Voltage-gated Ca2+ influx and insulin secretion in human and mouse β-cells are impaired by the mitochondrial Na+/Ca2+ exchange inhibitor CGP-37157

Glucose-induced insulin release from pancreatic beta-cells relies largely on glucose metabolism and mitochondrial ATP synthesis. Inhibiting the mitocbondrial Na+/Ca2+ exchanger (mNCE) using 7-Cbloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzotbiazepin-2(3H)-one (CGP-37157) has been suggested to enhance ATP synthesis and insulin secretion from rat islets by promoting mitochondrial Ca2+ accumulation. In this study we examined the effects of CGP-37157 on human and mouse islet cells. Surprisingly, we found that insulin secretion from perifused islets was reduced by CGP-37157. Cytosolic Ca2+ Measurements revealed that CGP-37157 dose-dependently blocked glucose- and KCI-stimulated Ca2+ signals in both human and mouse P-cells. Conversely, CGP-37157 induced mitochondrial hyperpolarization, NAD(P)H rises, and triggered diazoxide- and nifedipine-sensitive cytosolic Ca2+ transients in a subset of quiescent cells bathed in sub-stimulatory glucose, which is in accord with metabolic activation by the compound. Hence, while blocking mNCE with CGP-37157 may augment metabolism of human and mouse P-cells, the propagation of metabolic signals is hampered by simultaneous inhibition of voltage-gated Ca2+ influx, and ultimately insulin secretion. Efforts to use CGP-37157 or design related compounds for therapeutic purposes should take these competing effects into account. (c) 2007 Elsevier B.V. All rights reserved.