A brief review of the normal physiology of insulin secretion is given. The dual role of glucose to directly stimulate insulin release and to potentiate insulin secretion to other islet regulators is emphasized. The B cell of the pancreatic islet is discussed as a metabolic integrator for nutrients, modulated by neural and hormonal input. A feedback model for the normal regulation of glucose concentrations is also described. This model is based on a closed loop between the islet, the liver and peripheral tissues for the production and utilization of glucose. Diabetes mellitus with overt hyperglycemia is characterized by impaired pancreatic B-cell function; however, in noninsulin-dependent diabetic subjects, many aspects of insulin secretion are maintained by a compensatory increase in plasma glucose concentration. The model shows why this increase in plasma glucose occurs and the importance of this hyperglycemia to the restoration of insulin responses to nonglucose secretagogues, second-phase insulin secretion to glucose and basal insulin. The model can account for the usual stability of plasma glucose in noninsulin-dependent diabetes mellitus and the very high glucose levels and lack of glucose stability in insulin-dependent diabetes mellitus. Sulfonylurea drugs increase insulin secretion, but this increase is dependent on the glucose level. Thus, the augmented B-cell function can be masked by a decrease in plasma glucose concentrations. During long-term therapy, the insulin level and responses are unchanged despite lower concentrations of glucose. Therefore, it is hypothesized that sulfonylureas still act by enhancement of B-cell function.