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The adaptive increase in insulin secretion in early stages of obesity serves as a safeguard mechanism to maintain glucose homeostasis that cannot be sustained, and the eventual decompensation of β cells is a key event in the pathogenesis of diabetes. Here we describe a crucial system orchestrated by a transcriptional cofactor CtBP2. In cultured β cells, insulin gene expression is coactivated by CtBP2. Global genomic mapping of CtBP2 binding sites identifies a key interaction between CtBP2 and NEUROD1 through which CtBP2 decompacts chromatin in the insulin gene promoter. CtBP2 expression is diminished in pancreatic islets in multiple mouse models of obesity, as well as human obesity. Pancreatic β cell-specific CtBP2-deficient mice manifest glucose intolerance with impaired insulin secretion. Our transcriptome analysis highlights an essential role of CtBP2 in the maintenance of β cell integrity. This system provides clues to the molecular basis in obesity and may be targetable to develop therapeutic approaches. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Motohiro Sekiya, Yang Ma, Kenta Kainoh, Kenji Saito, Daichi Yamazaki, Tomomi Tsuyuzaki, Wanpei Chen, Putu Indah Paramita Adi Putri, Hiroshi Ohno, Takafumi Miyamoto, Yoshinori Takeuchi, Yuki Murayama, Yoko Sugano, Yoshinori Osaki, Hitoshi Iwasaki, Naoya Yahagi, Hiroaki Suzuki, Kaori Motomura, Takashi Matsuzaka, Kazuya Murata, Seiya Mizuno, Satoru Takahashi, Hitoshi Shimano. Loss of CtBP2 may be a mechanistic link between metabolic derangements and progressive impairment of pancreatic β cell function. Cell reports. 2023 Aug 29;42(8):112914

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PMID: 37557182

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