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

Ca2+ extrusion from the beta-cell is mediated by two processes the Na/Ca exchanger (NCX) and the plasma membrane Ca2+-ATPase (PMCA). Gain of function studies show that overexpression of NCX or PMCA leads to endoplasmic reticulum (ER) Ca2+ depletion with subsequent ER stress, decrease in beta-cell proliferation and beta-cell death by apoptosis. Interestingly, chronic exposure to cytokines or high free fatty acid concentrations also induce ER Ca2+ depletion and beta-cell death in diabetes. Loss of function studies show, on the contrary, that heterozygous inactivation of NCX1 (Ncx1+/-) leads to an increase in beta-cell function (insulin production and release), and a fivefold increase in both beta-cell mass and proliferation. The mutation also increases beta-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 beta-cell function that are opposite to the major abnormalities seen in diabetes. This provides a unique model for the prevention and treatment of beta-cell dysfunction in diabetes and following islet transplantation.