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Recent research has greatly expanded the domain of insulin action. The classical action of insulin is the control of glucose metabolism through the dual feedback loop linking plasma insulin with plasma glucose concentrations. This canon has been revised to incorporate the impact of insulin resistance or insulin deficiency, both of which alter glucose homeostasis through maladaptive responses (namely, chronic hyperinsulinaemia and glucose toxicity). A large body of knowledge is available on the physiology, cellular biology and molecular genetics of insulin action on glucose production and uptake. More recently, a number of newer actions of insulin have been delineated from 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-thrombotic milieu. Preliminary evidence indicates that hyperinsulinaemia per se may be pro-oxidant both in vitro and in vivo. Insulin plays a role in mediating diet-induced thermogenesis, and insulin resistance may therefore be implicated in the defective thermogenesis of diabetes. In the kidney, insulin spares sodium and uric acid from excretion; in chronic hyperinsulinaemic states, these effects may contribute to high blood pressure and hyperuricaemia. Insulin hyperpolarises the plasma membranes of both excitable and non-excitable tissues, with consequences ranging from baroreceptor desensitisation to cardiac refractoriness (prolongation of QT interval). Under some circumstances insulin is vasodilatory-the mechanism involving both the sodium-potassium pump and intracellular calcium transients. Finally, by crossing the blood-brain barrier insulin exerts a host a central effects (sympatho-excitation, vagal withdrawal, stimulation of corticotropin releasing factor), collectively resembling a stress reaction. Description and understanding of these new roles, their interactions, the interplay between insulin resistance and hyperinsulinaemia, and their implications for cardiovascular disease have only begun.

Plasma glucose concentration is the best predictor for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, obesity is also a recognized risk factor for development of the disease, and is easier to track over time. Thus obesity could be of considerable clinical importance as a predictor of diabetes. Studies have shown that the degree of overweight, the change in weight and the duration of overweight are all separate predictors of diabetes. The British Regional Heart Study showed that an increasing body mass index (BMI) was associated with increased risk of developing diabetes, even at BMI values not considered obese. A separate study showed that weight gain increased the risk of diabetes independently of BMI, while weight loss decreased the risk. The duration of obesity was also an important factor in developing NIDDM. A long duration increased the risk of diabetes, irrespective of the final BMI value. The effects of obesity on insulin action have also been investigated. Studies have shown that insulin sensitivity is inversely related to insulin secretion, with a disproportionate increase in insulin secretion seen with decreasing sensitivity. A recent European study showed that the prevalence of both insulin hypersecretion and insulin resistance increased with increasing BMI. Thus, in obesity, higher insulin levels are necessary to maintain glucose tolerance, leading to increased stress on the beta-cells. In obese individuals, weight loss improved insulin sensitivity in proportion to the degree of weight loss, leading to decreased insulin secretion. Weight loss can therefore, at least in the short term, act to decrease the risk of developing diabetes by reducing insulin resistance, and thus relieving beta-cell stress, the factor ultimately responsible for hyperglycaemia in predisposed individuals.