Pdia4 regulates β-cell pathogenesis in diabetes: molecular mechanism and targeted therapy

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, Wen Chin Yang

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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 p22phox. 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.

Original languageEnglish
Article numbere11668
JournalEMBO Molecular Medicine
Volume13
Issue number10
DOIs
Publication statusPublished - Oct 7 2021

Keywords

  • diabetes
  • Pdia4
  • ROS
  • β-cell failure
  • β-cells

ASJC Scopus subject areas

  • Molecular Medicine

Fingerprint

Dive into the research topics of 'Pdia4 regulates β-cell pathogenesis in diabetes: molecular mechanism and targeted therapy'. Together they form a unique fingerprint.

Cite this