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J. Biol. Chem., Vol. 281, Issue 31, 22142-22151, August 4, 2006

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Glucose Acutely Decreases pH of Secretory Granules in Mouse Pancreatic Islets

MECHANISMS AND INFLUENCE ON INSULIN SECRETION^*

Patrick Stiernet¹, Yves Guiot, Patrick Gilon², and Jean-Claude Henquin³

From the Units of Endocrinology and Metabolism, and Pathology, University of Louvain Faculty of Medicine, B-1200 Brussels, Belgium

Glucose-induced insulin secretion requires a rise in -cell cytosolic Ca²⁺ ([Ca²⁺]_c) that triggers exocytosis and a mechanistically unexplained amplification of the action of [Ca²⁺]_c. Insulin granules are kept acidic by luminal pumping of protons with simultaneous Cl^- uptake to maintain electroneutrality. Experiments using patched, dialyzed -cells prompted the suggestion that acute granule acidification by glucose underlies amplification of insulin secretion. However, others found glucose to increase granular pH in intact islets. In this study, we measured islet granular pH with Lysosensor DND-160, a fluorescent dye that permits ratiometric determination of pH < 6in acidic compartments. Stimulation of mouse islets with glucose reversibly decreased granular pH by mechanisms that are dependent on metabolism and Cl^- ions but independent of changes in [Ca²⁺]_c and protein kinase A or C activity. Granular pH was increased by concanamycin (blocker of the vesicular type H⁺-ATPase) > methylamine (weak base) > Cl^- omission. Concanamycin and methylamine did not alter glucose-induced [Ca²⁺]_c increase in islets but strongly inhibited the two phases of insulin secretion. Omission of Cl^- did not affect the first phase but decreased the second phase of both [Ca²⁺]_c and insulin responses. Neither experimental condition affected the [Ca²⁺]_c rise induced by 30 mM KCl, but the insulin responses were inhibited by concanamycin > methylamine and not affected by Cl^- omission. The amplification of insulin secretion by glucose was not suppressed. We conclude that an acidic granular pH is important for insulin secretion but that the acute further acidification produced by glucose is not essential for the augmentation of secretion via the amplifying pathway.

Received for publication, December 12, 2005 , and in revised form, June 6, 2006.

^* This work was supported in part by Grant 3.4552.04 from the Fonds National de la Recherche Scientifique, Grant ARC 05/10-328 from the Direction de la Recherche Scientifique of the French Community of Belgium, and Grant PAI 5/17 from the Interuniversity Poles of Attraction Program, Belgian Science Policy. 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 Aspirant of the Fonds National de la Recherche Scientifique, Brussels.

² Directeur de Recherches of the Fonds National de la Recherche Scientifique, Brussels.

³ To whom correspondence should be addressed: Unité d'Endocrinologie et Métabolisme, UCL 55.30, Ave. Hippocrate 55, B-1200 Brussels, Belgium. Tel.: 32-2-764-5529; Fax: 32-2-764-5532; E-mail: henquin{at}endo.ucl.ac.be.

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