Diabetes: Causes and consequences

1. Diabetes: Causes and consequences Carlos O. Mendivil , MD

2. A syndrome Heterogeneous Characterized by high blood glucose Not curable as of today Potentially fatal (directly or indirectly) What is Diabetes? It is:

3. What causes Diabetes Mellitus? Multifactorial Environmental factors Genetic factors There is always a deficit of INSULIN ACTION

4. 9 25 0 0 ´05 ´63 Year What causes Diabetes Mellitus? Trends in the prevalence and incidence of diabetes and obesity in the US Obesity prevalence Diabetes incidence % Diabetes prevalence ADA Scientific Sessions, Chicago, 2007

5. Why is there insuficient insulin action? 1 Secretory dysfunction in pancreatic beta cells Relative or absolute deficit of insulin secretion 2 Insulin resistance Insuficient tissue response to the actions of insulin, DESPITE NORMAL CONCENTRATIONS of insulin

6. How does diabetes affect the body ? • Insuficient insulin action alters metabolism of: • Lipids • Carbohydrates • - Proteins Complications Acute Chronic • Severe • Disabling • - Debilitating • Costly • - Some of them may cause death Life-threatening

7. The chronic complications of diabetes Microvascular Macrovascular Coronary disease Nephropathy Neuropathy Cerebrovascular disease Retinopathy Peripheral Arterial disease + Orthopedic alterations Metabolic alterations Diabetic foot

8. DM is the #1 cause of renal failure worldwide Why are the complications of diabetes important? The kidney foundation: www.kidney.org

9. Worlwide #1 cause of: Acquired blindness Amputation not due to trauma Contributes importantly to the risk of: Myocardial infarction (heart attacks) Cerebrovascular disease (strokes) Why are the complications of diabetes important?

10. Diabetic retinopathy www.ambrosio-eye-care-boston.com

11. Diabetic nephropathy

12. The progression of diabetic nephropathy http://www.videolife.tk/video/ikGl7DPXUK0/Diabetic-Nephropathy.html

13. Diabetic neuropathy

14. The “diabetic foot”

16. Diabetes and erectile dysfunction

17. % Why are the complications of diabetes important? Diabetes and risk of myocardial infarction 45 20 18,8 3,5 NO DM NO prior MI NO DM Prior MI DM NO prior MI DM + prior MI Haffner et al NEJM 1997

18. Why are the complications of diabetes important? Because they can be avoided !! Joslin fifty year medal Given to patients who live at least 50 years after the diagnosis of type 1 diabetes More than 2,500 granted so far

19. Diagnosis of Diabetes Mellitus 1 Random plasma glucose 2 Fasting plasma glucose (FPG) 3 Oral glucose tolerance test (OGTT) 4 Glycated hemoglobin (A1c)

20. Fasting Normal IFG DM 100 mg/dL 126 mg/dL Postload Normal IGT DM 140 mg/dL 200 mg/dL Pre- diabetes A1c Normal DM 6% 6.5%

21. What’s the difference ? Diabetes Care 2003; suppl 1:S5

22. When two different tests classify a patient differently, he must be classified in the most severe category

23. Which tests DO NOTdiagnose diabetes ? Capillary glucose Fructosamine C peptide Insulinemia Triglycerides

24. Classification of Diabetes Mellitus

25. Classification of Diabetes Mellitus Type1 Type 2 Gestational Other types

26. Destruction of beta cells Autoimmune process Total or near total insulin deficiency Insulin required for survival More incident in infancy and puberty High propensity to ketoacidosis Predilection for female gender and caucasian ethnicity Type 1 diabetes

27. Classification of Diabetes Mellitus Type1 Type 2 Gestational Other types

28. Relative secretory dysfunction of beta cells Relative insulin deficit Peripheral resistance to insulin actions 80% of patients are overweight More incident in adulthood and older age Less prone to ketoacidosis Not as much gender/ethnicity imbalance Type 2

