Pdia4 regulates β‐cell pathogenesis in diabetes: molecular mechanism and targeted therapy
| Autor: | Greta Yang, Shou-Hsien Huang, Tzung-Yan Chen, Ming-Guang Huang, Cicero Lee-Tian Chang, Shuo-Wen Hsu, Meng-Ting Yang, Tien-Fen Kuo, Chun-Yen Yang, Si-Tse Jiang, Ching-Shan Feng, Chung-Yu Huang, Keng-Chang Tsai, Tuan-Nan Wen, Wen-Chin Yang, Shu-Huei Kao |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Blood Glucose
Medicine (General) medicine.medical_treatment Cell Protein Disulfide-Isomerases Regulator Pharmacology QH426-470 Article Diabetes Mellitus Experimental Targeted therapy Pathogenesis Mice R5-920 Diabetes mellitus medicine β‐cells Genetics Animals Molecular Biology of Disease Pdia4 chemistry.chemical_classification geography Reactive oxygen species geography.geographical_feature_category diabetes business.industry ROS Articles Islet medicine.disease Pathophysiology Metabolism medicine.anatomical_structure chemistry Molecular Medicine Reactive Oxygen Species business β‐cell failure |
| Zdroj: | EMBO Molecular Medicine, Vol 13, Iss 10, Pp n/a-n/a (2021) EMBO Molecular Medicine |
| ISSN: | 1757-4676 1757-4684 |
| Popis: | 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. Pancreatic β‐cell failure is associated with diabetes. Pdia4, a protein disulfide isomerase, is identified as a crucial regulator of β‐cell pathogenesis and diabetes. |
| Databáze: | OpenAIRE |
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