Sulfonylurea-mediated stimulation of insulin exocytosis via an ATP-sensitive K+ channel-independent action

Several reports indicate that hypoglycemic sulfonylureas augment Ca2+-dependent insulin secretion via mechanisms other than inhibition of the ATP-sensitive K+ channel. The effect involves a 65-kd protein in the granule membrane and culminates in intragranular acidification. Lowering of granule pH is necessary fore the insulin granule to gain release competence. Proton pumping into the granule is driven by a v-type H+-ATPase, but requires simultaneous CI- uptake into the granule via metabolically regulated CIC-3 CI- channels to maintain electroneutrality. Here we discuss the possibility that modulation of granule CIC-3 channels represents the mechanism whereby sulfonylureas directly potentiate the beta-cell exocytotic machinery.