Role of NFkappaB Signaling in Edothelial Dysfunction in Insulin Resistance

描述（由申请人提供）：大多数2型糖尿病（T2DM）患者的死亡是由于动脉粥样硬化（1,2）。内皮功能障碍在糖尿病的早期发展，是动脉粥样硬化发展中最早发现的异常。T2DM被认为是一种慢性、低度炎症状态，细胞培养和动物研究结果表明，循环单核细胞（MNC）炎症通路活性的增加有助于内皮功能障碍和动脉粥样硬化的发展。具体来说，KB激酶抑制剂(IKK)/ KB抑制剂(KB)/核因子KB （NFkB）通路被游离脂肪酸（FFA）、细胞因子和氧化应激激活，诱导促炎分子的转录，这些分子与内皮功能障碍和动脉粥样硬化的发病机制有关。然而，尚不清楚T2DM受试者是否在MNC中IKK/kB/NFkB通路的活性增加。我们将验证T2DM的内皮功能障碍与MNC中IKK/kB/NFkB通路活性增加相关的假设，以及acpimox降低血浆FFA浓度将降低IKK/kB/NFkB信号传导并改善内皮功能。我们还将验证体育锻炼引起的内皮功能改善涉及IKK/kB/NFkB信号减少的假设。

DESCRIPTION (provided by applicant): Most deaths in subjects with type 2 diabetes mellitus (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.