Sulfonylureas and meglitinides: insights into physiology and translational clinical utility

β-Cell insulin secretion is primarily regulated by a plasma membrane ATP-dependent K+ (K_ATP) channel. Increasing levels of ATP/ADP, which reflect increasing plasma glucose, close the channel and stimulate insulin secretion. The regulatory subunit (SUR1) of the K_ATP channel has binding sites which recognize the sulfonylurea and benzamido moieties. Activation of these binding sites close the K_ATP channel independent of the ATP/ADP ratio and stimulate insulin secretion independent of plasma glucose. Sulfonylureas and meglitinides are effective agents to treat hyperglycemia in type 2 diabetes because of their ability to bypass β-cell glucose abnormalities. The effects of individual sulfonylureas and meglitinides are dependent on oral absorption, SUR binding characteristics, duration of action, metabolism, and excretion. Side effects are clinically significant hypoglycemia and weight gain. Controversial data have implicated some of them in increased mortality. Glucose-dependent insulin secretagogues (incretins) have advantages over sulfonylureas by low rates of mild hypoglycemia and no weight gain.