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Targeting the Underlying Pathophysiology of Type 2 Diabetes

Targeting the Underlying Pathophysiology of Type 2 Diabetes. Aim. Provide practical guidance on improving diabetes care through highlighting the need to: understand that insulin resistance and b -cell dysfunction are core defects of type 2 diabetes address the underlying pathophysiology.

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Targeting the Underlying Pathophysiology of Type 2 Diabetes

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  1. Targeting the Underlying Pathophysiology of Type 2 Diabetes

  2. Aim Provide practical guidance on improving diabetes care through highlighting the need to: • understand that insulin resistance and b-cell dysfunction are core defects of type 2 diabetes • address the underlying pathophysiology

  3. Type 2 diabetes • Characterized by chronic hyperglycemia • Associated with microvascular and macrovascular complications • Generally arises from a combination of insulin resistance and -cell dysfunction Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc

  4. IR What is insulin resistance? • Major defect in individuals with type 2 diabetes1 • Reduced biological response to insulin1–3 • Strong predictor of type 2 diabetes4 • Closely associated with obesity5 1American Diabetes Association. Diabetes Care 1998; 21:310–314. 2Beck-Nielsen H & Groop LC. J Clin Invest 1994; 94:1714–1721. 3Bloomgarden ZT. Clin Ther 1998; 20:216–231. 4Haffner SM, et al. Circulation 2000; 101:975–980. 5Boden G. Diabetes 1997; 46:3–10.

  5.    What is -cell dysfunction? • Major defect in individuals with type 2 diabetes • Reduced ability of -cells to secrete insulin in response to hyperglycemia DeFronzo RA, et al. Diabetes Care 1992; 15:318–354.

  6. Genetic susceptibility, obesity, Western lifestyle Insulin resistance b-cell dysfunction  IR Type 2 diabetes Insulin resistance and -cell dysfunction are core defects of type 2 diabetes Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.

  7. Insulin resistance Increased insulinresistance Insulin secretion Hyperinsulinemia, then -cell failure Post-prandial glucose Abnormal glucose tolerance Fasting glucose Hyperglycemia *IGT = impaired glucose tolerance Normal IGT* Type 2 diabetes Adapted from Type 2 Diabetes BASICS. International Diabetes Center (IDC), Minneapolis, 2000. How do insulin resistance and -cell dysfunction combine to cause type 2 diabetes?

  8. How is insulin resistance measured? • Several methods exist, including: • continuous sampling of insulin/glucose1 • gold standard, but impractical for large-scale use • single measure of insulin/glucose2 • simple estimate from fasting insulin and glucose • useful for assessment on a larger scale 1Bergman RN, et al. Eur J Clin Invest 2002; 32 (Suppl. 3):35–45. 2Matthews DR, et al. Diabetologia 1985; 28:412–419.

  9. More than 80% of patients progressing to type 2 diabetes are insulin resistant Insulin sensitive;low insulin secretion (16%) Insulin sensitive;good insulin secretion (1%) Insulin resistant;low insulin secretion (54%) 83% Insulin resistant; good insulin secretion (29%) Haffner SM, et al. Circulation 2000; 101:975–980.

  10. IR Insulin resistance – reduced response to circulating insulin Insulin resistance Adiposetissue Liver Muscle  Glucoseoutput  Glucose uptake  Glucoseuptake Hyperglycemia

  11. Overall, 75% of patients with type 2 diabetes die from cardiovascular disease Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences.

  12. Insulin resistance is as strong a risk factor for cardiovascular disease as smoking 1.8 1.6 1.4 Odds ratio for incident CVD 1.2 1.0 0.8 0.6 Age Smoking Insulinresistance Total cholesterol:HDL cholesterol Bonora E, et al. Diabetes Care 2002; 25:1135–1141.

  13. IR Insulin resistance is closely linked to cardiovascular disease Present in> 80%of people with type 2 diabetes1 Approximatelydoublesthe risk of a cardiac event2 Implicated in almosthalfof CHD events in individuals with type 2 diabetes2 Insulin resistance 1Haffner SM, et al. Circulation 2000; 101:975–980. 2Strutton D, et al. Am J Man Care 2001; 7:765–773.

