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Diabetes Types 1 and 2

Diabetes Types 1 and 2. Darrell M Wilson, MD dwilson@stanford.edu. Insulin dependent IDDM Juvenile onset Brittle Type 1. Non-insulin dependent NIDDM Adult onset Type 2. Diabetes Mellitus. Atypical Diabetes. Costs Continue to Increase (U.S.) (in Billions of Dollars).

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Diabetes Types 1 and 2

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  1. DiabetesTypes 1 and 2 Darrell M Wilson, MD dwilson@stanford.edu

  2. Insulin dependent IDDM Juvenile onset Brittle Type 1 Non-insulin dependent NIDDM Adult onset Type 2 Diabetes Mellitus Atypical Diabetes

  3. Costs Continue to Increase (U.S.)(in Billions of Dollars) Diabetes Care 26:917-932, 2003

  4. ADA Classification, 2004

  5. MODY • MODY 1 • hepatocyte nuclear factor-4-alpha (600281) • MODY 2 • glucokinase IV (125851) • MODY 3 • hepatocyte nuclear factor-1-alpha (600496)

  6. Glucose Sensing Closes K+ channel Opens Ca++ channel Glucose Insulin GLUT-2 Ca++granule translocation & exocytosis K+depolarizes cell Glucose Glucokinase Glucose 6-phosphate Sulphonylurea receptor closes K+channel Glycolysis ATP

  7. Environmental triggers Genetics Insulitis Type 1 Diabetes Diabetes Exposure Renal Complications Eye Complications Large Vessels

  8. Honeymoon

  9. Incidence – EuropeBy Pediatric Age Group Green Diabetol 2001

  10. Travis, DM in Children, MPCP#29, 1987

  11. Incidental hyperglycemia Incidentally discovered diabetes routine sports PE relative with diabetes The polys, No DKA Diabetic ketoacidosis Modes of Discovery

  12. Symptoms and Signs

  13. ADA Guidelines for Diabetes 1. Symptoms + casual glucose >200 2. Fasting plasma glucose >125 3. Glucose in OGTT @ 2 hr >200 • OGTT not recommend for routine clinical practice • in absence of metabolic decompensation, must be repeated on a different day • Normal – fasting <100, 2 hr <140

  14. Pitfalls in the Diagnosis of Diabetes • Think diabetes • in flu season • polyuria • Never ignore a parent • Never ignore the diagnosis • delay is the deadliest form of denial

  15. Initial Phases of Management • Diagnosis • Metabolic control • Patient and family education • techniques • physiology • diet • Family support

  16. Diabetic Emergencies • Diabetic Ketoacidosis (DKA) • recurrent DKA • Severe Hypoglycemia • Hyperosmolar Non-ketotic Coma (HNC)

  17. What Kills Diabetics in DKA? • Cerebral edema (brain swelling) • Hyperkalemia • Hypokalemia • Dehydration

  18. Treatment Goals • First order view • replace missing insulin • Second order view • do it correctly • avoid high blood glucose • avoid low blood glucose • continue to have a life • Limits of current technology

  19. Insulin Replacement • Conventional insulin therapy • pump or injection • can be closed loop, but often fully open loop • Transplants • Bio-sensing polymers • Glucose sensing mechanical pumps

  20. The Core Compromise of Diabetes

  21. Acute DKA brain swelling metabolic others Hypoglycemia Chronic Complications macrovascular heart lower extremities microvascular retinopathy nephropathy neuropathy What Kills Diabetics?

  22. Historical Control Concepts • “Keep them sweet” • a bit of glucose in the urine • Very limited technology for monitoring • Most pediatricians (still) don’t have to deal with complications http://jchemed.chem.wisc.edu/JCESoft/CCA/CCA5/MAIN/1ORGANIC/ORG18/TRAM18/B/1001311/PICTURE.HTM?3

  23. Measurement of Glucose • Direct • Methods • meters • future sensors • Data analysis • average • variability • extremes

  24. Measuring GlucoseMeters 2005 www.diabeteshealth.com

  25. GlucoseData Analysis

  26. GlucoseData Analysis

  27. Burmeister DTT 2:12, 2000

  28. Measurement of Glucose • Indirect • Glycated proteins • glycated hemoglobin • total glycated hemoglobin • hemoglobin A1c (HbA1c) • glycated albumin • glycated LDL • other glycated proteins

  29. Hemoglobin A1c http://www.cem.msu.edu/~cem252/sp97/ch18/ch18s20.GIF

  30. Hemoglobin A1c http://home.comcast.net/~creationsunltd/images/comparebsandhga1c.gif

  31. DCCT DCCT NEJM, 329:977,1993

  32. Glucose Control DCCT NEJM, 329:977,1993

  33. Glucose ControlGlycosylated Hemoglobin DCCT NEJM, 329:977,1993

  34. RetinopathyPrimary Prevention DCCT NEJM, 329:977,1993

  35. AlbuminuriaPrimary Prevention >300 mg/24hr >40 mg/24hr DCCT NEJM, 329:977,1993

  36. Who Gets Complications? • Only about 50% of diabetics appear to be at high risk for complications • Potential risk areas • Lipoprotein metabolism • Glycation pathways • Oxidation pathways • The hemostatic cascade • Other candidate genes.

  37. Mechanisms of Complications • The “glucose hypothesis” • acute/reversible • increased polyols (sugar alcohols) • sorbitol in insulin independent tissues • increase in NADH/NAD+ ratios • decreased myoinositol • early glycation products • chronic/irreversible • advanced glycation end-products (AGE)

  38. Other Factors Associated with Complications • Hypertension • Lipids • Smoking • Age • Sex • Ethnicity • SES

  39. Risk Modifiers • Direct treatment • laser treatment of retinopathy • kidney transplant • CVS

  40. Risks of Tight Control • Hypoglycemia • relationship to age • permanent damage • performance impairment • detection • often missed, frequently at night

  41. Neurogenic adrenergic anxiety tremor palpitations increased HR cholinergic sweating hunger paraesthesias Neuroglycopenic changes in mentation coma rarely focal seizures death Symptoms of Hypoglycemia

  42. Driving While Low Cox, Diabetes, 42:239, 1993

  43. Seizures Are Bad (Duh!) • 16 children, 7 years, 9 had seizures • lower perceptual, motor, memory, attention • Rovet, J Peds, 134:503, 1999 • 55 children, 2.6 years, 8 had seizures • decreased memory skills • Kaufman, J Diab Compli, 13:31, 1999

  44. How Low Should We Go? • Current answer - As low as possible without significant hypoglycemia • actual glycemic goals vary: • age • personality • family support • medical support • etc

  45. The Era of Attempted Tight Control • Hyperglycemia causes (correlates with) complications • DCCT data (among others) • New technology • blood glucose meters • glycated hemoglobin • insulin delivery systems • pumps • inhaled insulin • insulin analogs (eg lispro)

  46. Current Practice • As low as possible without (significant) hypoglycemia • Limited by technology • Limited by family time • Limited by professional time

  47. Insulin Types • Very short acting • Lispro, Insulin aspart, insulin glulisine • Short acting • Regular, Semi-lente • Intermediate acting • NPH, Lente • Long acting • insulin detemir, Ultralente • Very long acting • Glargine

  48. Insulin Action(hours)

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