Mechanisms for oxidative stress in diabetic cardiovascular disease.

Obesity, metabolic syndrome, and diabetes are increasingly prevalent in Western society, and they markedly increase the risk for atherosclerotic vascular disease, the major cause of death in diabetics. Although recent evidence suggests a causal role for oxidative stress in insulin resistance, diabetes, and atherosclerosis, there is considerable controversy regarding its nature, magnitude, and underlying mechanisms. Glucose promotes glycoxidation reactions in vitro, and products of glycoxidation and lipoxidation are elevated in plasma and tissue from humans suffering from diabetes, but the exact relationships between hyperglycemia and oxidative stress are poorly understood. This review focuses on molecular mechanisms of increased oxidative stress in diabetes, the relationship of oxidant production to hyperglycemia, and the potential interaction of reactive carbonyls and lipids in oxidant generation. Using highly sensitive and specific gas chromatography-mass spectrometry, molecular signatures of specific oxidation pathways were identified in tissues of diabetic humans and animals. These studies support the hypothesis that unique reactive intermediates generated in localized microenvironments of vulnerable tissues promote diabetic damage. Therapies interrupting these reactive pathways in vascular tissue might help prevent cardiovascular disease in this high-risk population.