Antioxidant Anti-Inflammatory Treatment in Type 2 Diabetes

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In the last few decades, the occurrence of type 2 diabetes has rapidly increased internationally, and it has been estimated that the number of diabetic patients will more than double within 15 years (1). Type 2 diabetes is mainly characterized by the development of increased morbidity and mortality for cardiovascular disease (CVD); thus, it has been suggested that diabetes may be considered a CVD (1). However, diabetes is also characterized by dramatic microangiophatic complications, such as retinopathy, nephropathy, and neuropathy (1). Recent evidence suggests that glucose overload may damage the cells through oxidative stress (2). This is currently the basis of the “unifying hypothesis” that hyperglycemia-induced oxidative stress may account for the pathogenesis of all diabetic complications (2). It has been suggested that the following four key biochemical changes induced by hyperglycemia are all activated by a common mechanism—overproduction of superoxide radicals (2): 1 ) increased flux through the polyol pathway (in which glucose is reduced to sorbitol, reducing levels of both NADPH and reduced glutathione); 2 ) increased formation of advanced glycation end products (AGEs); 3 ) activation of protein kinase C (with effects ranging from vascular occlusion to expression of proinflammatory genes), and 4 ) increased shunting of excess glucose through the hexosamine pathway (mediating increased transcription of genes for inflammatory cytokines). Excess plasma glucose drives excess production of electron donors (mainly -NADH/H+) from the tricarboxylic acid cycle; in turn, this surfeit results in the transfer of single electrons (instead of the usual electron pairs) to oxygen, producing superoxide radicals and other reactive oxygen species (instead of the usual H2O end product). The superoxide anion itself inhibits the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GADPH), and consequently, glucose and glycolytic intermediates spill into the polyol and hexosamine pathways, as well as additional pathways that culminate in protein kinase …