Glucose stimulates Ca2+ influx and insulin secretion in 2-week-old β-cells lacking ATP-sensitive K+ channels

Abstract

In adult β-cells glucose-induced insulin secretion involves two mechanisms (a) a KATP channel-dependent Ca2+ influx and rise of cytosolic [Ca2+]c and (b) a KATP channel-independent amplification of secretion without further increase of [Ca2+]c. Mice lacking the high affinity sulfonylurea receptor (Sur1KO), and thus KATP channels, have been developed as a model of congenital hyperinsulinism. Here, we compared [Ca2+] c and insulin secretion in overnight cultured islets from 2-week-old normal and Sur1KO mice. Control islets proved functionally mature: the magnitude and biphasic kinetics of [Ca2+]c and insulin secretion changes induced by glucose, and operation of the amplifying pathway, were similar to adult islets. Sur1KO islets perifused with 1 mM glucose showed elevation of both basal [Ca2+]c and insulin secretion. Stimulation with 15 mM glucose produced a transient drop of [Ca 2+]c followed by an overshoot and a sustained elevation, accompanied by a monophasic, 6-fold increase in insulin secretion. Glucose also increased insulin secretion when [Ca2+]c was clamped by KCl. When Sur1KO islets were cultured in 5 instead of 10 mM glucose, [Ca 2+]c and insulin secretion were unexpectedly low in 1 mM glucose and increased following a biphasic time course upon stimulation by 15 mM glucose. This KATP channel-independent first phase [Ca 2+]c rise was attributed to a Na+-, Cl --, and Na+-pump-independent depolarization of β-cells, leading to Ca2+ influx through voltage-dependent calcium channels. Glucose indeed depolarized Sur1KO islets under these conditions. It is suggested that unidentified potassium channels are sensitive to glucose and subserve the acute and long-term metabolic control of [Ca 2+]c in β-cells without functional KATP channels. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.