title: Antioxidants Complement the Requirement for Protein Chaperone Function to Maintain β-Cell Function and Glucose Homeostasis.
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 β-cell failure, we analyzed mice with the deletion of P58(IPK)/DnajC3, an ER luminal co-chaperone. P58(IPK-/-) mice become diabetic as a result of decreased β-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 β-cell function and ameliorated the diabetic phenotype in P58(IPK-/-) mice, suggesting P58(IPK) deletion causes β-cell death through ER stress. Significantly, a diet of chow supplemented with antioxidant dramatically and rapidly restored β-cell function in P58(IPK-/-) mice and corrected abnormal localization of MafA, a critical transcription factor for β-cell function. Antioxidant feeding also preserved β-cell function in Akita mice that express mutant misfolded proinsulin. Therefore defective protein folding in the β-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.
authors: Degenerative Diseases Program, Sanford-Burnham Medical Research Institute, La Jolla, CA Soonchunhyang Institute of Med-Bio Science (SIMS), Soonchunhyang University, Cheonan-si, Republic of Korea.
authors: Jaeseok
authors: J
authors: Han
authors: Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI.
authors: Benbo
authors: B
authors: Song
authors: Degenerative Diseases Program, Sanford-Burnham Medical Research Institute, La Jolla, CA.
authors: Jiun
authors: J
authors: Kim
authors: Degenerative Diseases Program, Sanford-Burnham Medical Research Institute, La Jolla, CA.
authors: Vamsi K
authors: VK
authors: Kodali
authors: Degenerative Diseases Program, Sanford-Burnham Medical Research Institute, La Jolla, CA.
authors: Anita
authors: A
authors: Pottekat
authors: Degenerative Diseases Program, Sanford-Burnham Medical Research Institute, La Jolla, CA.
authors: Miao
authors: M
authors: Wang
authors: Degenerative Diseases Program, Sanford-Burnham Medical Research Institute, La Jolla, CA Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI.
authors: Justin
authors: J
authors: Hassler
authors: Degenerative Diseases Program, Sanford-Burnham Medical Research Institute, La Jolla, CA.
authors: Shiyu
authors: S
authors: Wang
authors: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI.
authors: Subramaniam
authors: S
authors: Pennathur
authors: School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea.
authors: Sung Hoon
authors: SH
authors: Back
authors: Department of Microbiology, University of Washington, Seattle, WA.
authors: Michael G
authors: MG
authors: Katze
authors: Degenerative Diseases Program, Sanford-Burnham Medical Research Institute, La Jolla, CA Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI rkaufman@sanfordburnham.org.
authors: Randal J
authors: RJ
authors: Kaufman
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011384:Proinsulin / Q000378:metabolism; D017510:Protein Folding / Q000187:drug effects
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; C500846:Dnajc3 protein, mouse; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D011384:Proinsulin