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World J Diabetes. Mar 15, 2015; 6(2): 326-332
Published online Mar 15, 2015. doi: 10.4239/wjd.v6.i2.326
Role of oxidative stress in endothelial insulin resistance
Francesco Paneni, Sarah Costantino, Francesco Cosentino
Francesco Paneni, Sarah Costantino, Francesco Cosentino, Cardiology Unit, Department of Medicine, Karolinska University Hospital, 17176 Stockholm, Sweden
Author contributions: Paneni F and Costantino S developed the concept and wrote the manuscript; Cosentino F revised the manuscript for important intellectual content.
Conflict-of-interest: The authors do not have any conflict of interest with regard to the present article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Francesco Paneni, MD, PhD, FESC, Cardiology Unit, Department of Medicine, Karolinska University Hospital, Solna, 17176 Stockholm, Sweden. francesco.paneni@ki.se
Telephone: +46-8-51779413 Fax: +46-8-344964
Received: September 22, 2014
Peer-review started: September 23, 2014
First decision: November 3, 2014
Revised: November 20, 2014
Accepted: December 29, 2014
Article in press: December 31, 2014
Published online: March 15, 2015
Abstract

The International Diabetes Federation estimates that 316 million people are currently affected by impaired glucose tolerance (IGT). Most importantly, recent forecasts anticipate a dramatic IGT increase with more that 470 million people affected by the year 2035. Impaired insulin sensitivity is major feature of obesity and diabetes and is strongly linked with adverse cardiometabolic phenotypes. However, the etiologic pathway linking impaired glucose tolerance and cardiovascular disease remains to be deciphered. Although insulin resistance has been attributed to inflammatory programs starting in adipose tissue, emerging evidence indicates that endothelial dysfunction may represent the upstream event preceding peripheral impairment of insulin sensitivity. Indeed, suppression of reactive oxygen species-dependent pathways in the endothelium has shown to restore insulin delivery to peripheral organs by preserving nitric oxide (NO) availability. Here we describe emerging theories concerning endothelial insulin resistance, with particular emphasis on the role oxidative stress. Complex molecular circuits including endothelial nitric oxide synthase, prostacyclin synthase, mitochondrial adaptor p66Shc, nicotinamide adenine dinucleotide phosphate-oxidase oxidase and nuclear factor kappa-B are discussed. Moreover, the review provides insights on the effectiveness of available compounds (i.e., ruboxistaurin, sildenafil, endothelin receptor antagonists, NO donors) in restoring endothelial insulin signalling. Taken together, these aspects may significantly contribute to design novel therapeutic approaches to restore glucose homeostasis in patients with obesity and diabetes.

Keywords: Endothelium, Insulin resistance, Oxidative stress, Obesity, Cardiometabolic risk, Vascular disease

Core tip: We present here the most recent advances in the understanding of endothelial insulin resistance, with a particular focus on the role of oxidative stress. The molecular pathways described may be instrumental for the development of mechanism-based therapeutic strategies to prevent maladaptive endothelial insulin signalling in patients with cardiometabolic disturbances.