eHSP72 (extracellular heat-shock protein 72) is increased in the plasma of both types of diabetes and is positively correlated with inflammatory markers. Since aging is associated with a low-grade inflammation and IR (insulin resistance), we aimed to: (i) analyse the concentration of eHSP72 in elderly people and determine correlation with insulin resistance, and (ii) determine the effects of eHSP72 on β-cell function and viability in human and rodent pancreatic β-cells. Fasting blood samples were collected from 50 older people [27 females and 23 males; 63.4±4.4 years of age; BMI (body mass index)=25.5±2.7 kg/m2]. Plasma samples were analysed for eHSP72, insulin, TNF (tumour necrosis factor)-α, leptin, adiponectin and cortisol, and glycaemic and lipid profile. In vitro studies were conducted using rodent islets and clonal rat and human pancreatic β-cell lines (BRIN-BD11 and 1.1B4 respectively). Cells/islets were incubated for 24 h with eHSP72 (0, 0.2, 4, 8 and 40 ng/ml). Cell viability was measured using three different methods. The impact of HSP72 on β-cell metabolic status was determined using Seahorse Bioscience XFe96 technology. To assess whether the effects of eHSP72 were mediated by Toll-like receptors (TLR2/TLR4), we co-incubated rodent islets with eHSP72 and the TLR2/TLR4 inhibitor OxPAPC (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine; 30 μg/ml). We found a positive correlation between plasma eHSP72 and HOMA-IR (homoeostasis model assessment of IR) (r=0.528, P<0.001), TNF-α (r=0.389, P<0.014), cortisol (r=0.348, P<0.03) and leptin/adiponectin (r=0.334, P<0.03). In the in vitro studies, insulin secretion was decreased in an eHSP72 dose-dependent manner in BRIN-BD11 cells (from 257.7±33 to 84.1±10.2 μg/mg of protein per 24 h with 40 ng/ml eHSP72), and in islets in the presence of 40 ng/ml eHSP72 (from 0.48±0.07 to 0.33±0.009 μg/20 islets per 24 h). Similarly, eHSP72 reduced β-cell viability (at least 30% for BRIN-BD11 and 10% for 1.1B4 cells). Bioenergetic studies revealed that eHSP72 altered pancreatic β-cell metabolism. OxPAPC restored insulin secretion in islets incubated with 40 ng/ml eHSP72. In conclusion, we have demonstrated a positive correlation between eHSP72 and IR. In addition, we suggest that chronic eHSP72 exposure may mediate β-cell failure.
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Research Article|
February 03 2014
Elevated levels of extracellular heat-shock protein 72 (eHSP72) are positively correlated with insulin resistance in vivo and cause pancreatic β-cell dysfunction and death in vitro
Mauricio Krause;
*Food for Health Ireland (FHI), Department of Agriculture, Food Science & Veterinary Medicine, Institute of Food Health, University College Dublin, Dublin, Ireland
†Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
‡Institute for Sport and Health, University College Dublin, Dublin, Ireland
§Biomedical Research Group, Department of Science, ITT Dublin, Ireland
Correspondence: Dr Mauricio Krause (email [email protected] or [email protected]) or Professor Philip Newsholme (email [email protected]).
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Kevin Keane;
Kevin Keane
∥School of Biomedical Sciences, CHIRI - Biosciences, Curtin University, Perth, Western Australia 6845
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Josianne Rodrigues-Krause;
Josianne Rodrigues-Krause
§Biomedical Research Group, Department of Science, ITT Dublin, Ireland
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Domenico Crognale;
Domenico Crognale
*Food for Health Ireland (FHI), Department of Agriculture, Food Science & Veterinary Medicine, Institute of Food Health, University College Dublin, Dublin, Ireland
‡Institute for Sport and Health, University College Dublin, Dublin, Ireland
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Brendan Egan;
Brendan Egan
*Food for Health Ireland (FHI), Department of Agriculture, Food Science & Veterinary Medicine, Institute of Food Health, University College Dublin, Dublin, Ireland
‡Institute for Sport and Health, University College Dublin, Dublin, Ireland
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Giuseppe De Vito;
Giuseppe De Vito
*Food for Health Ireland (FHI), Department of Agriculture, Food Science & Veterinary Medicine, Institute of Food Health, University College Dublin, Dublin, Ireland
‡Institute for Sport and Health, University College Dublin, Dublin, Ireland
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Colin Murphy;
Colin Murphy
§Biomedical Research Group, Department of Science, ITT Dublin, Ireland
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Philip Newsholme
*Food for Health Ireland (FHI), Department of Agriculture, Food Science & Veterinary Medicine, Institute of Food Health, University College Dublin, Dublin, Ireland
∥School of Biomedical Sciences, CHIRI - Biosciences, Curtin University, Perth, Western Australia 6845
Correspondence: Dr Mauricio Krause (email [email protected] or [email protected]) or Professor Philip Newsholme (email [email protected]).
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Publisher: Portland Press Ltd
Received:
October 29 2013
Revision Received:
December 03 2013
Accepted:
December 11 2013
Accepted Manuscript online:
December 11 2013
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2014 Biochemical Society
2014
Clin Sci (Lond) (2014) 126 (10): 739–752.
Article history
Received:
October 29 2013
Revision Received:
December 03 2013
Accepted:
December 11 2013
Accepted Manuscript online:
December 11 2013
Citation
Mauricio Krause, Kevin Keane, Josianne Rodrigues-Krause, Domenico Crognale, Brendan Egan, Giuseppe De Vito, Colin Murphy, Philip Newsholme; Elevated levels of extracellular heat-shock protein 72 (eHSP72) are positively correlated with insulin resistance in vivo and cause pancreatic β-cell dysfunction and death in vitro. Clin Sci (Lond) 1 May 2014; 126 (10): 739–752. doi: https://doi.org/10.1042/CS20130678
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