Role of NFkappaB Signaling in Edothelial Dysfunction in Insulin Resistance

2型糖尿病(T2 DM)患者的大部分死亡是由于动脉粥样硬化(1，2)。内皮细胞 功能障碍在糖尿病病程早期发展，是最早可检测到的异常 动脉粥样硬化的发展。T2 DM被认为是一种慢性、低级别炎症状态，其结果 来自细胞培养和动物研究表明，循环中炎症途径的活性增加 单个核细胞(MNC)参与了内皮功能障碍和动脉粥样硬化的发展。 具体地说，抑制物Kb激酶(IKK)/抑制物Kb(KB)/核因子Kb(NFKB)途径，即 由游离脂肪酸(FFA)、细胞因子和氧化应激激活，诱导促炎性转录 与内皮功能障碍和动脉粥样硬化的发病机制有关的分子。 然而，目前尚不清楚T2 DM患者是否增加了IKK/kB/NFKB通路的活性 在跨国公司。我们将检验以下假设：T2 DM患者的内皮功能障碍与 MNC中IKK/kB/NFKB通路的活性，以及血浆FFA浓度的降低 Acipimox可减少IKK/kB/NFKB信号转导，改善内皮功能。我们还将测试 假设体育锻炼引起的内皮功能改善涉及到血管内皮细胞 IKK/kB/NFKB信令。

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.