Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice

Jeanette Schultz Johansen, Alex K Harris, David J Rychly, Adviye Ergul, Jeanette Schultz Johansen, Alex K Harris, David J Rychly, Adviye Ergul

Abstract

Cardiovascular complications, characterized by endothelial dysfunction and accelerated atherosclerosis, are the leading cause of morbidity and mortality associated with diabetes. There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Overproduction and/or insufficient removal of these free radicals result in vascular dysfunction, damage to cellular proteins, membrane lipids and nucleic acids. Despite overwhelming evidence on the damaging consequences of oxidative stress and its role in experimental diabetes, large scale clinical trials with classic antioxidants failed to demonstrate any benefit for diabetic patients. As our understanding of the mechanisms of free radical generation evolves, it is becoming clear that rather than merely scavenging reactive radicals, a more comprehensive approach aimed at preventing the generation of these reactive species as well as scavenging may prove more beneficial. Therefore, new strategies with classic as well as new antioxidants should be implemented in the treatment of diabetes.

Figures

Figure 1
Figure 1
Generation of reactive species in diabetes. Highlighted in gray are some of the most important ROS and RNS in vascular cells. Oxygen is converted to •O2- via the activation of enzymatic and nonenzymatic pathways, which is then dismutated to H2O2 by SOD. H2O2 can be converted to H2O by catalase or glutathione peroxidase (GSH-Px) or to •OH after reaction with Cu or Fe. Glutathione reductase regenerates glutathione (GSH). In addition, •O2- reacts rapidly with •NO to form ONOO-.
Figure 2
Figure 2
Current working model for the generation of reactive species and downstream targets in diabetes. Excess generation of mitochondrial ROS due to hyperglycemia initiates a vicious circle by activating stress-sensitive pathways such as NF-κB, p38 MAPK and Jak/STAT, polyol (sorbitol) and hexosamine pathways, PKC and AGEs. Enhanced production of AGEs, sorbitol and proinflammatory cytokines exerts a positive feedback on ROS and RNS synthesis and potentiates PKC-mediated vascular dysfunction by altering gene expression as well as vascular function and structure.

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