Pdia4 regulates β‐cell pathogenesis in diabetes: molecular mechanism and targeted therapy
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...
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-09-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201911668 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Tien‐Fen Kuo |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-cdf054b19b8a4d15ad574bedf038d2a8 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-cdf054b19b8a4d15ad574bedf038d2a82025-08-20T03:46:21ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-09-01131012110.15252/emmm.201911668Pdia4 regulates β‐cell pathogenesis in diabetes: molecular mechanism and targeted therapyTien‐Fen Kuo0Shuo‐Wen Hsu1Shou‐Hsien Huang2Cicero Lee‐Tian Chang3Ching‐Shan Feng4Ming‐Guang Huang5Tzung‐Yan Chen6Meng‐Ting Yang7Si‐Tse Jiang8Tuan‐Nan Wen9Chun‐Yen Yang10Chung‐Yu Huang11Shu‐Huei Kao12Keng‐Chang Tsai13Greta Yang14Wen‐Chin Yang15Agricultural Biotechnology Research Center, Academia SinicaAgricultural Biotechnology Research Center, Academia SinicaAgricultural Biotechnology Research Center, Academia SinicaDepartment of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing UniversityDepartment of Aquaculture, National Taiwan Ocean UniversityAgricultural Biotechnology Research Center, Academia SinicaAgricultural Biotechnology Research Center, Academia SinicaAgricultural Biotechnology Research Center, Academia SinicaNational Laboratory Animal Center, National Applied Research LaboratoriesInstitute of Plant and Microbial Biology, Academia SinicaAgricultural Biotechnology Research Center, Academia SinicaPhD Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical UniversityPhD Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical UniversityNational Research Institute of Chinese Medicine, Ministry of Health and WelfareAgricultural Biotechnology Research Center, Academia SinicaAgricultural Biotechnology Research Center, Academia SinicaAbstract 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.https://doi.org/10.15252/emmm.201911668diabetesPdia4ROSβ‐cell failureβ‐cells |
| spellingShingle | 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 Pdia4 regulates β‐cell pathogenesis in diabetes: molecular mechanism and targeted therapy EMBO Molecular Medicine diabetes Pdia4 ROS β‐cell failure β‐cells |
| title | Pdia4 regulates β‐cell pathogenesis in diabetes: molecular mechanism and targeted therapy |
| title_full | Pdia4 regulates β‐cell pathogenesis in diabetes: molecular mechanism and targeted therapy |
| title_fullStr | Pdia4 regulates β‐cell pathogenesis in diabetes: molecular mechanism and targeted therapy |
| title_full_unstemmed | Pdia4 regulates β‐cell pathogenesis in diabetes: molecular mechanism and targeted therapy |
| title_short | Pdia4 regulates β‐cell pathogenesis in diabetes: molecular mechanism and targeted therapy |
| title_sort | pdia4 regulates β cell pathogenesis in diabetes molecular mechanism and targeted therapy |
| topic | diabetes Pdia4 ROS β‐cell failure β‐cells |
| url | https://doi.org/10.15252/emmm.201911668 |
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