Inhibition of β-Cell Sodium-Calcium Exchange Enhances Glucose-Dependent Elevations in Cytoplasmic Calcium and Insulin Secretion

OBJECTIVE-The sodium-calcium exchanger isoform 1 (NCX1) regulates cytoplasmic calcium (Ca2+) required for insulin secretion in beta-cells. NCX1 is alternatively spliced, resulting in the expression of splice variants in different tissues such as NCX1.3 and -1.7 in beta-cells. As pharmacological inhibitors of NCX1 splice variants are in development, the pharmacological profile of beta-cell NCX1.3 and -1.7 and the cellular effects of NCX1 inhibition were investigated. RESEARCH DESIGN AND METHODS-The patch-clamp technique was used to examine the pharmacological profile of the NCX1 inhibitor KB-R7943 on recombinant NCX1.3 and -1.7 activity. Ca2+ imaging and membrane capacitance were used to assess the effects of KB-R7943 on Ca-c(2+) and insulin secretion in mouse and human beta-cells and islets. RESULTS-NCX1.3 and -1.7 calcium extrusion (forward-mode) activity was similar to 16-fold more sensitive to KB-R7943 inhibition compared with cardiac NCX1.1 (IC50s = 2.9 and 2.4 vs. 43.0 vino1/1, respectively). In single mouse/human beta-cells, 1 umo1/1 KB-R7943 increased insulin granule exocytosis but was without effect on alpha-cell glucagon granule exocytosis. KB-R7943 also augmented sulfonylurea and glucose-stimulated Ca-c(2+) levels and insulin secretion in mouse and human islets, although KB-R7943 was without effect under nonstirnulated conditions. CONCLUSIONS-Islet NCX1 splice variants display a markedly greater sensitivity to pharmacological inhibition than the cardiac NCX1.1 splice variant. NCX1 inhibition resulted in glucosedependent increases in Ca-c(2+) and insulin secretion in mouse and human islets. Thus, we identify beta-cell NCX1 splice variants as targets for the development of novel glucose-sensitive insulinotropic drugs for type 2 diabetes. Diabetes 59:1686-1693, 2010