  14. Hyperglycemia Dyslipidemia Hypertension Damage to blood vessels Clotting abnormalities Inflammation Insulin resistance IR Atherosclerosis Insulin resistance is linked to a range of cardiovascular risk factors Zimmet P. Trends Cardiovasc Med 2002; 12:354–362.

  15. ~90% of people with type 2 diabetes are overweight or obese World Health Organization, 2005. http://www.who.int/dietphysicalactivity/publications/facts/obesity

  16. How is -cell function measured? • -cell function is difficult to measure and most methods are impractical for large-scale use1 • Homeostasis model assessment (HOMA) provides a simple estimate of -cell function2 • Proinsulin:insulin ratio is sometimes used as a marker of -cell dysfunction1 1Matthews DR, et al. Diabetologia 1985; 28:412–419. 2Bergman RN, et al. Eur J Clin Invest 2002; 32 (Suppl. 3):35–45.

  17. Why does the -cell fail? Oversecretion of insulin to compensate for insulin resistance1,2 Glucotoxicity2 Lipotoxicity3 Chronic hyperglycemia High circulating free fatty acids Pancreas -cell dysfunction 1Boden G & Shulman GI. Eur J Clin Invest 2002; 32:14–23. 2Kaiser N, et al. J Pediatr Endocrinol Metab 2003; 16:5–22. 3Finegood DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20–S27.

  18. Diet Sulfonylurea or insulin Median HbA1c (%) 6.2% upper limit of normal range 0 3 6 9 12 15 Years from randomization Glycemic control declines over time 9 8 7 6 0 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837–853.

  19. Loss of -cell function occurs before diagnosis 100 Up to 50% loss Diagnosis 80 60 -cell function (%) 40 20 0 1 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 2 3 4 5 6 Time from diagnosis (years) Holman RR. Diabetes Res Clin Prac 1998; 40 (Suppl.):S21–S25.

  20. Oral antidiabetic agents – do they target insulin resistance and -cell dysfunction?

  21. Barriers to achieving good glycemic control Inadequate targeting of underlying pathophysiology

  22. -glucosidase inhibitors Sulfonylureas/meglitinides  Carbohydrate breakdown/absorption  Insulin secretion Primary sites of action of oral antidiabetic agents Biguanides Thiazolidinediones  Insulin resistance  Glucoseoutput  Insulin resistance Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40. Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.

  23. IR The dual action of thiazolidinediones reduces HbA1c + -cell function Insulin resistance HbA1c Lebovitz HE, et al. J Clin Endocrinol Metab 2001; 86:280–288.

  24. Potential to prevent progression to type 2 diabetes in at-risk women Troglitazone reduced progression to type 2 diabetes by > 50% Troglitazone* 400 mg/day 0.6 Placebo 0.5 0.4 Proportion with diabetes 0.3 0.2 0.1 0.0 60 0 10 20 30 40 50 Time on trial (months) *Troglitazone is no longer available Buchanan TA, et al. Diabetes 2002; 51:2796–2803.

  25. Can thiazolidinediones delay progression from IGT to T2DM? Placebo Rosiglitazone 8 mg/day 100 T2DM 11% 80 IGT 56% 60 Subjects (%) IGT IGT IGT 100% 100% 89% 40 NGT 20 44% 0 Screening Week 12 Screening Week 12 Bennett SM, et al. Diabet Med 2004; 21:415–422.

  26. Sulfonylureas/insulin Metformin Myocardial infarction All-cause mortality Myocardial infarction All-cause mortality 21% 8% 39% 36% Not significant Not significant Significant Significant Does decreasing insulin resistance decrease macrovascular complications? UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854–865.

  27. Insulin sensitizers reduce cardiovascular events in type 2 diabetes 60 50 40 30 12-month combined event rate (%) 20 10 0 Non-sensitizers Sensitizers Kao JA, et al. J Am Coll Cardiol 2004; 43:37A.

  28. How can diabetes care and outcomes be improved? The Global Partnership recommends: Address the underlying pathophysiology, including treatment of insulin resistance Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.

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