Fasting plasma glucose levels are constant from day to day in normal individuals. This constancy is due to a close co-ordination between glucose production by the liver and glucose uptake in peripheral tissues. This review focusses on the key role of the endocrine pancreas alpha- and beta-cells to provide this co-ordination. Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by fasting hyperglycemia. The degree of fasting hyperglycemia, in turn, is correlated with the basal rate of hepatic glucose production. This increased rate of glucose release by the liver results in part from impaired hepatic sensitivity to insulin, but is largely due to reduced insulin secretion and increased glucagon secretion. Though basal immunoreactive insulin and glucagon levels in patients with NIDDM may appear normal when compared to those of healthy individuals, islet function testing at matched glucose levels reveals impairments of basal, steady-state, and stimulated insulin and glucagon secretion due to a reduction in beta-cell secretory capacity and a reduced ability of glucose to suppress glucagon release. The degree of impaired beta-cell responsiveness to glucose is closely related to the degree of fasting hyperglycemia, but in a curvilinear fashion. Thus, islet alpha- and beta-cell function is reduced by more than 50% in NIDDM by the time that clinical fasting hyperglycemia develops (140 mg/dL). The efficiency of glucose uptake by the peripheral tissues is also impaired due to a combination of decreased insulin secretion and defective cellular insulin action.(ABSTRACT TRUNCATED AT 250 WORDS)