Inhibition of beta-cell sodium-calcium exchange enhances glucose-dependent elevations in cytoplasmic calcium and insulin secretion.

objectiveThe sodium-calcium exchanger isoform 1 (NCX1) regulates cytoplasmic calcium (Ca(2+)(c)) 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

methodsThe patch-clamp technique was used to examine the pharmacological profile of the NCX1 inhibitor KB-R7943 on recombinant NCX1.3 and -1.7 activity. Ca(2+) imaging and membrane capacitance were used to assess the effects of KB-R7943 on Ca(2+)(c) and insulin secretion in mouse and human beta-cells and islets.

resultsNCX1.3 and -1.7 calcium extrusion (forward-mode) activity was approximately 16-fold more sensitive to KB-R7943 inhibition compared with cardiac NCX1.1 (IC(50s) = 2.9 and 2.4 vs. 43.0 micromol/l, respectively). In single mouse/human beta-cells, 1 micromol/l 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(2+)(c) levels and insulin secretion in mouse and human islets, although KB-R7943 was without effect under nonstimulated conditions.

conclusionsIslet NCX1 splice variants display a markedly greater sensitivity to pharmacological inhibition than the cardiac NCX1.1 splice variant. NCX1 inhibition resulted in glucose-dependent increases in Ca(2+)(c) 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.