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Targeting the Underlying Pathophysiology of Type 2 Diabetes

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Targeting the Underlying Pathophysiology of Type 2 Diabetes PowerPoint Presentation

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Slide 1 - Targeting the Underlying Pathophysiology of Type 2 Diabetes
Slide 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
Slide 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
Slide 4 - Major defect in individuals with type 2 diabetes1 Reduced biological response to insulin1–3 Strong predictor of type 2 diabetes4 Closely associated with obesity5 What is insulin resistance? 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.
Slide 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.
Slide 6 - 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.
Slide 7 - How do insulin resistance and -cell dysfunction combine to cause type 2 diabetes?
Slide 8 - 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 How is insulin resistance measured? 1Bergman RN, et al. Eur J Clin Invest 2002; 32 (Suppl. 3):35–45. 2Matthews DR, et al. Diabetologia 1985; 28:412–419.
Slide 9 - More than 80% of patients progressing to type 2 diabetes are insulin resistant Insulin resistant;low insulin secretion (54%) Insulin resistant; good insulin secretion (29%) Insulin sensitive;good insulin secretion (1%) Insulin sensitive;low insulin secretion (16%) 83% Haffner SM, et al. Circulation 2000; 101:975–980.
Slide 10 - Insulin resistance – reduced response to circulating insulin Insulin resistance  Glucose output  Glucose uptake  Glucose uptake Hyperglycemia Liver Muscle Adiposetissue
Slide 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.
Slide 12 - Insulin resistance is as strong a risk factor for cardiovascular disease as smoking 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Odds ratio for incident CVD Age Smoking Total cholesterol:HDL cholesterol Insulinresistance Bonora E, et al. Diabetes Care 2002; 25:1135–1141.
Slide 13 - Insulin resistance is closely linked to cardiovascular disease Present in > 80% of people with type 2 diabetes1 Approximately doubles the risk of a cardiac event2 Implicated in almost half of 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.
Slide 14 - Insulin resistance is linked to a range of cardiovascular risk factors Zimmet P. Trends Cardiovasc Med 2002; 12:354–362.
Slide 15 - ~90% of people with type 2 diabetes are overweight or obese World Health Organization, 2005. http://www.who.int/dietphysicalactivity/publications/facts/obesity
Slide 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.
Slide 17 - Why does the -cell fail? Chronic hyperglycemia Oversecretion of insulin to compensate for insulin resistance1,2 High circulating free fatty acids Glucotoxicity2 Pancreas Lipotoxicity3 -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.
Slide 18 - Glycemic control declines over time 9 8 7 6 0 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837–853.
Slide 19 - Loss of -cell function occurs before diagnosis Time from diagnosis (years) Up to 50% loss 100 80 60 40 -cell function (%) 20 0 Diagnosis -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 1 2 3 4 5 6 Holman RR. Diabetes Res Clin Prac 1998; 40 (Suppl.):S21–S25.
Slide 20 - Oral antidiabetic agents – do they target insulin resistance and -cell dysfunction?
Slide 21 - Barriers to achieving good glycemic control Inadequate targeting of underlying pathophysiology
Slide 22 - Primary sites of action of oral antidiabetic agents  Glucose output  Insulin resistance Biguanides  Insulin resistance Thiazolidinediones 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.
Slide 23 - The dual action of thiazolidinediones reduces HbA1c + HbA1c Insulin resistance -cell function Lebovitz HE, et al. J Clin Endocrinol Metab 2001; 86:280–288.
Slide 24 - Potential to prevent progression to type 2 diabetes in at-risk women Troglitazone reduced progression to type 2 diabetes by > 50% Proportion with diabetes 0.5 0.6 0.4 0.3 0.2 0.1 0.0 Time on trial (months) 10 0 20 30 40 50 60 Placebo Troglitazone* 400 mg/day Buchanan TA, et al. Diabetes 2002; 51:2796–2803. *Troglitazone is no longer available
Slide 25 - Subjects (%) 100 Screening 80 60 40 20 0 Week 12 Screening Week 12 Placebo Rosiglitazone 8 mg/day IGT 100% IGT 89% T2DM 11% IGT 100% NGT 44% IGT 56% Can thiazolidinediones delay progression from IGT to T2DM? Bennett SM, et al. Diabet Med 2004; 21:415–422.
Slide 26 - Does decreasing insulin resistance decrease macrovascular complications? UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854–865.
Slide 27 - Insulin sensitizers reduce cardiovascular events in type 2 diabetes 12-month combined event rate (%) 0 10 20 30 40 Non-sensitizers Sensitizers 50 60 Kao JA, et al. J Am Coll Cardiol 2004; 43:37A.
Slide 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.