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Sci. Signal., 16 March 2010
Vol. 3, Issue 113, p. ra19
[DOI: 10.1126/scisignal.2000771]

RESEARCH ARTICLES

Cholinergic Augmentation of Insulin Release Requires Ankyrin-B

Jane A. Healy1,2, Kent R. Nilsson1,3, Hans E. Hohmeier3,4,5, Jelena Berglund1,6,7, Jonathan Davis1, Janis Hoffman1, Martin Kohler7, Luo-Sheng Li7, Per-Olof Berggren7, Christopher B. Newgard3,4,5, and Vann Bennett1,2,6*

1 Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
2 Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
3 Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
4 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
5 Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27710, USA.
6 Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
7 Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, S-17176 Stockholm, Sweden.

Abstract: Parasympathetic stimulation of pancreatic islets augments glucose-stimulated insulin secretion by inducing inositol trisphosphate receptor (IP3R)–mediated calcium ion (Ca2+) release. Ankyrin-B binds to the IP3R and is enriched in pancreatic beta cells. We found that ankyrin-B–deficient islets displayed impaired potentiation of insulin secretion by the muscarinic agonist carbachol, blunted carbachol-mediated intracellular Ca2+ release, and reduced the abundance of IP3R. Ankyrin-B–haploinsufficient mice exhibited hyperglycemia after oral ingestion but not after intraperitoneal injection of glucose, consistent with impaired parasympathetic potentiation of glucose-stimulated insulin secretion. The R1788W mutation of ankyrin-B impaired its function in pancreatic islets and is associated with type 2 diabetes in Caucasians and Hispanics. Thus, defective glycemic regulation through loss of ankyrin-B–dependent stabilization of IP3R is a potential risk factor for type 2 diabetes.

* To whom correspondence should be addressed. E-mail: benne012{at}mc.duke.edu

Citation: J. A. Healy, K. R. Nilsson, H. E. Hohmeier, J. Berglund, J. Davis, J. Hoffman, M. Kohler, L.-S. Li, P.-O. Berggren, C. B. Newgard, V. Bennett, Cholinergic Augmentation of Insulin Release Requires Ankyrin-B. Sci. Signal. 3, ra19 (2010).

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