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J. Biol. Chem., Vol. 282, Issue 3, 1747-1756, January 19, 2007

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Glucose Stimulates Ca²⁺ Influx and Insulin Secretion in 2-Week-old -Cells Lacking ATP-sensitive K⁺ Channels^*

Andras Szollosi, Myriam Nenquin, Lydia Aguilar-Bryan, Joseph Bryan^¶, and Jean-Claude Henquin¹

From the Unit of Endocrinology and Metabolism, University of Louvain Faculty of Medicine, UCL 55.30, Avenue Hippocrate 55, B-1200 Brussels, Belgium and the Departments of Medicine and ^¶Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

In adult -cells glucose-induced insulin secretion involves two mechanisms (a) a K_ATP channel-dependent Ca²⁺ influx and rise of cytosolic [Ca²⁺]_c and (b) a K_ATP channel-independent amplification of secretion without further increase of [Ca²⁺]_c. Mice lacking the high affinity sulfonylurea receptor (Sur1KO), and thus K_ATP 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 [Ca²⁺]_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, [Ca²⁺]_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 K_ATP channel-independent first phase [Ca²⁺]_c rise was attributed to a Na⁺-, Cl^--, and Na⁺-pump-independent depolarization of -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 [Ca²⁺]_c in -cells without functional K_ATP channels.

Received for publication, October 20, 2006 , and in revised form, November 22, 2006.

^* This work was supported by the Fonds National de la Recherche Scientifique (Grant 3.4552.04), the Belgian Science Policy (Grant PAI 5/17), the Direction de la Recherche Scientifique of the French Community of Belgium (Grant ARC 05/10-328), and by NIDDK, National Institutes of Health Grant DK52771, and the Juvenile Diabetes Research Foundation (Grant 1-2005-950). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 32-2-764-5529; Fax: 32-2-764-5532; E-mail: henquin{at}endo.ucl.ac.be.

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