1 / 28

Targeting the Underlying Pathophysiology of Type 2 Diabetes

Targeting the Underlying Pathophysiology of Type 2 Diabetes. This slideset was developed with support from GlaxoSmithKline. Aim. Provide practical guidance on improving diabetes care through highlighting the need to:

janeg
Download Presentation

Targeting the Underlying Pathophysiology of Type 2 Diabetes

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Targeting the Underlying Pathophysiology of Type 2 Diabetes This slideset was developed with support from GlaxoSmithKline

  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.

More Related