title: The pathological role of advanced glycation end products-downregulated heat shock protein 60 in islet β-cell hypertrophy and dysfunction.
abstract: Heat shock protein 60 (HSP60) is a mitochondrial chaperone. Advanced glycation end products (AGEs) have been shown to interfere with the β-cell function. We hypothesized that AGEs induced β-cell hypertrophy and dysfunction through a HSP60 dysregulation pathway during the stage of islet/β-cell hypertrophy of type-2-diabetes. We investigated the role of HSP60 in AGEs-induced β-cell hypertrophy and dysfunction using the models of diabetic mice and cultured β-cells. Hypertrophy, increased levels of p27Kip1, AGEs, and receptor for AGEs (RAGE), and decreased levels of HSP60, insulin, and ATP content were obviously observed in pancreatic islets of 12-week-old db/db diabetic mice. Low-concentration AGEs significantly induced the cell hypertrophy, increased the p27Kip1 expression, and decreased the HSP60 expression, insulin secretion, and ATP content in cultured β-cells, which could be reversed by RAGE neutralizing antibody. HSP60 overexpression significantly reversed AGEs-induced hypertrophy, dysfunction, and ATP reduction in β-cells. Oxidative stress was also involved in the AGEs-decreased HSP60 expression in β-cells. Pancreatic sections from diabetic patient showed islet hypertrophy, increased AGEs level, and decreased HSP60 level as compared with normal subject. These findings highlight a novel mechanism by which a HSP60-correlated signaling pathway contributes to the AGEs-RAGE axis-induced β-cell hypertrophy and dysfunction under diabetic hyperglycemia.
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Institute of Nuclear Energy Research, Atomic Energy Council, Executive Yuan, Taoyuan, Taiwan.
authors.forename: Siao-Syun
authors.initials: SS
authors.lastname: Guan
authors.affiliation: Biomedical Sciences, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Meei-Ling
authors.initials: ML
authors.lastname: Sheu
authors.affiliation: Department of Orthopaedics, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Rong-Sen
authors.initials: RS
authors.lastname: Yang
authors.affiliation: Department of Geriatrics and Gerontology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ding-Cheng
authors.initials: DC
authors.lastname: Chan
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Cheng-Tien
authors.initials: CT
authors.lastname: Wu
authors.affiliation: Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ting-Hua
authors.initials: TH
authors.lastname: Yang
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Integrated Diagnostics and Therapeutics and Internal Medicine, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan.
authors.forename: Chih-Kang
authors.initials: CK
authors.lastname: Chiang
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.|Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Shing-Hwa
authors.initials: SH
authors.lastname: Liu
mesh_terms: D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism / Q000473:pathology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D051381:Rats; D015398:Signal Transduction
chemical_list: D018834:Chaperonin 60; D017127:Glycation End Products, Advanced
keywords: Pathology Section; advanced glycation end products; diabetes; heat shock protein 60; β-cell hypertrophy