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Diabetes Obes Metab. 2012 Oct;14 Suppl 3:136-42. doi: 10.1111/j.1463-1326.2012.01649.x.

β-Cell preservation and regeneration in diabetes by modulation of β-cell Ca²⁺ homeostasis.

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  • 1Laboratoire de Pharmacodynamie et de Thérapeutique, Université Libre de Bruxelles, Faculté de Médicine, B-1070, Brussels, Belgium. herchu@ulb.ac.be

Abstract

Ca(2+) extrusion from the β-cell is mediated by two processes the Na/Ca exchanger (NCX) and the plasma membrane Ca(2+) -ATPase (PMCA). Gain of function studies show that overexpression of NCX or PMCA leads to endoplasmic reticulum (ER) Ca(2+) depletion with subsequent ER stress, decrease in β-cell proliferation and β-cell death by apoptosis. Interestingly, chronic exposure to cytokines or high free fatty acid concentrations also induce ER Ca(2+) depletion and β-cell death in diabetes. Loss of function studies show, on the contrary, that heterozygous inactivation of NCX1 (Ncx1(+/-)) leads to an increase in β-cell function (insulin production and release), and a fivefold increase in both β-cell mass and proliferation. The mutation also increases β-cell resistance to hypoxia, and Ncx1(+/-) islets show a two to four times higher rate of diabetes cure than Ncx1(+/+) islets when transplanted in diabetic animals. Thus, down-regulation of the Na/Ca exchanger leads to various changes in β-cell function that are opposite to the major abnormalities seen in diabetes. This provides a unique model for the prevention and treatment of β-cell dysfunction in diabetes and following islet transplantation.

© 2012 Blackwell Publishing Ltd.

PMID:
22928574
[PubMed - indexed for MEDLINE]
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