Patients with impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) are more resistant to insulin-stimulated glucose uptake than are individuals with normal glucose tolerance. Evidence has also been published showing that first-degree relatives of patients with NIDDM are insulin resistant when compared with a matched group of relatives of subjects with normal glucose tolerance. In addition, the ability of insulin to stimulate glucose uptake varies approximately fourfold in individuals with normal glucose tolerance, and insulin resistance of a degree comparable to that seen in patients with IGT or with Type II diabetes is present in a significant portion of the normal population. Given a defect in insulin-stimulated glucose uptake, glucose tolerance can only be maintained if insulin-resistant individuals continue to secrete greater than normal amounts of insulin. As a corollary, glucose homeostasis will decompensate when the insulin secretory response begins to decrease, and the greater the decline in insulin secretion, the larger the increase in plasma glucose concentration. Resistance to insulin-stimulated glucose uptake and compensatory hyperinsulinemia seems to represent the basic defect in patients with NIDDM, with failure of beta-cell function and subsequent development of fasting hyperglycemia only occurring later. This general formulation has received considerable support from longitudinal studies of the natural history of NIDDM. The fact that an increase in ambient insulin concentration can prevent gross decompensation of glucose tolerance in an insulin-resistant individual does not mean that this compensatory response is benign.(ABSTRACT TRUNCATED AT 250 WORDS)