Impaired insulin secretion by diphenyleneiodium associated with perturbation of cytosolic Ca2+ dynamics in pancreatic β-cells

Hirofumi Imoto, Nobuhiro Sasaki, Masanori Iwase, Udai Nakamura, Miwako Oku, Kazuo Sonoki, Yuji Uchizono, Mitsuo Iida

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20 Citations (Scopus)

Abstract

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 ([Ca 2+]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 effect on mastoparan-induced insulin secretion at 3.3 and 16.7 mM glucose under Ca 2+-free conditions. DPI significantly suppressed islet glucose oxidation and ATP content through its known inhibitory action on complex I in the mitochondrial respiratory chain. On the other hand, DPI altered [Ca 2+]i dynamics in response to high glucose and membrane depolarization, and DPI per se dose-dependently increased [Ca2+] i. The DPI-induced [Ca2+]i rise was associated with a transient increase in insulin secretion and was attenuated by removal of extracellular Ca2+, by L-type voltage-dependent Ca2+ channel blockers, by mitochondrial inhibitors, or by addition of 0.1 or 1.0 μM H2O2 exogenously. Our results showed that DPI impairment of insulin secretion involved altered Ca2+ signaling, suggesting that NADPH oxidase may modulate Ca2+ signaling in β-cells.

Original languageEnglish
Pages (from-to)5391-5400
Number of pages10
JournalEndocrinology
Volume149
Issue number11
DOIs
Publication statusPublished - Nov 2008

All Science Journal Classification (ASJC) codes

  • Endocrinology

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    Imoto, H., Sasaki, N., Iwase, M., Nakamura, U., Oku, M., Sonoki, K., Uchizono, Y., & Iida, M. (2008). Impaired insulin secretion by diphenyleneiodium associated with perturbation of cytosolic Ca2+ dynamics in pancreatic β-cells. Endocrinology, 149(11), 5391-5400. https://doi.org/10.1210/en.2008-0186