1. Diabetes Mellitus Talya Wolak

2. Overview Diabetes mellitus is a chronic disorder characterized by the impaired metabolism of glucose Late development of vascular and neuropathic complications

3. Classification Type 1 -A. Immune-mediated B. Idiopathic Type 2 Other specific types Gestasional diabetes mellitus

4. Other Specific Types Of Diabetes Endocrinopathies—acromegaly, cushing's syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma Genetic defects of cell function –MODY Drug- or chemical-induced—Vacor, pentamidine, nicotinic acid, glucocorticoids, thyroid hormone, diazoxide, -adrenergic agonists, thiazides, phenytoin, -interferon, protease inhibitors, clozapine, beta blockers

5. How To Define Diabetes? The spectrum of fasting plasma glucose and the response to an oral glucose load varies among normal individuals DM is defined as the level of glycemia at which diabetes-specific complications occur

6. Terminology Diabetes Mellitus -DM Fasting plasma glucose -FPG Impaired fasting glucose –IFG Impaired glucose tolerance –IGT

7. Diagnostic Criteria For DM FPG at or above 126 mg/dL A two-hour value in an OGTT (2-h PG) at or above 200 mg/dL A random plasma glucose concentration 200 mg/dL in the presence of symptoms.

8. Diabetes Mellitus IGF&IGTNormal FPG>=126 mg/dL IGF- FPG :100- 126 mg/dL FPG<100 mg/dL 2H-PG>=200 mg/dL IGT - 2H-PG: 140-200 mg/dL 2H-PG<140 mg/dL PG>200 + SYMPTOMS

9. Impaired Glucose Tolerance -IGT Category between normality and diabetes Subjects with IGT are at increased risk of developing overt diabetes and atherosclerotic vascular disease

10. Con… Abnormalities on screening tests for diabetes should be repeated before making a definitive diagnosis of DM Unless acute metabolic derangements or a markedly elevated plasma glucose are present

11. Type 2 DM Screening The FPG as a screening test for type 2 DM is recommended

12. Why ? Type 2 DM may be present for up to a decade before diagnosis A large number of individuals who meet the current criteria for DM are asymptomatic.

13. 50% of individuals with type 2 DM have one or more diabetes-specific complications at the time of their diagnosis Treatment of type 2 DM may favorably alter the natural history of DM

14. Type I DM Screening Screening for type 1 DM is no recommended In contrast to type 2 DM, a long asymptomatic period of hyperglycemia is rare prior to the diagnosis of type 1 DM

15. Prevalence of DM Has risen dramatically over the past two decades The prevalence of both type 1 and type 2 DM is increasing worldwide The prevalence of type 2 DM is expected to rise more - increasing obesity and reduced activity levels

17. Type IA Pthogenesis

18. Decline

19. Beta cell mass then begins to decline, and insulin secretion becomes progressively impaired, although normal glucose tolerance is maintained. Residual functional beta cells still exist but are insufficient in number to maintain glucose tolerance.

20. The events that trigger the transition from glucose intolerance to frank diabetes: associated with increased insulin requirements, as infections or puberty. Features of diabetes do not become evident until a majority of beta cells are destroyed ( 80%).

22. "Honeymoon" Phase Time glycemic control is achieved with modest doses of insulin or, rarely, insulin is not needed. fleeting phase of endogenous insulin production from residual beta cells disappears as the autoimmune process destroys the remaining beta cells The individual becomes completely insulin deficient

23. Genetic Factor Genetic susceptibility to type 1A DM involves multiple genes. The major susceptibility gene for type 1A DM is located in the HLA region on chromosome 6. The risk of developing type 1A DM is increased tenfold in relatives of individuals with the disease

24. Autoimmune Factors The pancreatic islets are infiltrated with lymphocytes - Insulitis Pancreatic islet molecules targeted by the autoimmune process include insulin, glutamic acid decarboxylase

25. Immunologic Markers -ICAs Islet cell autoantibodies (ICAs) - different antibodies directed at pancreatic islet molecules: GAD, insulin, IA-2/ICA-512, and an islet ganglioside Serve as a marker of the autoimmune process of type 1A DM. Assays for autoantibodies to GAD-65 are available.

26. Testing for ICAs Classifying the type of DM as type IA Identifying nondiabetic individuals at risk for developing type 1A DM

27. ICAs Are Present : In individuals diagnosed with new-onset type 1A DM (>75%) In individuals with newly diagnosed type 2 DM (5 to 10%) Individuals with GDM (<5%) 3 to 4% of first-degree relatives of individuals with type 1A DM

28. Markers Genetic markers -present from birth Immune markers - after the onset of the autoimmune process Metabolic markers can be detected with sensitive tests once enough beta-cell damage, but before the onset of symptomatic hyperglycemia

29. Prediction Of Type 1A DM ICAs In combination with impaired insulin secretion after intravenous glucose tolerance testing, they predict a >50% risk of developing type 1A DM within 5 years

30. Environmental Factors Trigger the autoimmune process in genetically susceptible individuals Viruses (coxsackie and rubella most prominently), bovine milk proteins None have been conclusively linked to diabetes

31. Prevention of Type 1A DM Though results in animal models are promising have not been successful in preventing type 1A DM in humans. The Diabetes Prevention Trial—type 1 recently concluded that administering insulin to individuals at high risk did not prevent type 1A DM

