Insulin: new roles for an ancient hormone

Recent research has greatly expanded the domain of insulin action. The clas sical action of insulin is the control of glucose metabolism through the du al feedback loop linking plasma insulin with plasma glucose concentrations. This canon has been revised to incorporate the impact of insulin resistanc e or insulin deficiency, both of which alter glucose homeostasis through ma ladaptive responses (namely, chronic hyperinsulinaemia and glucose toxicity ). A large body of knowledge is available on the physiology, cellular biolo gy and molecular genetics of insulin action on glucose production and uptak e. More recently, a number of newer actions of insulin have been delineated fr om in vitro and in vivo studies. In sensitive individuals, insulin inhibits lipolysis and platelet aggregation. In the presence of insulin resistance, dyslipidaemia, hyper-aggregation and anti-fibrinolysis may create a pro-th rombotic milieu. Preliminary evidence indicates that hyperinsulinaemia per se may be pro-oxidant both in vitro and in vivo. Insulin plays a role in me diating diet-induced thermogenesis, and insulin resistance may therefore be implicated in the defective thermogenesis of diabetes. In the kidney, insu lin spares sodium and uric acid from excretion; in chronic hyperinsulinaemi c states, these effects may contribute to high blood pressure and hyperuric aemia. Insulin hyperpolarises the plasma membranes of both excitable and no nexcitable tissues, with consequences ranging from baroreceptor desensitisa tion to cardiac refractoriness (prolongation of QT interval). Under some ci rcumstances insulin is vasodilatory-the mechanism involving bath the sodium -potassium pump and intracellular calcium transients. Finally, by crossing the blood-brain barrier insulin exerts a host a central effects (sympatho-e xcitation, vagal withdrawal, stimulation of corticotropin releasing factor) , collectively resembling a stress reaction. Description and understanding of these new roles, their interactions, the i nterplay between insulin resistance and hyperinsulinaemia, and their implic ations for cardiovascular disease have only begun.