The pathological role of advanced glycation end productsdownregulated heat shock protein 60 in islet β-cell hypertrophy and dysfunction
Journal
Oncotarget
Journal Volume
7
Journal Issue
17
Pages
23072-23087
Date Issued
2016
Author(s)
Guan S.-S.
Sheu M.-L.
Wu C.-T.
Liu S.-H.
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 axisinduced β-cell hypertrophy and dysfunction under diabetic hyperglycemia.
SDGs
Other Subjects
adenosine 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 Transduction
Publisher
Impact Journals LLC
Type
journal article