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J. Biol. Chem., Vol. 282, Issue 20, 14768-14776, May 18, 2007

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Overnight Culture Unmasks Glucose-induced Insulin Secretion in Mouse Islets Lacking ATP-sensitive K⁺ Channels by Improving the Triggering Ca²⁺ Signal^*

From the Unit of Endocrinology and Metabolism, University of Louvain Faculty of Medicine, UCL55.30, B-1200 Brussels, Belgium

A current model ascribes glucose-induced insulin secretion to the interaction of a triggering pathway (K_ATP channel-dependent Ca²⁺ influx and rise in cytosolic [Ca²⁺]_c) and an amplifying pathway (K_ATP channel-independent augmentation of secretion without further increase of [Ca²⁺]_c). However, several studies of sulfonylurea receptor 1 null mice (Sur1KO) failed to measure significant effects of glucose in their islets lacking K_ATP channels. We addressed this issue that challenges the model. Compared with controls, fresh Sur1KO islets showed slightly elevated basal [Ca²⁺]_c and insulin secretion. In 15 mM glucose, the absolute rate of secretion was 3-fold lower in Sur1KO than control islets, with only poor increase above base line. Overnight culture of Sur1KO islets in 10 mM glucose (not in 5 mM) augmented basal insulin secretion and considerably improved the response to 15 mM glucose, which reached higher values than in control islets, in which culture had little impact. Glucose stimulation during KCl depolarization showed that the amplifying pathway is functional in fresh and cultured Sur1KO islets. The differences in insulin secretion between fresh and cultured Sur1KO islets and between Sur1KO and control islets were not attributable to differences in insulin content, glucose oxidation rate, or synchronization of [Ca²⁺]_c oscillations. The unmasking of glucose-induced insulin secretion in -cells lacking K_ATP channels is paradoxically due to improvement in the production of a triggering signal (elevated [Ca²⁺]_c). The results show that K_ATP channels are not the only transducer of glucose effects on [Ca²⁺]_c in -cells. They explain controversies in the literature and refute arguments raised against the model implicating an amplifying pathway in glucose-induced insulin secretion.

Received for publication, February 16, 2007 , and in revised form, March 26, 2007.

^* This work was supported by the Fonds National de la Recherche Scientifique (3.4552.04), the Belgian Science Policy (PAI 5/17 and 6/40), and the Direction de la Recherche Scientifique of the French Community of Belgium (ARC 05/10-328). 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: Unité d'Endocrinologie et Métabolisme, UCL 55.30, Avenue Hippocrate 55, B-1200 Brussels, Belgium. Tel.: 32-2-7645529; Fax: 32-2-7645532; E-mail: henquin{at}endo.ucl.ac.be.

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