Insulin resistance syndrome: interaction with coagulation and fibrinolysis

Abstract

Insulin resistance represents a common metabolic abnormality leading to cardiovascular disease, the major cause of morbidity and mortality in most parts of the world. Insulin resistance is also associated with an increased risk of type 2 diabetes which is strongly associated with obesity. The insulin resistance of obese people and subjects with type 2 diabetes is characterised by defects at many levels, affecting insulin receptor concentration, glucose transport mechanisms and the activities of intracellular enzymes. Around 25% of western populations show some features of the insulin resistance syndrome (often referred to as syndrome X or the metabolic syndrome) ie, a clustering of metabolic, atheromatous risk factors, including hypertriglyceridaemia, hyperinsulinaemia, hyper-tension, hypercholesterinaemia and obesity. However, the known metabolic cardiovascular risk factors associated with the insulin resistance syndrome do not sufficiently explain the excess vascular risk attributed to this syndrome. The observation, that increased plasma plasminogen activator inhibitor 1 (PAI-1) levels were associated with insulin resistance and atherothrombosis added for the first time a pathological basis for an association of the insulin resistance syndrome not only with metabolic, atheromatous (atherosclerotic) risk but also with atherothrombotic risk. It is very likely that not only PAI-1, but also other abnormalities in haemostatic variables contribute to this excess vascular risk. Knowledge of how haemostatic variables cluster with classical metabolic risk factors associated with the insulin resistance syndrome could help to better understand the pathogenesis of cardiovascular diseases. Indeed, many coagulation and fibrinolytic proteins have been shown to be associated with features of the insulin resistance syndrome and these associations suggest that some coagulation and fibrinolytic proteins have a role in atherothrombotic disorders, principally through an association with other established metabolic (atheromatous) risk factors in the presence of underlying insulin resistance. Interestingly, new therapeutic approaches in the prevention and treatment of insulin resistance do show some influence on coagulation and fibrinolysis. The newest drugs are the thiazolidinediones, a totally novel class of insulin sensitisers. They have the potential to offer improvements both in glycaemic control and in cardiovascular events.