The ultimate clinical utility of the sulfonylurea drugs in the treatment of insulin-independent diabetes mellitus will be determined only when the mechanisms of action of these agents are understood. We are presently evaluating the long-term effects of the sulfonylurea glipizide on a group of patients with insulin-independent diabetes. Our studies thus far indicate that a major effect of this drug is a potentiation of insulin action, which leads to an improvement in glucose utilization. However, glipizide, in distinction from those sulfonylureas that have been examined previously, also causes a long-term increase in glucose-stimulated insulin secretion. These effects are unrelated to diet therapy and can still be demonstrated in patients treated for more than 2 yr. Further investigation will determine whether sulfonylurea therapy can offer unique benefits to certain patients with insulin-independent diabetes.