The pathological role of advanced glycation end products-downregulated heat shock protein 60 in islet β-cell hypertrophy and dysfunction

Heat shock protein 60 (HSP60) is a mitochondrial chaperone. Advanced glycation end products (AGEs) have been shown to interfere with the beta-cell function. We hypothesized that AGEs induced beta-cell hypertrophy and dysfunction through a HSP60 dysregulation pathway during the stage of islet/beta-cell hypertrophy of type-2-diabetes. We investigated the role of HSP60 in AGEs-induced beta-cell hypertrophy and dysfunction using the models of diabetic mice and cultured beta-cells. Hypertrophy, increased levels of p27(Kip1), 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 p27(Kip1) expression, and decreased the HSP60 expression, insulin secretion, and ATP content in cultured beta-cells, which could be reversed by RAGE neutralizing antibody. HSP60 overexpression significantly reversed AGEs-induced hypertrophy, dysfunction, and ATP reduction in beta-cells. Oxidative stress was also involved in the AGEs-decreased HSP60 expression in beta-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 beta-cell hypertrophy and dysfunction under diabetic hyperglycemia.