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Introduction to Diabetes Mellitus

Introduction to Diabetes Mellitus. Philip E. Cryer, M.D. Irene E. and Michael M. Karl Professor of Endocrinology and Metabolism in Medicine, Washington University in St. Louis.

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Introduction to Diabetes Mellitus

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  1. Introduction to Diabetes Mellitus Philip E. Cryer, M.D. Irene E. and Michael M. Karl Professor of Endocrinology and Metabolism in Medicine, Washington University in St. Louis

  2. “One of the symptoms of an approaching nervous breakdown is the belief that one’s work is terribly important.” Bertrand Russell (1872-1970)

  3. Diabetes is Serious Increasingly Common ~26 million in U.S. ~285 million world-wide in 2010 (~438 million by 2030) Potentially Devastating 2 to 4-fold Increased Risk of MI or CVA, Most Common Cause of Blindness, ESRD, Nontraumatic Amputations Extraordinarily Expensive ~$245,000,000,000/year in U.S. Treatable, but Incurable, Chronic Disease Treatment Makes a Difference for People with Diabetes

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  5. Increased glucose production plus decreased glucose clearance into insulin-sensitive tissues (e.g., muscle)  hyperglycemia.  Polyuria (osmotic diuresis) and polydipsia  Weight loss despite polyphagia  Others  Blurred vision, Symptoms of vulvovaginitis or other infections Hyperglycemia Causes Symptomsof Diabetes Mellitus

  6. Diagnosis of Diabetes: Reproducibly elevated plasma glucose concentrations . . .  Fasting plasma glucose  126 mg/dL (7.0 mmol/L)  Random plasma glucose  200 mg/dL (11.1 mmol/L) Assessment of Glycemic Control:  Hemoglobin A1c  Self Monitoring of Blood Glucose  Continuous Glucose Sensing Diagnosis and Ongoing Assessment of Diabetes Mellitus

  7. Types of Diabetes Mellitus An estimated 26 million Americans, and 285 million people world-wide, have diabetes.  Type 1 Diabetes Mellitus ( 5%)  Type 2 Diabetes Mellitus ( 95%)  Other types of diabetes include that due to pregnancy, pancreatectomy or pancreatitis, Cushing’s syndrome, Acromegaly, Pheochromocytoma or Glucagonoma among others.

  8. Characteristics of Types 1 and 2 Diabetes Mellitus T1DM T2DM (~0.25%) (~5.0%) Typical Age of Onset (years) < 30 > 40 Typical Body Habitus Lean Obese More Common in Minorities No Yes Clinical Onset Weeks Years Yes No Ketosis - Prone HLA (DR3/DR4; DQB non-Asp57) Associations Yes No Yes No Islet Cell, Insulin, GAD Antibodies

  9. Autoimmune pancreatic -cell destruction  absolute insulin deficiency  diabetes. Type 1 Diabetes Mellitus  Genetic susceptibility: ~25-50% concordance in monozygotic twins. ? Genes  Precipitating factor(s): Unknown (? viral infection, ? toxins, ? dietary factors)

  10. Initially insulin resistance with relative insulin deficiency, then progressive insulin deficiency. Type 2 Diabetes Mellitus  Genetic susceptibility: ~25-50% concordance in monozygotic twins. ? Genes  Precipitating factor(s): Obesity and Sedentary Life Style Regardless of which is the primary abnormality, relative or absolute insulin deficiency causes clinical diabetes.

