Role of NFkappaB Signaling in Edothelial Dysfunction in Insulin Resistance

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Most deaths in subjects with type 2 diabetes rnellitus (T2DM) are due to atherosclerosis (1,2). Endothelial dysfunction develops early in the course of diabetes, and is the earliest detectable abnormality in the development of atherosclerosis. T2DM is considered a state of chronic, low grade inflammation, and findings from cell culture and animal studies suggest that increased activity of inflammatory pathways in circulating mononuclear cells (MNC) contributes to the development of endothelial dysfunction and atherosclerosis. Specifically, the inhibitor KB kinase (IKK)/inhibitor KB (kB)/nuclear factor KB (NFKB) pathway, which is activated by free fatty acids (FFA), cytokines and oxidative stress, induces transcription of proinflammatory molecules that have been implicated in the pathogenesis of endothelial dysfunction and atherosclerosis. However, it is not known whether subjects with T2DM have increased activity of the IKK/kB/NFKB pathway in MNC. We will test the hypotheses that endothelial dysfunction in T2DM is associated with increased activity of the IKK/kB/NFKB pathway in MNC, and that a reduction in plasma FFA concentrations with Acipimox will reduce IKK/kB/NFKB signaling and improve endothelial function. We will also test the hypothesis that the improvement in endothelial function caused by physical training involves a decrease in IKK/kB/NFKB signaling.