Review
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Jun 10, 2015; 6(5): 679-692
Published online Jun 10, 2015. doi: 10.4239/wjd.v6.i5.679
Endothelial dysfunction as a predictor of cardiovascular disease in type 1 diabetes
Marcello C Bertoluci, Gislaine V Cé, Antônio MV da Silva, Marco V Wainstein, Winston Boff, Marcia Puñales
Marcello C Bertoluci, Marco V Wainstein, Departamento de Medicina Interna, Universidade Federal do Rio Grande do Sul, Porto Alegre RS 90035-003, Brazil
Marcello C Bertoluci, Serviço de Medicina Interna do Hospital de Clinicas de Porto Alegre, Porto Alegre RS 90035-903, Brazil
Marcello C Bertoluci, Programa de Pós-Graduação em Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre RS 90035-003, Brazil
Gislaine V Cé, Winston Boff, Marcia Puñales, Instituto da Criança com Diabetes - Grupo Hospitalar Conceição, Porto Alegre RS 91350-250, Brasil
Antônio MV da Silva, Departamento de Fisioterapia e Reabilitação, Universidade Federal de Santa Maria, Santa Maria RS 97105-900, Brasil
Marco V Wainstein, Serviço de Cardiologia do Hospital de Clínicas de Porto Alegre, Porto Alegre RS 90035-903, Brazil
Author contributions: Bertoluci MC, Puñales M, Cé GV, da Silva AMV, Wainstein MV and Boff W contributed to this paper.
Conflict-of-interest: Dr. Wainstein reports grants and other from Biotronik, grants and other from Abbott Vascular, other from BBraun, outside the submitted work. The other authors declare not to have any type of conflict-of-interest related to the present review.
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: Marcello C Bertoluci, MD, DMSc, Serviço de Medicina Interna do Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcellos 2350- Sala 700, Santa Cecília, Porto Alegre 90035-003, Brazil. mbertoluci@uol.com.br
Telephone: +55-51-33598000 Fax: +55-51-33598000
Received: November 6, 2014
Peer-review started: November 10, 2014
First decision: February 7, 2015
Revised: March 11, 2015
Accepted: April 1, 2015
Article in press: April 7, 2015
Published online: June 10, 2015
Processing time: 225 Days and 8.2 Hours
Abstract

Macro and microvascular disease are the main cause of morbi-mortality in type 1 diabetes (T1DM). Although there is a clear association between endothelial dysfunction and atherosclerosis in type 2 diabetes, a cause-effect relationship is less clear in T1DM. Although endothelial dysfunction (ED) precedes atherosclerosis, it is not clear weather, in recent onset T1DM, it may progress to clinical macrovascular disease. Moreover, endothelial dysfunction may either be reversed spontaneously or in response to intensive glycemic control, long-term exercise training and use of statins. Acute, long-term and post-prandial hyperglycemia as well as duration of diabetes and microalbuminuria are all conditions associated with ED in T1DM. The pathogenesis of endothelial dysfunction is closely related to oxidative-stress. NAD(P)H oxidase over activity induces excessive superoxide production inside the mitochondrial oxidative chain of endothelial cells, thus reducing nitric oxide bioavailability and resulting in peroxynitrite formation, a potent oxidant agent. Moreover, oxidative stress also uncouples endothelial nitric oxide synthase, which becomes dysfunctional, inducing formation of superoxide. Other important mechanisms are the activation of both the polyol and protein kinase C pathways as well as the presence of advanced glycation end-products. Future studies are needed to evaluate the potential clinical applicability of endothelial dysfunction as a marker for early vascular complications in T1DM.

Keywords: Endothelial dysfunction; Type 1 diabetes; Cardiovascular disease

Core tip: Endothelial dysfunction is an early finding in the natural history of type 1 diabetes and is predictive for microvascular disease and premature atherosclerosis. Decreased nitric oxide due oxidative stress is the central pathogenetic mechanism. Polyol pathway activation, protein kinase C (PKC) activation and advanced glycation product formation are also important. Long-term hyperglycemia, repeated hypoglycemia and microalbuminuria are factors associated. Intensive glycemic control and exercise training ameliorate endothelial dysfunction. Statins and renin-angiotensin system blockers are partially effective and may be influenced by hyperglycemia. There is a possible clinical benefit for the use of vitamin E and vitamin C that are still to be confirmed. PKC inhibitors are still investigative.