity in U.S. is due to inactivity

  35. County-level Estimates of Leisure-time Physical Inactivity among Adults aged ≥ 20 years: United States 2004 Percent

  36. County-level Estimates of Leisure-time Physical Inactivity among Adults aged ≥ 20 years: United States 2005 Percent

  37. County-level Estimates of Leisure-time Physical Inactivity among Adults aged ≥ 20 years: United States 2006 Percent

  38. County-level Estimates of Leisure-time Physical Inactivity among Adults aged ≥ 20 years: United States 2007 Percent

  39. County-level Estimates of Leisure-time Physical Inactivity among Adults aged ≥ 20 years: United States 2008 Percent

  40. Hypothesis Obesity in U.S. is due to inactivity This is not the whole story and perhaps not where the majority of prevention efforts should be directed

  41. Hypothesis Obesity is due to access to inexpensive, high calorie foods

  42. Distribution of Food Stores by HFA Index Franco et al. Am J Clin Nutr, 2009

  43. Low caloric density foods are common in supermarkets in the suburbs

  44. High caloric density foods are common in convenience stores in the inner-city Franco et al. J Epidemiol Comm Health 2007

  45. The Principles and Practice of Medicine Sir William Osler 1909 Diabetes Mellitus “It is a disease of the higher class.” “Diabetes is comparatively rare in the colored race….” Cumulative Lifetime Risk for Diabetes in US by Age, Sex, and Ethnicity Narayan, K.M.V. et al. JAMA 2003;290:1884-1890

  46. What Explains the “Missing Heritability” of T2DM • A diet of excessive calories and the associated obesity causes insulin resistance in the body. • This produces a stress on the beta cell to make more insulin, which in patients with certain gene variants, causes diabetes. • Excessive or deficient caloric exposure during fetal or early life may also change the expression of these gene variants-epigenetic changes

  47. Primary Prevention For Diabetes • Given that over 98% of all diabetes is type 2, primary prevention efforts must first address obesity. • Exercise alone is helpful but unlikely to curb the high rates of U.S. obesity and T2DM. • Changes in diets coupled with interventions to control appetite (drugs/surgery) are needed.

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