Published online Jun 10, 2015. doi: 10.4239/wjd.v6.i5.679
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
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.
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.