Research Papers: Pathology:
The pathological role of advanced glycation end products-downregulated heat shock protein 60 in islet β-cell hypertrophy and dysfunction
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Siao-Syun Guan1,2,*, Meei-Ling Sheu3,*, Rong-Sen Yang4,*, Ding-Cheng Chan5,*, Cheng-Tien Wu1, Ting-Hua Yang6, Chih-Kang Chiang1,7 and Shing-Hwa Liu1,8,9
1 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
2 Institute of Nuclear Energy Research, Atomic Energy Council, Executive Yuan, Taoyuan, Taiwan
3 Biomedical Sciences, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan
4 Department of Orthopaedics, College of Medicine, National Taiwan University, Taipei, Taiwan
5 Department of Geriatrics and Gerontology, College of Medicine, National Taiwan University, Taipei, Taiwan
6 Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan
7 Department of Integrated Diagnostics and Therapeutics and Internal Medicine, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan
8 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
9 Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
* These authors have contributed equally to this work
Shing-Hwa Liu, email:
Chih-Kang Chiang, email:
Keywords: diabetes, advanced glycation end products, β-cell hypertrophy, heat shock protein 60, Pathology Section
Received: March 16, 2016 Accepted: March 29, 2016 Published: April 05, 2016
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.
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