Type II Diabetes Mellitus and Cardiovascular DiseasePresentation Transcript
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
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
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:
Clinical indicators of the Insulin Resistance Syndrome
+ Insulin resistance
+ Type 2 diabetes or IGT
+ Dyslipidaemia ( TG, LDLc, HDLc)
+ Central obesity
+ Hyperinsulinaemia (initially)
DeFronzo RA, Ferrannini E . Diabetes Care 1991; 14 (3):173–194
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 10 100 1,000 10,000 100,000 Lean Obese Type 2 diabetes
Pancreatic -cell Insulin resistance Liver HYPERGLYCAEMIA Islet -cell degranulation Reduced insulin content 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 Muscle (PKC
Why is the prevalence of insulin resistance increasing?
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
Relative risk of type 2 diabetes according to BMI in US women aged 30 to 55 years Colditz GA et al . Annals of Internal Medicine 1995; 122 : 481-86. Body mass index (kg/m 2 ) Age-adjusted relative risk
Why does obesity cause type 2 diabetes?
high levels of free fatty acids found in obese or overweight patients, interfere with glucose metabolism
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 glucose transport hexokinase glucose 6-P phosphofructokinase glycogen content
Differences between visceral and subcutaneous fat Visceral fat Subcutaneous fat 6-20% of total body fat 80% of total body fat Greater number of smaller cells Smaller number of large cells with richer blood supply with poorer blood supply Intra-abdominal with direct Extra-abdominal drainage to portal vein Greater catecholamine-induced Reduced catecholamine-induced lipolysis lipolysis Reduced insulin inhibition of Increased insulin inhibition of lipolysis lipolysis
How can the impact of diabetes and metabolic syndrome to cause vascular disease be reduced?
How can insulin resistance be reduced? Lifestyle Weight reduction - optimum BMI in Caucasians? Increasing levels of energy expenditure Medication Metformin & Glitazones
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 endpoint Risk reduction p value Any diabetes-related endpoint 32% 0.002 Diabetes-related deaths 42% 0.017 All-cause mortality 36% 0.011 Myocardial infarction 39% 0.010 Data taken from UK Prospective Diabetes Study (UKPDS) group. Lancet 1998; 352 : 854-65.
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
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
Combination therapy? PPAR gamma and PPAR alpha agonists
Future challenges for type 2 diabetes management Glucose control -cell function Adverse experiences Complications Drug interactions Insulin resistance