http://scholars.ntou.edu.tw/handle/123456789/20410
標題: | Pdia4 regulates beta-cell pathogenesis in diabetes: molecular mechanism and targeted therapy | 作者: | Kuo, Tien-Fen Hsu, Shuo-Wen Huang, Shou-Hsien Chang, Cicero Lee-Tian Feng, Ching-Shan Huang, Ming-Guang Chen, Tzung-Yan Yang, Meng-Ting Jiang, Si-Tse Wen, Tuan-Nan Yang, Chun-Yen Huang, Chung-Yu Kao, Shu-Huei Tsai, Keng-Chang Yang, Greta Yang, Wen-Chin |
關鍵字: | PROTEIN DISULFIDE-ISOMERASE;ENDOPLASMIC-RETICULUM STRESS;CHRONIC OXIDATIVE STRESS;ENZYME GENE-EXPRESSION;GLUCOSE TOXICITY;IDENTIFICATION;DYSFUNCTION;INHIBITION;VIABILITY;FAILURE | 公開日期: | 7-十月-2021 | 出版社: | WILEY | 卷: | 13 | 期: | 10 | 來源出版物: | EMBO MOL MED | 摘要: | Loss of beta-cell number and function is a hallmark of diabetes. beta-cell preservation is emerging as a promising strategy to treat and reverse diabetes. Here, we first found that Pdia4 was primarily expressed in beta-cells. This expression was up-regulated in beta-cells and blood of mice in response to excess nutrients. Ablation of Pdia4 alleviated diabetes as shown by reduced islet destruction, blood glucose and HbA1c, reactive oxygen species (ROS), and increased insulin secretion in diabetic mice. Strikingly, this ablation alone or in combination with food reduction could fully reverse diabetes. Conversely, overexpression of Pdia4 had the opposite pathophysiological outcomes in the mice. In addition, Pdia4 positively regulated beta-cell death, dysfunction, and ROS production. Mechanistic studies demonstrated that Pdia4 increased ROS content in beta-cells via its action on the pathway of Ndufs3 and p22(phox). Finally, we found that 2-beta-D-glucopyranosyloxy1-hydroxytrideca 5,7,9,11-tetrayne (GHTT), a Pdia4 inhibitor, suppressed diabetic development in diabetic mice. These findings characterize Pdia4 as a crucial regulator of beta-cell pathogenesis and diabetes, suggesting Pdia4 is a novel therapeutic and diagnostic target of diabetes. |
URI: | http://scholars.ntou.edu.tw/handle/123456789/20410 | ISSN: | 1757-4676 | DOI: | 10.15252/emmm.201911668 |
顯示於: | 03 GOOD HEALTH AND WELL-BEING |
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