32. Type II Pthogenesis

33. Type 2 DM 1.Insulin resistance 2.Abnormal insulin secretion Insulin resistance precedes insulin secretory defects Diabetes develops only if insulin secretion becomes inadequate

34. Genetic Considerations Type 2 DM has a strong genetic component. Major genes that predispose to this disorder have yet to be identified The disease is polygenic and multifactorial Insulin resistance is present in many nondiabetic, first-degree relatives of individuals with type 2 DM

35. Some Numbers The concordance of type 2 DM in identical twins is between 70 and 90% If both parents have type 2 DM, the risk approaches 40%

36. Pathophysiology -Type 2 DM Peripheral insulin resistance Impaired insulin secretion Excessive hepatic glucose production

37. Insulin Resistance Insulin resistance is a state in which a given concentration of insulin is associated with a subnormal glucose response

38. Early Stages Insulin resistance Pancreatic beta cells compensate by increasing insulin output - hyperinsulinisim Glucose tolerance remains normal

39. Impaired Glucose Tolerance As insulin resistance and compensatory hyperinsulinemia progress Pancreatic islets are unable to sustain the hyperinsulinemic state - Impaired insulin secretion IGT- elevations in postprandial glucose develops

40. Diabetes Mellitus A further decline in insulin secretion An increase in hepatic glucose production Fasting hyperglycemia Overt diabetes mellitus

41. In The End… Ultimately, beta cell failure may ensue. Markers of inflammation such as IL-6 and C-reactive protein are often elevated in type 2 diabetes May become insulin deficient

42. Insulin Resistance The decreased ability of insulin to act effectively on peripheral target tissues - muscle and liver Prominent feature of type 2 DM Results from a combination of genetic susceptibility and obesity

43. Supernormal levels of circulating insulin will normalize the plasma glucose Reduced sensitivity, and a reduced maximal response, indicating an overall decrease in maximum glucose utilization (30 to 60% lower than normal individuals).

44. Insulin Resistance- hyperglycemia 1.Impairs glucose utilization by insulin- sensitive tissues 2.Increases hepatic glucose output Both effects contribute to the hyperglycemia.

45. FPG Versus IGT Increased hepatic glucose output predominantly accounts for increased FPG levels Decreased peripheral glucose usage results in postprandial hyperglycemia - IGT

46. Molecular Mechanism Of Insulin Resistance Insulin receptor levels and tyrosine kinase activity in skeletal muscle are reduced, - not primary defect Postreceptor defects are believed to play the predominant role in insulin resistance

47. Free Fatty Acids Free fatty acids a common feature of obesity : 1.Can impair glucose utilization in skeletal muscle 2.Promote glucose production by the liver 3.Impair beta cell function

48. Obesity

49. Visceral or central obesity (as evidenced by the hip-waist ratio), is very common in type 2 DM. Adipocytes secrete a number of biologic products (leptin, TNF-, free fatty acids, resistin, and adiponectin) Modulate insulin secretion, insulin action, and body weight contribute to the insulin resistance.

50. Impaired Insulin Secretion Insulin secretion initially increases in response to insulin resistance to maintain normal glucose tolerance The insulin secretory defect progresses to a state of grossly inadequate insulin secretion

51. Why? Excluded mutations in islet candidate genes Islet amyloid polypeptide found in the islets of individuals with long-standing type 2 DM Glucose toxicity Lipotoxicity

52. Glucose Toxicity & Lipotoxicity Chronic hyperglycemia paradoxically impairs islet function Leads to a worsening of hyperglycemia. Improvement in glycemic control associated with improved islet function Elevation of free fatty acid levels and dietary fat also worsen islet function.

53. Increased Hepatic Glucose Production Insulin resistance in the liver - failure of hyperinsulinemia to suppress gluconeogenesis Fasting hyperglycemia Decreased glycogen storage by the liver in the postprandial state

54. Insulin secretory abnormalities Insulin resistance in skeletal muscle. Increased hepatic glucose production.

55. Insulin Resistance Syndromes The metabolic syndrome The insulin resistance syndrome Syndrome X

56. Definition The presence of any three of the following traits: 1.Abdominal obesity- a waist circumference in men >102 cm and in women >88 cm 2.Serum triglycerides 150 mg/dL 3.Serum HDL cholesterol <40 mg/dL in men and <50 mg/dL in women.

57. Definition con. 4. Blood pressure >130/85 mmHg. 5. Fasting plasma glucose > 110 mg/dL

58. Rare Forms Of Severe Insulin Resistance Include features of type 2 DM or IGT Type A- young women Type B- middle-aged women Severe hyperinsulinemia, obesity, and features of hyperandrogenism

59. Polycystic Ovary Syndrome PCOS Premenopausal women - chronic anovulation and hyperandrogenism Insulin resistance Increases the risk for type 2 DM. Both metformin and the thiazolidinediones attenuate hyperinsulinemia, ameliorate hyperandrogenism, induce ovulation, and improve plasma lipids

60. Prevention in IGT Intensive changes in life-style in individuals with : 1.Diet 2.Exercise for 30 min/day five times/week Prevented or delayed the development of type 2 diabetes by 58% compared to placebo

61. Prevention in IGT con. Metformin prevented or delayed diabetes by 31% compared to placebo

62. For Who? Strong family history IFG or IGT Strongly encouraged to maintain a normal body mass index (BMI) and engage in regular physical activity.