New mechanisms for sulfonylurea control of insulin secretion

Oral antidiabetic sulfonylureas like tolbutamide and glyburide have been used to treat patients with noninsulin dependent diabetes mellitus. These agents lower blood glucose by stimulating insulin secretion from the pancreatic islets of Langerhans. A major component of this stimulation is sulfonylurea-mediated closure of the ATP-inhibited potassium channels (K(ATP) channels) of islet β-cells. Closure of these channels leads to cell depolarization, calcium uptake, and insulin exocytosis. Progress leading up to the recent cloning of the high-affinity sulfonylurea receptor and reconstitution of the K(ATP) channel is reviewed in this article together with new data showing that sulfonylureas may control secretion by activating a novel chloride ion channel, inhibiting an islet Na/K/ATPase or via distal stimulation of granule exocytosis by a kinase C dependent mechanism.