Hypertension affects 20-60% of people with type 2 diabetes and people with hypertension are more than twice as likely to develop diabetes. Together, hypertension and diabetes are potent risk factors for cardiovascular disease. Resistance to insulin-mediated glucose uptake and dysfunction(s) of the vascular endothelial monolayer are important pathophysiological features of both conditions which are associated with obesity and accelerated atherosclerosis. In recent years, it has become clear that insulin has important vascular actions. These have been studied in intact humans, in isolated human vessels, in cultured human aortic endothelial cells, in vascular tissue from insulin resistant animals, and in 'knockout' models. Current data suggest that insulin utilises remarkably similar postreceptor signalling mechanisms in regulating nitric oxide synthesis to those used in promoting glucose uptake in 'classical' target tissues (i.e. muscle and fat). These signalling pathways include both the 'classical' PI 3-kinase dependent pathway and the 'alternative' CAP/ Cbl pathway. It is therefore hypothesised that inherited or acquired defects in insulin signalling, as expressed in common insulin resistant states, have parallel effects on insulin sensitivity and endothelial function. By this characterisation, endothelial dysfunction is an intrinsic feature of the insulin resistance underlying type 2 diabetes. Moreover, early evidence suggests that novel adipocyte-derived factors may have parallel effects on insulin signalling in classical insulin target tissues and in the vaculature. As increasing obesity in the general population is also reflected in patients with type 1 diabetes, particularly in the U.S.A, such mechanisms are also increasingly relevant to the pathogenesis of cardiovascular disease in type 1 diabetes. The effects of currently-available insulin-sensitising therapies (e.g. metformin, thiazolidinediones) on these pathways is providing insights which may reveal novel and more specific therapeutic targets for the prevention and treatment of hypertension and other vascular complications in people with insulin resistance and/or diabetes.
03 - 05 Nov 2003
Society for Endocrinology