Methylglyoxal impairs endothelial insulin sensitivity both in vitro and in vivo
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- 作者：Cecilia Nigro (1) (2)
Gregory A. Raciti (1) (2)
Alessia Leone (1) (2)
Thomas H. Fleming (3)
Michele Longo (1) (2)
Immacolata Prevenzano (1) (2)
Francesca Fiory (1) (2)
Paola Mirra (1) (2)
Vittoria D’Esposito (1) (2)
Luca Ulianich (1) (2)
Peter P. Nawroth (3)
Pietro Formisano (1) (2)
Francesco Beguinot (1) (2)
Claudia Miele (1) (2) - 关键词：Endothelial dysfunction ; Glyoxalase ; 1 ; Insulin resistance ; Methylglyoxal ; Nitric oxide
- 刊名：Diabetologia
- 出版年：2014
- 出版时间：July 2014
- 年：2014
- 卷：57
- 期：7
- 页码：1485-1494
- 全文大小：
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Gregory A. Raciti (1) (2)
Alessia Leone (1) (2)
Thomas H. Fleming (3)
Michele Longo (1) (2)
Immacolata Prevenzano (1) (2)
Francesca Fiory (1) (2)
Paola Mirra (1) (2)
Vittoria D’Esposito (1) (2)
Luca Ulianich (1) (2)
Peter P. Nawroth (3)
Pietro Formisano (1) (2)
Francesco Beguinot (1) (2)
Claudia Miele (1) (2)
1. Institute of Experimental Endocrinology and Oncology ‘G. Salvatore- National Council of Research, Via Pansini 5, 80131, Naples, Italy
2. Department of Translational Medical Sciences, University of Naples ‘Federico II- Naples, Italy
3. Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany - ISSN：1432-0428
文摘
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.