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ID 114932
タイトル別表記
Glucotoxicity Induces Insulin Promoter DNA Methylation in Beta Cells
著者
Ishikawa, Kota Nagoya University
Tsunekawa, Shin Nagoya University
Ikeniwa, Makoto Nagoya University
Izumoto, Takako Nagoya University
Iida, Atsushi Nagoya University
Ogata, Hidetada Nagoya University
Uenishi, Eita Nagoya University
Seino, Yusuke Nagoya University
Ozaki, Nobuaki Nagoya University
Sugimura, Yoshihisa Nagoya University
Hamada, Yoji Nagoya University
Shinjo, Keiko Nagoya City University
Kondo, Yutaka Nagoya City University
Oiso, Yutaka Nagoya University
資料タイプ
学術雑誌論文
抄録
Recent studies have implicated epigenetics in the pathophysiology of diabetes. Furthermore, DNA methylation, which irreversibly deactivates gene transcription, of the insulin promoter, particularly the cAMP response element, is increased in diabetes patients. However, the underlying mechanism remains unclear. We aimed to investigate insulin promoter DNA methylation in an over-nutrition state. INS-1 cells, the rat pancreatic beta cell line, were cultured under normal-culture-glucose (11.2 mmol/l) or experimental-high-glucose (22.4 mmol/l) conditions for 14 days, with or without 0.4 mmol/l palmitate. DNA methylation of the rat insulin 1 gene (Ins1) promoter was investigated using bisulfite sequencing and pyrosequencing analysis. Experimental-high-glucose conditions significantly suppressed insulin mRNA and increased DNA methylation at all five CpG sites within the Ins1 promoter, including the cAMP response element, in a time-dependent and glucose concentration-dependent manner. DNA methylation under experimental-high-glucose conditions was unique to the Ins1 promoter; however, palmitate did not affect DNA methylation. Artificial methylation of Ins1 promoter significantly suppressed promoter-driven luciferase activity, and a DNA methylation inhibitor significantly improved insulin mRNA suppression by experimental-high-glucose conditions. Experimental-high-glucose conditions significantly increased DNA methyltransferase activity and decreased ten-eleven-translocation methylcytosine dioxygenase activity. Oxidative stress and endoplasmic reticulum stress did not affect DNA methylation of the Ins1 promoter. High glucose but not palmitate increased ectopic triacylglycerol accumulation parallel to DNA methylation. Metformin upregulated insulin gene expression and suppressed DNA methylation and ectopic triacylglycerol accumulation. Finally, DNA methylation of the Ins1 promoter increased in isolated islets from Zucker diabetic fatty rats. This study helps to clarify the effect of an over-nutrition state on DNA methylation of the Ins1 promoter in pancreatic beta cells. It provides new insights into the irreversible pathophysiology of diabetes.
掲載誌名
PLOS ONE
ISSN
19326203
出版者
PLOS
10
2
開始ページ
e0115350
発行日
2015-02-06
権利情報
© 2015 Ishikawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License(https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
出版社版
部局
先端酵素学研究所