1. Type 2 diabetes and cardiovascular disease Christopher D. Byrne FRCPath FRCP PhD Professor of Endocrinology & Metabolism Director of Wellcome Trust Clinical Research Facility Southampton University Hospitals Trust

4. Impact of diabetes on the average annual age-adjusted incidence/1,000 cardiovascular events in men and women aged 45-74 years from the Framingham study

6. STABLE ATHEROSCLEROTIC PLAQUE fibrous cap (smooth muscle cells & matrix) lipid core adventitia endothelial cells intimal smooth muscle cells (repair phenotype) medial smooth muscle cells (contractile phenotype)

7. adventitia lipid core UNSTABLE CORONARY ARTERY DISEASE

8. Accumulation of modified lipid Endothelial cell activation Inflammatory cell migration Inflammatory cell activation Smooth muscle cell recruitment Proliferation and matrix synthesis Fibrous cap formation Plaque rupture Platelet aggregation Thrombosis Smooth muscle cell apoptosis Matrix degradation PATHOGENESIS OF ATHEROSCLEROSIS Growth factors Growth factors

9. Insulin resistance  -cell dysfunction Type 2 diabetes Adapted from: Beck-Nielson H et al. J Clin Invest 1994;94:1714–1721 and Saltiel AR, Olefsky JM. Diabetes 1996;45:1661–1669 What is Type 2 diabetes? A progressive metabolic disorder characterised by:

10. Insulin resistance and insulin hypersecretion precede type 2 diabetes Insulin Insulin Macrovascular sensitivity secretion disease 30% 50% 50% 50% 70–100% 40% 70% 150% 10% 100% 100% Adapted from: Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714–1721 IGT Impaired glucose metabolism Normal glucose metabolism Type 2 diabetes

11. Clinical indicators of the Insulin Resistance Syndrome + Insulin resistance + Type 2 diabetes or IGT + Dyslipidaemia ( TG, LDLc, HDLc) + Central obesity + Hypertension + Hyperinsulinaemia (initially) + Atherosclerosis DeFronzo RA, Ferrannini E. Diabetes Care 1991;14(3):173–194

12. Glucose uptake in insulin-resistant subjects: impaired in patients with type 2 diabetes Adapted from Baron AD. Am J Physiol 1994;267:E187–E202 Serum insulin (pmol/L) Whole-body glucose uptake (µmol/m 2 /min) 3,000 1,500 1,000 500 0 2,000 2,500 101001,00010,000100,000 Lean Obese Type 2 diabetes

13. Pancreatic  -cell Insulin resistance Liver HYPERGLYCAEMIA Islet  -cell degranulation Reduced insulin content Muscle (PKC  Adipose tissue Decreased glucose transport & activity (expression) of GLUT-4 Increased lipolysis Elevated plasma NEFA + - Low plasma insulin Increased glucose output Elevated TNF  Insulin resistance and  -cell dysfunction produce hyperglycaemia in type 2 diabetes Modified from: Turner N, Clapham JC. Prog Drug Res 1998;51:34–94

14. Why is the prevalence of insulin resistance increasing?

16. Relative risk of death due to cardiovascular disease according to BMI among non-smoking women aged 30 to 55 years Manson, J.E. et al. New England Journal of Medicine 1995; 333: 677-85. Body mass index (kg/m 2 ) Relative risk of death P<0.001

17. Relative risk of type 2 diabetes according to BMI in US women aged 30 to 55 years Body mass index (kg/m 2 ) Age-adjusted relative risk Colditz GA et al. Annals of Internal Medicine 1995; 122: 481-86.

18. Why does obesity cause type 2 diabetes? high levels of free fatty acids found in obese or overweight patients, interfere with glucose metabolism

19. Mechanisms of insulin resistance linking fatty acid and glucose metabolism Increased adipocyte lipolysis (central obesity) FFAs acetyl CoA (cellular) hepatic gluconeogenesis NADH/NAD citrate glycogen synthase pyruvate dehydrogenase plasma glucose transport hexokinaseglucose 6-P phosphofructokinase glycogen content

20. Differences between visceral and subcutaneous fat Visceral fatSubcutaneous fat 6-20% of total body fat80% of total body fat Greater number of smaller cellsSmaller number of large cells with richer blood supplywith poorer blood supply Intra-abdominal with direct Extra-abdominal drainage to portal vein Greater catecholamine-inducedReduced catecholamine- induced lipolysislipolysis Reduced insulin inhibition ofIncreased insulin inhibition of lipolysislipolysis

21. How can the impact of diabetes and metabolic syndrome to cause vascular disease be reduced?

24. August 1999 How can insulin resistance be reduced? Lifestyle Weight reduction - optimum BMI in Caucasians? Increasing levels of energy expenditure Medication Metformin & Glitazones Lifestyle Weight reduction - optimum BMI in Caucasians? Increasing levels of energy expenditure Medication Metformin & Glitazones

25. Reduction in risk of various clinical endpoints with metformin (n=342) compared with a conventional policy in overweight patients (BMI=31) with type 2 diabetes Clinical endpointRisk reductionp value Any diabetes-related endpoint32%0.002 Diabetes-related deaths42%0.017 All-cause mortality36%0.011 Myocardial infarction39%0.010 Data taken from UK Prospective Diabetes Study (UKPDS) group. Lancet 1998; 352: 854-65.

26. How does activation of PPAR  enhance insulin action and normalise blood glucose? Glitazone and insulin PPAR  Pre-adipocyte Adipocyte Increased differentiation Reversal of TNF  -induced insulin resistance Increased insulin sensitivity and capacity for glucose disposal/lipid storage Reduced lipolysis and free fatty acid availability Skeletal muscle Liver Euglycaemia Increased glucose disposal Reduced hepatic glucose output PPAR  GLUT-4  TG & PKC 

27. Treatment with glitazones Diagnosis Diet and Exercise Sulphonylurea HbA 1c > 7% Can’t use Metformin Metformin HbA 1c > 7% Obese Add Glitazone HbA 1c > 7% Overweight Normal weight

28. Combination therapy? PPAR gamma and PPAR alpha agonists

29. Future challenges for type 2 diabetes management Glucose control Adverse experiencesComplications Drug interactions  -cell function Insulin resistance