REDUCED insulin-mediated glucose uptake, or insulin resistance, is a metabolic defect characteristic of virtually all patients with non-insulin-dependent diabetes mellitus (NIDDM). The cause of insulin resistance remains unknown, but in the past decade, since the development of the hyperinsulinemic-glucoseclamp technique, considerable progress has been made in identifying the insulin-resistant tissues and metabolic pathways responsible for decreased insulin action. DeFronzo et al. l ,2 and subsequently others demonstrated that most of the glucose that leaves the plasma during hyperinsulinemia enters peripheral tissues rather than the gut or liver, and that insulin resistance in patients with NIDDM is largely a result of decreased glucose uptake by these peripheral tissues. Since little of the glucose taken up by peripheral tissues under the mediation of insulin could be recovered from adipose tissue, investigators concluded that most of the glucose was taken up by skeletal muscle.