29. Classification of Diabetes Mellitus Type1 Type 2 Gestational Other types

30. Gestational diabetes Any degree of carbohydrate intolerance That is discovered during pregnancy

31. Classification of Diabetes Mellitus Type1 Type 2 Gestational Other types

32. What’s the origin of type 1 diabetes ?

33. Environmental trigger Loss of first peak of insulin secretion IGT IFG T1DM Compl The natural history of type 1 diabetes 100% Genetic susceptibility Auto immunity % intact beta cells Time

34. 100% % intact beta cells Genetic susceptibility Time The natural history of type 1 diabetes

35. Genetic susceptibility to type 1 diabetes RISK MARKERS HLA Class II IDDM 1-12 markers HLA DR HLA DQ HLA Gene cluster in chromosome 6p Class 1 Class 2 DP DQ alfa DQ beta DR A B C

36. Lymphocyte selection during embryonic life Recognizes very well x “Half recognizes” Does not recognize x Pre-T lymphocyte Proteins of the body Thymus dendritic cell T-cell receptor HLA class II molecule

37. Hypotheses about HLA and type 1 diabetes Some class II HLA’s present self-antigens better Sme HLA class II activate helper lymphocytes better Some HLA’s class II activate regulatory T Lymphocytes better

38. Environmental trigger 100% % intact beta cells Genetic susceptibility Time The natural history of type 1 diabetes

39. Environmental trigger 100% Genetic susceptibility % intact beta cells Auto immunity Time The natural history of type 1 diabetes

40. How is the autoimmune process manifested? IAA Insulin Antibodies ICA Islet Cell Antibodies GADA Glutamic Acid Decarboxylase Antibodies IA-2 Ab’s against IA-2 phosphatase

41. Environmental trigger Loss of first insulin Secretory peak 100% Genetic susceptibility % intact B cells Auto immunity IGT IFG T1 DM The natural history of type 1 diabetes What determines the speed of progression ?

42. Determining factors in the progression of type 1 diabetes Earlierage at diagnosis Faster progression Age Faster progression Sex Male Faster progression # of antibodies More Ketoacidosis at diagnosis Faster progression

43. Environmental trigger Loss of first insulin Secretory peak Genetic susceptibility Auto immunity IGT IFG T1 DM Compl The natural history of type 1 diabetes

44. What is the origin of type 2 diabetes ? The Natural History of Insulin Secretory Dysfunction and Insulin Resistance in the Pathogenesis of type 2 Diabetes Mellitus Journal of Clinical Investigation, Vol 104 #6 Sep 1999

45. Type 2 diabetes is characterized by 4 basic metabolic Disturbances: Obesity Insulin resistance Insulin secretory dysfunction Increase in hepatic glucose production (HGP)

46. Methods 1982 404 individuals from the Gila River community in Arizona Clinical history, physical exam, routine labs Measurement of: Body composition Insulin sensitivity Fat distribution Hepatic glucose production Glucose tolerance Yearly follow-ups for over a decade (11 yrs) Bogardus et al, JCI 2000

47. Fasting 30 m post 120 min post 2000 1800 1600 1400 1200 1000 pmol/L 800 600 400 200 NGT NGT IGT NGT DM2 NGT Insulin response Progressors Nonprogressors

48. 5 4,5 4 3,5 3 2,5 2 1,5 1 0,5 NGT NTG NGT NTG DM2 NTG Insulin sensitivity in muscle Progressors Nonprogressors M (mg/Kg EBMS/min)

49. Beta cell function 500 Progressors 450 Nonprogressors 400 350 300 Acute Insulin Response (microUI/ml) 250 200 150 100 50 NTG NTG IHC NGT DM2 NGT

50. Liver glucose production 5 Progressors 4,5 Nonprogressors 4 3,5 3 EGO (mg/Kg EBMS/min) 2,5 2 1,5 1 0.5 NTG NTG IHC NGT DM2 NGT