The Na/Ca exchanger and the Plasma Membrane Ca-ATPase in β-cell function and diabetes.

The rat pancreatic β-cell expresses 6 splice variants of the Plasma Membrane Ca-ATPase (PMCA) and two splice variants of the Na/Ca exchanger 1 (NCX1). In the β-cell Na/Ca exchange displays a high capacity, contributes to both Ca outflow and influx and participates to the control of insulin release. Gain of function studies show that overexpression of PMCA2 or NCX1 leads to endoplasmic reticulum (ER) Ca depletion with subsequent ER stress, decrease in β-cell proliferation and β-cell death by apoptosis. Loss of function studies show, on the contrary, that heterozygous inactivation of NCX1 (Ncx1) leads to an increase in β-cell function and a 5 fold increase in both β-cell mass and proliferation. The mutation also increases β-cell resistance to hypoxia, and Ncx1 islets show a 2-4 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. In addition, the β-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 KBR-7943. Heterozygous inactivation of PMCA2 leads to apparented, though not completely similar results.These provide 2 unique models for the prevention and treatment of β-cell dysfunction in diabetes and following islet transplantation.