ApoA-1 in Diabetes: Damaged Goods

Diabetes is a major risk factor for the development of atherosclerosis. In addition to increased risk of stroke, myocardial infarction, and peripheral vascular disease, diabetics suffer from a particularly aggressive form of atherosclerosis with greater in-hospital mortality following myocardial infarction and a higher incidence of heart failure, if they survive (1–3). While diabetics often have other accompanying risk factors for atherosclerosis (e.g., hypertension hypercholesterolemia, obesity), the additional risk conferred by diabetes and the particularly aggressive vascular and myocardial disease that affects diabetics suggest that diabetes-associated atherosclerosis involves unique pathogenic mechanisms. The systemic metabolic disturbances of diabetes, including hyperglycemia and hyperlipidemia, likely play a central role in the pathogenesis of diabetes-associated atherosclerosis through the generation of oxidative stress. Hyperglycemia causes increased flux through the polyol pathway, formation of advanced glycation end products, activation of protein kinase C isoforms, and increased hexosamine pathway flux, all of which may contribute to increased oxidative stress (4–6). Excessive free fatty acids delivered to nonadipose tissues can lead to reactive oxygen species (ROS) formation through cycles of oxidative phosphorylation, activation of NADPH oxidase, and alterations in mitochondrial structure that precipitate ROS production (7–9). In addition to evidence for activation of these pathways in cultured endothelial cells, human studies support the notion of increased systemic oxidative stress in diabetic subjects in …