Sulfonylurea-mediated stimulation of insulin exocytosis via an ATP-sensitive K+ channel-independent action.
Several reports indicate that hypoglycemic sulfonylureas augment Ca(2+)-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 for the insulin granule to gain release competence. Proton pumping into the granule is driven by a v-type H(+)-ATPase, but requires simultaneous Cl(-) uptake into the granule via metabolically regulated ClC-3 Cl(-) channels to maintain electroneutrality. Here we discuss the possibility that modulation of granule ClC-3 channels represents the mechanism whereby sulfonylureas directly potentiate the beta-cell exocytotic machinery.
Renström
Erik
E
Department of Molecular and Cellular Physiology, Institute of Physiology, Lund University, Lund, Sweden. erik.renstrom@mphy.lu.se
Barg
Sebastian
S
Thévenod
Frank
F
Rorsman
Patrik
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D018118:Chloride Channels / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
D018118:Chloride Channels; C115376:ClC-3 channel; D007328:Insulin; D015221:Potassium Channels; D013453:Sulfonylurea Compounds; D000255:Adenosine Triphosphate