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⁺_c) required for insulin secretion in β-cells. NCX1 is alternatively spliced, resulting in the expression of splice variants in different tissues such as NCX1.3 and -1.7 in β-cells. As pharmacological inhibitors of NCX1 splice variants are in development, the pharmacological profile of β-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 Ca²⁺_c and insulin secretion in mouse and human β-cells and islets. RESULTS-NCX1.3 and -1.7 calcium extrusion (forward-mode) activity was ∼16-fold more sensitive to KB-R7943 inhibition compared with cardiac NCX1.1 (IC_50s = 2.9 and 2.4 vs. 43.0 μmol/l, respectively). In single mouse/human β-cells, 1 μmol/l KB-R7943 increased insulin granule exocytosis but was without effect on α-cell glucagon granule exocytosis. KB-R7943 also augmented sulfonylurea and glucose-stimulated Ca²⁺_c levels and insulin secretion in mouse and human islets, although KB-R7943 was without effect under nonstimulated 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 glucose-dependent increases in Ca ²⁺_c and insulin secretion in mouse and human islets. Thus, we identify β-cell NCX1 splice variants as targets for the development of novel glucose-sensitive insulinotropic drugs for type 2 diabetes.