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Endocrinology. 2014 Mar;155(3):758-68. doi: 10.1210/en.2013-1519. Epub 2013 Jan 1.

Calcium efflux from the endoplasmic reticulum leads to β-cell death.

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Department of Medicine (T.H., J.M., K.K., M.H., S.L., F.U.), Division of Endocrinology, Metabolism, and Lipid Research, and Department of Pathology and Immunology (F.U.), Washington University School of Medicine, St Louis, Missouri 63110; and Cardiovascular-Metabolics Research Laboratories (T.H.), Daiichi Sankyo Co, Ltd, Tokyo 103-8426, Japan.


It has been established that intracellular calcium homeostasis is critical for survival and function of pancreatic β-cells. However, the role of endoplasmic reticulum (ER) calcium homeostasis in β-cell survival and death is not clear. Here we show that ER calcium depletion plays a critical role in β-cell death. Various pathological conditions associated with β-cell death, including ER stress, oxidative stress, palmitate, and chronic high glucose, decreased ER calcium levels and sarcoendoplasmic reticulum Ca(2+)-ATPase 2b expression, leading to β-cell death. Ectopic expression of mutant insulin and genetic ablation of WFS1, a causative gene for Wolfram syndrome, also decreased ER calcium levels and induced β-cell death. Hyperactivation of calpain-2, a calcium-dependent proapoptotic protease, was detected in β-cells undergoing ER calcium depletion. Ectopic expression of sarcoendoplasmic reticulum Ca(2+)-ATPase 2b, as well as pioglitazone and rapamycin treatment, could prevent calcium efflux from the ER and mitigate β-cell death under various stress conditions. Our results reveal a critical role of ER calcium depletion in β-cell death and indicate that identification of pathways and chemical compounds restoring ER calcium levels will lead to novel therapeutic modalities and pharmacological interventions for type 1 and type 2 diabetes and other ER-related diseases including Wolfram syndrome.

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