Guan S.-S.Sheu M.-L.RONG-SEN YANGDING-CHENG CHANWu C.-T.TING-HUA YANGCHIH-KANG CHIANGLiu S.-H.2020-11-302020-11-3020161949-2553https://www.scopus.com/inward/record.uri?eid=2-s2.0-84966692566&doi=10.18632%2foncotarget.8604&partnerID=40&md5=e5f99ec020ed4776f2ef84af626c6af9https://scholars.lib.ntu.edu.tw/handle/123456789/522974Heat 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 axisinduced β-cell hypertrophy and dysfunction under diabetic hyperglycemia.[SDGs]SDG3adenosine triphosphate; advanced glycation end product; advanced glycation end product receptor; chaperonin 60; cyclin dependent kinase inhibitor 1B; insulin; advanced glycation end product; chaperonin 60; aged; animal cell; animal experiment; animal model; Article; cell size; cell viability; controlled study; down regulation; human; human tissue; insulin release; male; mouse; non insulin dependent diabetes mellitus; nonhuman; oxidative stress; pancreas islet beta cell; protein expression; protein function; rat; signal transduction; animal; cell culture; drug effects; experimental diabetes mellitus; hypertrophy; metabolism; pancreas islet beta cell; pathology; Aged; Animals; Cells, Cultured; Chaperonin 60; Diabetes Mellitus, Experimental; Down-Regulation; Glycation End Products, Advanced; Humans; Hypertrophy; Insulin-Secreting Cells; Male; Mice; Oxidative Stress; Rats; Signal Transductionjournal article10.18632/oncotarget.8604270569032-s2.0-84966692566