Antioxidants Complement the Requirement for Protein Chaperone Function to Maintain beta-Cell Function and Glucose Homeostasis
- Authors
- Han, Jaeseok; Song, Benbo; Kim, Jiun; Kodali, Vamsi K.; Pottekat, Anita; Wang, Miao; Hassler, Justin; Wang, Shiyu; Pennathur, Subramaniam; Back, Sung Hoon; Katze, Michael G.; Kaufman, Randal J.
- Issue Date
- Aug-2015
- Publisher
- American Diabetes Association
- Keywords
- ER stress Diabetes
- Citation
- Diabetes, v.64, no.8, pp 2892 - 2904
- Pages
- 13
- Journal Title
- Diabetes
- Volume
- 64
- Number
- 8
- Start Page
- 2892
- End Page
- 2904
- URI
- https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/10440
- DOI
- 10.2337/db14-1357
- ISSN
- 0012-1797
1939-327X
- Abstract
- Proinsulin misfolding in the endoplasmic reticulum (ER) initiates a cell death response, although the mechanism(s) remains unknown. To provide insight into how protein misfolding may cause beta-cell failure, we analyzed mice with the deletion of P58(IPK)/DnajC3, an ER luminal cochaperone. P58(IPK-/-) mice become diabetic as a result of decreased beta-cell function and mass accompanied by induction of oxidative stress and cell death. Treatment with a chemical chaperone, as well as deletion of Chop, improved beta-cell function and ameliorated the diabetic phenotype in P58(IPK-/-) mice, suggesting P58(IPK) deletion causes beta-cell death through ER stress. Significantly, a diet of chow supplemented with antioxidant dramatically and rapidly restored beta-cell function in P58(IPK-/-) mice and corrected abnormal localization of MafA, a critical transcription factor for beta-cell function. Antioxidant feeding also preserved beta-cell function in Akita mice that express mutant misfolded proinsulin. Therefore defective protein folding in the beta-cell causes oxidative stress as an essential proximal signal required for apoptosis in response to ER stress. Remarkably, these findings demonstrate that antioxidant feeding restores cell function upon deletion of an ER molecular chaperone. Therefore antioxidant or chemical chaperone treatment may be a promising therapeutic approach for type 2 diabetes.
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Collections - Graduate School > Department of Integrated Biomedical Science > 1. Journal Articles
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