Palmitate induces reactive oxygen species production and β‐cell dysfunction by activating nicotinamide adenine dinucleotide phosphate oxidase through Src signaling

Journal of Diabetes Investigation

Yuichi Sato¹  Shimpei Fujimoto¹  Eri Mukai¹  Hiroki Sato¹  Yumiko Tahara¹  Kasane Ogura¹  Gen Yamano¹  Masahito Ogura¹  Kazuaki Nagashima¹ 

[1] Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan

关键词: Lipotoxicity;    Pancreatic β‐cells;    Reactive oxygen species;   

DOI  :  10.1111/jdi.12124

来源: Wiley

【 摘 要 】

Abstract

Aims/Introduction

Chronic hyperlipidemia impairs pancreatic β-cell function, referred to as lipotoxicity. We have reported an important role of endogenous reactive oxygen species (ROS) overproduction by activation of Src, a non-receptor tyrosine kinase, in impaired glucose-induced insulin secretion (GIIS) from diabetic rat islets. In the present study, we investigated the role of ROS production by Src signaling in palmitate-induced dysfunction of β-cells.

Materials and Methods

After rat insulinoma INS-1D cells were exposed to 0.6 mmol/L palmitate for 24 h (palmitate exposure); GIIS, ROS production and nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity were examined with or without exposure to10 μmol/L 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), a Src inhibitior, for 30 or 60 min.

Results

Exposure to PP2 recovered impaired GIIS and decreased ROS overproduction as a result of palmitate exposure. Palmitate exposure increased activity of NOX and protein levels of NOX2, a pathological ROS source in β-cells. Palmitate exposure increased the protein level of p47^phox, a regulatory protein of NOX2, in membrane fraction compared with control, which was reduced by PP2. Transfection of small interfering ribonucleic acid of p47^phox suppressed the augmented p47^phox protein level in membrane fraction, decreased augmented ROS production and increased impaired GΙIS by palmitate exposure. In addition, exposure to PP2 ameliorated impaired GIIS and decreased ROS production in isolated islets of KK-A^y mice, an obese diabetic model with hyperlipidemia.

Conclusions

Activation of NOX through Src signaling plays an important role in ROS overproduction and impaired GΙIS caused by chronic exposure to palmitate, suggesting a lipotoxic mechanism of β-cell dysfunction of obese mice.

【 授权许可】

CC BY-NC-ND   
© 2013 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and Wiley Publishing Asia Pty Ltd

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