Impaired Insulin Secretion by Diphenyleneiodium Associated with Perturbation of Cytosolic Ca2+ Dynamics in Pancreatic β-Cells

Pancreatic islets express the superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, but its role remains unknown. To address this, we studied the mechanisms of impaired insulin secretion induced by diphenyleneiodium (DPI), an NADPH oxidase inhibitor. We investigated the effects of DPI on glucose- and nonfuel-stimulated insulin secretion, islet glucose metabolism, and intracellular Ca2+ concentration ([Ca2+]i) dynamics in rat islets and β-cell line RINm5F cells. DPI did not affect insulin secretion at 3.3 mm glucose but totally suppressed insulin secretion stimulated by 16.7 mm glucose (percentage of control, 9.2 ± 1.2%; P <0.001). DPI also inhibited insulin release by high K+-induced membrane depolarization (percentage of control, 36.0 ± 5.3%; P <0.01) and protein kinase C activation (percentage of control, 30.2 ± 10.6% in the presence of extracellular Ca2+, P <0.01; percentage of control, 42.0 ± 4.7% in the absence of extracellular Ca2+, P <0.01). However, DPI had no ef...