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Methylglyoxal impairs endothelial insulin sensitivity both in vitro and in vivo

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Abstract

Aims/hypothesis

Insulin exerts a direct action on vascular cells, thereby affecting the outcome and progression of diabetic vascular complications. However, the mechanism through which insulin signalling is impaired in the endothelium of diabetic individuals remains unclear. In this work, we have evaluated the role of the AGE precursor methylglyoxal (MGO) in generating endothelial insulin resistance both in cells and in animal models.

Methods

Time course experiments were performed on mouse aortic endothelial cells (MAECs) incubated with 500 μmol/l MGO. The glyoxalase-1 inhibitor S-p-bromobenzylglutathione-cyclopentyl-diester (SpBrBzGSHCp2) was used to increase the endogenous levels of MGO. For the in vivo study, an MGO solution was administrated i.p. to C57BL/6 mice for 7 weeks.

Results

MGO prevented the insulin-dependent activation of the IRS1/protein kinase Akt/endothelial nitric oxide synthase (eNOS) pathway, thereby blunting nitric oxide (NO) production, while extracellular signal-regulated kinase (ERK1/2) activation and endothelin-1 (ET-1) release were increased by MGO in MAECs. Similar results were obtained in MAECs treated with SpBrBzGSHCp2. In MGO- and SpBrBzGSHCp2-exposed cells, inhibition of ERK1/2 decreased IRS1 phosphorylation on S616 and rescued insulin-dependent Akt activation and NO generation, indicating that MGO inhibition of the IRS1/Akt/eNOS pathway is mediated, at least in part, by ERK1/2. Chronic administration of MGO to C57BL/6 mice impaired whole-body insulin sensitivity and induced endothelial insulin resistance.

Conclusions/interpretation

MGO impairs the action of insulin on the endothelium both in vitro and in vivo, at least in part through an ERK1/2-mediated mechanism. These findings may be instrumental in developing novel strategies for preserving endothelial function in diabetes.

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Abbreviations

ECE:

Endothelin-converting enzyme

ENOS:

Endothelial nitric oxide synthase

ERK:

Extracellular signal-regulated kinase

ET-1:

Endothelin-1

Glo1:

Glyoxalase-1

MAEC:

Mouse aortic endothelial cell

MAPK:

Mitogen-activated protein kinase

MGO:

Methylglyoxal

NO:

Nitric oxide

PI3K:

Phosphatidylinositol 3-kinase

SpBrBzGSHCp2:

S-p-Bromobenzylglutathione-cyclopentyl-diester

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Acknowledgements

The authors wish to dedicate this work to the memory of Prof. Angelika Bierhaus (Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany). Some of the data were presented as an abstract at the EASD meeting, Lisbon, in 2011 and at the IR2013 Symposium, Barcelona, in 2013.

Funding

The study was supported in part by the Ministero dell’Università e della Ricerca Scientifica, grants PRIN (2009FATXW3_003 to CM and 2009C2LTS2_002 to FB), SID-FO.DI.RI (2013 to CM), MERIT (RBNE08NKH7 to FB) and P.O.R. Campania FSE 2007-2013 Project CREMe, and by grants from the Deutsche Forschungsgemeinschaft (BI-1281/3-1 to A. Bierhaus/T. H. Fleming) and the Dietmar-Hopp-Stiftung (to A. Bierhaus/T. H. Fleming).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

CN conceived and designed the experiments, acquired data, analysed data and wrote the manuscript. GAR reviewed/edited the manuscript and collected and analysed data. AL, IP, ML, FF, PM, LU and VD collected data and revised the manuscript. THF and PPN provided reagents/materials, acquired data and critically reviewed the manuscript. PF and FB interpreted data and reviewed/edited the manuscript. CM designed the research and supervised the project, reviewed/edited the manuscript and contributed to the discussion. CM is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors approved the final version of the manuscript.

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Authors and Affiliations

  1. Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, National Council of Research, Via Pansini 5, 80131, Naples, Italy

    Cecilia Nigro, Gregory A. Raciti, Alessia Leone, Michele Longo, Immacolata Prevenzano, Francesca Fiory, Paola Mirra, Vittoria D’Esposito, Luca Ulianich, Pietro Formisano, Francesco Beguinot & Claudia Miele

  2. Department of Translational Medical Sciences, University of Naples ‘Federico II’, Naples, Italy

    Cecilia Nigro, Gregory A. Raciti, Alessia Leone, Michele Longo, Immacolata Prevenzano, Francesca Fiory, Paola Mirra, Vittoria D’Esposito, Luca Ulianich, Pietro Formisano, Francesco Beguinot & Claudia Miele

  3. Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany

    Thomas H. Fleming & Peter P. Nawroth

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  1. Cecilia Nigro
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Correspondence to Claudia Miele.

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Nigro, C., Raciti, G.A., Leone, A. et al. Methylglyoxal impairs endothelial insulin sensitivity both in vitro and in vivo. Diabetologia 57, 1485–1494 (2014). https://doi.org/10.1007/s00125-014-3243-7

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  • DOI: https://doi.org/10.1007/s00125-014-3243-7

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