INSULIN AS A VASCULAR HORMONE - IMPLICATIONS FOR THE PATHOPHYSIOLOGY OF CARDIOVASCULAR-DISEASE

1. Metabolic disorders, such as obesity and non-insulin-dependent diab etes mellitus, and cardiovascular disorders, such as essential hyperte nsion, congestive cardiac failure and atherosclerosis, have two featur es in common, namely relative resistance to insulin-mediated glucose u ptake and vascular endothelial dysfunction. 2. Significant increases i n limb blood how occur in response to systemic hyperinsulinaemia, alth ough there is marked variation in the results due to a number of confo unding factors, including activation of the sympathetic nervous system . Local hyperinsulinaemia has a less marked vasodilator action despite similar plasma concentrations, but this can be augmented by co-infusi ng D-glucose. 3. Insulin may stimulate endothelial nitric oxide produc tion or may act directly on vascular smooth muscle via stimulation of the Na+-H+ exchanger and Na+/K+-ATPase, leading to hyperpolarization o f the cell membrane and consequent closure of voltage-gated Ca2+ chann els. 4. There is evidence both for and against the existence of a func tional relationship between insulin-mediated glucose uptake (insulin s ensitivity) and insulin-mediated vasodilation (which can be regarded a s a surrogate measure for endothelial function). 5. If substrate deliv ery is the rate-limiting step for insulin-mediated glucose uptake (in other words, if skeletal muscle blood how is a determinant of glucose uptake), then endothelial dysfunction, resulting in a relative inabili ty of mediators, including insulin, to stimulate muscle blood flow, ma y be the underlying mechanism accounting for the association of athero sclerosis and other cardiovascular disorders with insulin resistance. 6. Glucose uptake may determine peripheral blood how via stimulation o f ATP-dependent ion pumps with consequent vasorelaxation. 7. A 'third factor' may cause both insulin resistance and endothelial dysfunction in cardiovascular disease. Candidates include skeletal muscle fibre ty pe and capillary density, distribution of adiposity and endogenous cor ticosteroid production. 8. A complex interaction between endothelial d ysfunction, abnormal skeletal muscle blood flow and reduced insulin-me diated glucose uptake may be central to the link between insulin resis tance, blood pressure, impaired glucose tolerance and the risk of card iovascular disease. An understanding of the primary mechanisms resulti ng in these phenotypes may reveal new therapeutic targets in metabolic and cardiovascular disease.