Selectivity of prandial glucose regulators: nateglinide, but not repaglinide, accelerates exocytosis in rat pancreatic A-cells

The effects of the two prandial glucose regulators, repaglinide and nategli nide, on ATP-sensitive K+ (K-ATP) channel activity, membrane potential and exocytosis in single rat pancreatic A-cells were investigated using the pat ch-clamp technique. K-ATP channel activity was reversibly blocked by repagl inide (K-d = 22 nM) and nateglinide (K-d = 410 nM) and this was associated with membrane depolarisation and initiation of electrical activity. The eff ect of repaglinide and nateglinide on stimulation of glucagon secretion by direct interference with the exocytotic machinery was investigated by the u se of capacitance measurements. Nateglinide, but not repaglinide, at concen trations similar to those required to block K-ATP channels potentiated Ca2-evoked exocytosis 3-fold. In alpha TC1-9 glucagonoma cells addition of nat eglinide, but not repaglinide, was associated with stimulation of glucagon secretion. These results indicate that the fast-acting insulin secretagogue nateglinide is glucagonotropic primarily by stimulating Ca2+-dependent exo cytosis. (C) 1999 Elsevier Science B.V. All lights reserved.