  11. Acute Complications: Diabetic Ketoacidosis, Nonketotic Hyperosmolar Syndrome, (Hypoglycemia) Chronic Complications: Specific  Retinopathy, Nephropathy, Neuropathy (“microvascular” complications) Nonspecific  Premature Atherosclerosis (“macrovascular” complications) Complications of Diabetes Mellitus

  12. Treatment , including glycemic control, makes a difference for people with diabetes (DCCT, UKPDS). Treatment of Diabetes Mellitus • Diet/Exercise • Oral Hypoglycemic Agents • Parenteral GLP-1 Receptor Agonists • Insulin • Risk Factor Reduction Sulfonylureas, Glinides Biguanides (metformin) Thiazolidinediones -Glucosidase Inhibitors DPP-IV Inhibitors SGLT-2 Inhibitors (prevention of chronic complications Were it not for iatrogenic hypoglycemia, diabetes would be rather easy to treat.

  13. “Contradictions do not exist. Whenever you are facing a contradiction, check your premises. You will find that one of them is wrong.” Ayn Rand (1905-1982) Atlas Shrugged (1957)

  14. Washington University in St. Louis and Diabetes Research Philip E. Cryer, M.D. Irene E. and Michael M. Karl Professor of Endocrinology and Metabolism in Medicine, Washington University in St. Louis

  15. The Crucible of Science. The Story of the Cori Laboratory By John H. Exton Oxford University Press, New York, 2013

  16. Carl and Gerty Cori Born, Prague, 1896 Married, Vienna, 1920 Medical Graduates, Prague, 1920 To U.S., Buffalo, 1922 Washington University in St. Louis, 1931-1957/1966 Carl: Chair of Pharmacology, 1931 Chair of Biological Chemistry, 1946 Gerty: Professor Nobel Prize in Physiology or Medicine, 1947

  17. Nobel Laureates, Cori Lab 1947 Carl and Gerty Cori Enzymatic mechanisms, and actions of insulin, glucagon and epinephrine on, glycogen and glucose metabolism 1959 Arthur Kornberg DNA polymerase 1959 Severo Ochoa Polynucleotide phosphorylase 1970 Luis Leloir Nucleotide-sugar combinations 1971 Earl Sutherland Cyclic AMP 1974 Christian de Duve Lysosomes 1992 Edwin Krebs Phosphorylation

  18. William H. Daughaday (1918-2013) Suburban Chicago, Harvard College and Medical School, and Washington University in St. Louis 1947 Barnes Hospital, Asst. Resident (131I therapy program) 1948 Washington University, Fellow (Cori lab) 1950 Director of the Metabolism Division (through 1984) Discovery of “sulfation factor” = somatomedin = insulin-like growth factor I and II. Also, Corticosteroid binding globulin. National Academy of Sciences, 1986.

  19. David M. Kipnis (1927- ) Baltimore, University of Maryland, John Hopkins, Duke and Washington University in St. Louis 1955 Washington University, Fellow (Cori lab) 1960 Metabolism Division 1973 Chair, Department of Medicine (through 1993) Studied insulin stimulation of glucose transport/phosphory- lation and of amino acid uptake in muscle, glucagon actions in vivo, cyclic nucleotides, alanine and glutamine metabolic cycles and islet biology. Demonstrated the incretin effect, insulin deficiency as a cause of diabetes, and generic mechanisms of glucose counterregulation in humans. National Academy of Sciences, 1981.

  20. Banting Medal for Scientific Achievement, American Diabetes Association 1955 Carl F. Cori 1969 Earl W. Sutherland 1970 Paul Lacy 1977 David M. Kipnis 1979 Charles R. Park 1987 Joseph Larner 1994 Philip E. Cryer 1995 Franz M. Matschinsky Koch Medal, The Endocrine Society William H. Daughaday

  21. More Recent Senior Washington University Diabetes Investigators M. Alan Permutt – islet biology including ER stress, Wolfram Gene Philip E. Cryer – glucose counterregulation and hypoglycemia in diabetes Emil R. Unanue – immunology of type 1 diabetes Clay F. Semenkovich – fatty acid synthase Kenneth Polonsky – calculation of insulin secretory rate Fumihiko Urano – islet biology including ER stress, Wolfram syndrome Jean E. Schaffer and Many Others (The Diabetes Research Center lists 119 investigators)

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