Abstract
Pancreatic islets have a central role in blood glucose homeostasis. In addition to insulin-producing β-cells and glucagon-secreting α-cells, the islets contain somatostatin-releasing δ-cells1. Somatostatin is a powerful inhibitor of insulin and glucagon secretion2. It is normally secreted in response to glucose3 and there is evidence suggesting its release becomes perturbed in diabetes4. Little is known about the control of somatostatin release. Closure of ATP-regulated K+-channels (KATP-channels)5 and a depolarization-evoked increase in cytoplasmic free Ca2+ concentration ([Ca2+]i)6,7,8 have been proposed to be essential. Here, we report that somatostatin release evoked by high glucose (≥10 mM) is unaffected by the KATP-channel activator diazoxide and proceeds normally in KATP-channel-deficient islets. Glucose-induced somatostatin secretion is instead primarily dependent on Ca2+-induced Ca2+-release (CICR). This constitutes a novel mechanism for KATP-channel-independent metabolic control of pancreatic hormone secretion.
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Acknowledgements
We thank M. A. Magnuson (Vanderbilt University) for supplying the SUR1-deficient mice. This work is supported by the Wellcome Trust, DiabetesUK and the European Union (Biosim, LSHB-CT-2004-005137; and Eurodia, SHM-CT-2006-518153). F.M.A. is a Royal Society Research Professor and P.R. is a Royal Society Wolfson Merit Award Research Fellow.
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Q.Z. performed most of the electrophysiological experiments, including those involving microfluorimetry and confocal imaging. C.P. performed all immunocytochemistry. S.G. participated in the early stages of the electrophysiological experiments were also performed by M. Braun. The PCR analyses were performed by M. Bengtsson. The hormone release measurements were performed by A.S. P.O.B., R.C., E.R. and T.S. provided SUR1−/−, Kir6.2STOP, and Cav2.3−/−, respectively. P.R.V.J. provided human islet cells (data not shown). L.E. analysed δ-cell ultrastructure using electron microscopy. F.M.A. contributed to the discussion of the data throughout the study and assisted with manuscript preparation. The study was initiated by P.R. who directed all experimental protocols used, performed some of the electrophysiological measurements, liaised with all co-authors and was the main author of the manuscript.
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Zhang, Q., Bengtsson, M., Partridge, C. et al. R-type Ca2+-channel-evoked CICR regulates glucose-induced somatostatin secretion. Nat Cell Biol 9, 453–460 (2007). https://doi.org/10.1038/ncb1563
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DOI: https://doi.org/10.1038/ncb1563
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