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.

Chaperonin 60 sustains osteoblast autophagy and counteracts glucocorticoid aggravation of osteoporosis by chaperoning RPTOR

“…Increasing evidence reveals that high dose of therapeutic glucocorticoid disturbs mitochondrial machinery provoking cell damage or tissue deterioration, like skeletal muscle wasting 28 , necroptosis of acute lymphoblastic leukemic cells 29 , and fat overproduction of adipose tissue 30 . Loss of HSP60 function also perturbs extracellular matrix metabolism and amplifies apoptotic programs 31 , 32 . This study showed that HSP60 maintained autophagic influx beneficial for fending off glucocorticoid-induced apoptosis and mineralized matrix underproduction, indicating that glucocorticoid stress cutoff a fine-tuned organelle crosstalk between autophagosome and mitochondria aggravating osteoblast dysfunction.…”

Phosphoproteomics Reveals the GSK3-PDX1 Axis as a Key Pathogenic Signaling Node in Diabetic Islets

“…Indeed, the proteomics data indicated a significant downregulation of many proteins involved in insulin granules exocytosis (Figure 3B; Table S1). Thus, our data provide a molecular explanation for the insulin secretion failure observed in islets from 10-to 13-week-old db/db mice (Do et al, 2014;Guan et al, 2016;Kim et al, 2015;Kondo et al, 2012). The lower [ATP]/[ADP] concentration ratio in db/db islets should promote AMPK activation, which is likely to be inhibited (Figure 2A).…”

HSP60 reduction protects against diet-induced obesity by modulating energy metabolism in adipose tissue

“…Mice heterozygous for the Hspd1 gene, encoding HSP60, (Hsp60 +/− mice) can serve as a genetic model for diabetes-related mitochondrial dysfunction, as db/db mice exhibit an approximately 50% reduction in HSP60 ([ 9 , 22 , 23 ], Attie Lab diabetes database http://diabetes.wisc.edu/ ). This model allows for an answer to the question of whether a mild generalized impairment in mitochondrial function due to decreased chaperone activity, as seen in diabetes, affects insulin action and obesity development.…”