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Science 318 (5854): 1299-1302

Copyright © 2007 by the American Association for the Advancement of Science

Requirement of Inositol Pyrophosphates for Full Exocytotic Capacity in Pancreatic β Cells

Christopher Illies,1 Jesper Gromada,2 Roberta Fiume,1 Barbara Leibiger,1 Jia Yu,1 Kirstine Juhl,3 Shao-Nian Yang,1 Deb K. Barma,4 John R. Falck,4 Adolfo Saiardi,5 Christopher J. Barker,1* Per-Olof Berggren1

Abstract: Inositol pyrophosphates are recognized components of cellular processes that regulate vesicle trafficking, telomere length, and apoptosis. We observed that pancreatic β cells maintain high basal concentrations of the pyrophosphate diphosphoinositol pentakisphosphate (InsP7 or IP7). Inositol hexakisphosphate kinases (IP6Ks) that can generate IP7 were overexpressed. This overexpression stimulated exocytosis of insulin-containing granules from the readily releasable pool. Exogenously applied IP7 dose-dependently enhanced exocytosis at physiological concentrations. We determined that IP6K1 and IP6K2 were present in β cells. RNA silencing of IP6K1, but not IP6K2, inhibited exocytosis, which suggests that IP6K1 is the critical endogenous kinase. Maintenance of high concentrations of IP7 in the pancreatic β cell may enhance the immediate exocytotic capacity and consequently allow rapid adjustment of insulin secretion in response to increased demand.

1 The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76, Stockholm, Sweden.
2 Diabetes and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
3 Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
4 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5 U.K. Medical Research Council (MRC) Cell Biology Unit and Laboratory for Molecular Cell Biology, Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK.

* To whom correspondence should be addressed. E-mail: chris.barker{at}ki.se

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