Open AccessPdia4 regulates β‐cell pathogenesis in diabetes: molecular mechanism and targeted therapy
Author(s) -
Kuo TienFen,
Hsu ShuoWen,
Huang ShouHsien,
Chang Cicero LeeTian,
Feng ChingShan,
Huang MingGuang,
Chen TzungYan,
Yang MengTing,
Jiang SiTse,
Wen TuanNan,
Yang ChunYen,
Huang ChungYu,
Kao ShuHuei,
Tsai KengChang,
Yang Greta,
Yang WenChin
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201911668
Subject(s) - diabetes mellitus , pathogenesis , islet , reactive oxygen species , insulin , medicine , p22phox , endocrinology , cell , microbiology and biotechnology , biology , nadph oxidase , biochemistry
Loss of β‐cell number and function is a hallmark of diabetes. β‐cell preservation is emerging as a promising strategy to treat and reverse diabetes. Here, we first found that Pdia4 was primarily expressed in β‐cells. This expression was up‐regulated in β‐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 β‐cell death, dysfunction, and ROS production. Mechanistic studies demonstrated that Pdia4 increased ROS content in β‐cells via its action on the pathway of Ndufs3 and p22 phox . Finally, we found that 2‐β‐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 β‐cell pathogenesis and diabetes, suggesting Pdia4 is a novel therapeutic and diagnostic target of diabetes.