Oral antidiabetic sulfonylureas like tolbutamide and glyburide have be
en used to treat patients with noninsulin dependent diabetes mellitus.
These agents lower blood glucose by stimulating insulin secretion fro
m the pancreatic islets of Langerhans. A major component of this stimu
lation is sulfonylurea-mediated closure of the ATP-inhibited potassium
channels (K-ATP channels) of islet beta-cells, closure of these chann
els leads to cell depolarization, calcium uptake, and insulin exocytos
is. Progress leading up to the recent cloning of the high-affinity sul
fonylurea 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, inhibit
ing an islet Na/K/ATPase or via distal stimulation of granule exocytos
is by a kinase C dependent mechanism.