Effect of insulinotropic agent nateglinide on Kv and Ca2+ channels in pancreatic β-cell

Novel insulinotropic agent nateglinide stimulates insulin via binding to sulfonylurea receptor and closing the ATP-dependent K+ (K-ATP) channels in pancreatic beta -cells, leading to an increase in [Ca2+](i) for exocytosis, The voltage-dependent Ca2+ channel and the delayed rectifier K+ (Kv) channels are also present in beta -cells and their activities determine the configuration of action potential and hence contribute to the regulation of [Ca2+], and insulin secretion. This study, by using the patch-clamp method in whole cell configuration, comparatively characterized the direct effects of sulfonylurea receptor ligands including nateglinide, glyburide, and repaglinide on Kv and Ca2+ channels. Each agent inhibited Kv currents in a concentration-dependent manner with effective concentration range two to three orders higher than that for blocking K-ATP channels. A marginal stimulation of Ca2+ current was observed with all drugs, while repaglinide at concentration greater than 300 nM inhibited Ca2+ current. The direct effects of these antidiabetic agents on Kv and Ca2+ channels may act concertedly with their primary action on KATP channels in regulating [Ca2+], and the stimulus-secretion coupling. (C) 2001 Elsevier Science B.V. All rights reserved.