Na+/Ca2+ Exchange and the Plasma Membrane Ca2+-ATPase in β-Cell Function and Diabetes

The rat pancreatic beta-cell expresses two splice variants of the Na+/Ca2+ exchanger 1 (NCX1) and six splice variants of the plasma membrane Ca2+-ATPase (PMCA). In the beta-cell, Na+/Ca2+ exchange displays a high capacity, contributes to both Ca2+ out flow and in flux and participates to the control of insulin release. Gain of function studies show that overexpression of NCX1 or PMCA2 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 acids concentration also induces ER Ca2+ depletion and beta-cell death in diabetes. Loss of function studies shows, 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 four to seven times higher rate of diabetes cure than Ncx1(+/+) islets when transplanted in diabetic animals. Thus, downregulation of the Na+/Ca2+ exchanger leads to various changes in beta-cell function that are opposite to the major abnormalities seen in diabetes. In addition, the beta-cell, which is an excitable cell, includes the mutually exclusive exon B in the alternative splicing region of NCX1, which confers a high sensitivity of its NCX splice variants (NCX1.3 & 1.7) to the inhibitory action of compounds like KB-R7943. This provides a unique model for the prevention and treatment of beta-cell dysfunction in diabetes and following islet transplantation.