Pdia4 regulates β-cell pathogenesis in diabetes: molecular mechanism and targeted therapy
Diabetes has been not curable for the past 2000 years due to loss of β-cell number and function. β-cell preservation is therefore a promising strategy to treat and reverse diabetes. In this publication, we first found that Pdia4 was primarily expressed in β-cells. This expression was up-regulated in β-cells 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 could fully reverse diabetes. Conversely, overexpression of Pdia4 had the opposite pathophysiological outcomes in the mice. Besides, Pdia4 positively regulated β-cell death, dysfunction and ROS production. Mechanistic studies demonstrated that Pdia4 increased ROS content in β-cells via its action on the ROS-generating pathways. Finally, we found that a Pdia4 inhibitor, a lead compound of PS1, a first-in-class drug for diabetes, suppressed diabetes in diabetic mice. These findings characterize Pdia4 as a crucial regulator of β-cell failure and diabetes, suggesting Pdia4 is a novel therapeutic target of diabetes. Pre-clinical studies of PS1 was completed and its clinical trials are under way.
Funding Sources: Ministry of Science and Technology and Academia Sinica.
Tien-Fen Kuo, Shuo-Wen Hsu, Shou-Hsien Huang, Cicero Lee-Tian Chang, Ching-Shan Feng, Ming-Guang Huang, Tzung-Yan Chen, Meng-Ting Yang, Si-Tse Jiang, Tuan-Nan Wen, Chun-Yen Yang, Chung-Yu Huang, Shu-Huei Kao, Keng-Chang Tsai, Greta Yang, and Wen-Chin Yang
(2021) Pdia4 regulates β-cell pathogenesis in diabetes: molecular mechanism and targeted therapy
EMBO Molecular Medicine, e11668