Oxidant Stress, Immune Dysregulation, and Vascular Function in Type I Diabetes

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Abstract
Although high glucose is an important contributor to diabetic vasculopathies, complications still occur in spite of tight glycemic control, suggesting that some critical event prior to or concurrent with hyperglycemia may contribute to early vascular changes. Utilizing previously published and new experimental evidence, this review will discuss how prior to the hyperglycemic state, an imbalance between oxidants and antioxidants may contribute to early vascular dysfunction and set in motion proinflammatory insults that are further amplified as the diabetes develops. This imbalance results from the resetting of the equilibrium between vessel superoxide/H2O2 production and/or decreased antioxidant defenses. Such an imbalance may cause endothelial dysfunction, characterized by abnormal endothelium-dependent vasoreactivity, as the first sign of blood vessel damage, followed by morphological changes of the vessel wall and inflammation. As such, increased oxidant stress in preglycemic states may be a critically central initiating event that underlies the pathogenesis of life-threatening vascular diseases in autoimmune diabetes. This review focuses on the relationship between oxidative stress, immune dysregulation, and vascular injury in type 1 diabetes, and how the discovery of novel pathways of vascular disease in nonobese diabetic mice may direct future studies in patients with type 1 diabetes.