Mechanisms of Vascular Dysfunction in Acute Insulin Resistance

患有胰岛素抵抗综合征的患者，包括肥胖、代谢综合征和 2糖尿病，有明显增加动脉粥样硬化的风险。越来越多的作品表明 胰岛素有助于维持血管细胞的动态平衡，局部的胰岛素抵抗 具有病理效应，包括内皮源性一氧化氮(NO)生物活性的丧失和 转化为可能促进血管重塑和动脉粥样硬化的促炎表型。 胰岛素介导的一氧化氮合酶激活依赖于Akt/PI3激酶和 线粒体衍生的活性氧物种。最近的研究表明，这些信号机制 还取决于AMP依赖的蛋白激酶(AMP激酶)的活性。我们的初步数据显示 一段时间的严格卧床休息或短期脂肪输注会在健康人群中产生急性胰岛素抵抗 与血管扩张功能明显受损有关的受试者。使用这种方法 提供了一个独特的机会来研究胰岛素抵抗的血管后果，而没有 患有更严重疾病的患者存在混杂因素。该项目将调查 急性胰岛素抵抗这些状态下血管功能障碍的可能机制 人类。在目标1中，我们将检验这样的假设，即激活AMP激酶将减弱不利影响 胰岛素抵抗对血管功能的影响 白细胞和肌肉，并通过确定血管功能障碍是否通过预处理来预防 二甲双胍，它能激活AMP激酶，增加胰岛素敏感性。在目标2中，我们将 探讨线粒体功能障碍在胰岛素抵抗血管功能障碍中的作用 测定氧化应激、线粒体膜电位和ROS的系统标志物 在白细胞中产生。此外，我们将确定线粒体导向的抗氧化剂是否 硫辛酸和乙酰-L-卡尼汀拮抗血管功能障碍和胰岛素抵抗。在目标3中，我们将测试 NFicB激活参与急性心肌梗死血管功能障碍发生的假说 通过检测循环黏附分子、促炎细胞因子和 脂肪因子。此外，我们将确定血管功能障碍是否可以通过治疗来预防 柳氮磺胺吡啶，它抑制NFkappaB的激活。我们建议这些翻译研究将 为胰岛素抵抗患者血管功能障碍的机制提供新的见解 将与肥胖背景下的血管疾病的预防和管理相关， 代谢综合征和2型糖尿病。

Patients with syndromes of insulin resistance, including obesity, the Metabolic Syndrome, and Type 2 diabetes mellitus, have markedly increased risk for atherosclerosis. A growing body of work has shown that insulin contributes to the maintenance of vascular cell homeostasis and that local insulin resistance has pathological effects including loss of the bioactivity of endothelium-derived nitric oxide (NO) and conversion to a pro-inflammatory phenotype that may promote vascular remodeling and atherosclerosis. Insulin-mediated activation of nitric oxide synthase depends on Akt/PI3 kinase and the availability of mitochondria-derived reactive oxygen species. Recent studies suggest that these signaling mechanisms also depend on the activity of AMP-dependent protein kinase (AMP kinase). Our preliminary data indicate that a period of strict bed rest or short-term lipid infusion produces acute insulin resistance in healthy subjects that is associated with a marked impairment of vasodilator function. Use of this methodology provides a unique opportunity to investigate the vascular consequences of insulin resistance without the confounding factors present in patients with more advanced disease. This project will investigate potential mechanisms accounting for vascular dysfunction in these states of acute insulin resistance in humans. In Aim 1, we will test the hypothesis that activation of AMP kinase will blunt the adverse effects of insulin resistance on vascular function by measuring basal and stimulated AMP kinase activity in leukocytes and muscle and by determining whether vascular dysfunction is prevented by pretreatment with metformin, which activates AMP kinase and increases insulin sensitivity.. In Aim 2, we will investigate the contribution of mitochondrial dysfunction to vascular dysfunction in insulin resistance by measuring systemic markers of oxidative stress and mitochondrial membrane potential and ROS production in leukocytes. In addition, we will determine whether the mitochondria-directed antioxidants lipoic acid and acetyl-L-carnitine blunt vascular dysfunction and insulin resistance. In Aim 3, we will test the hypothesis that activation of NFicB contributes to the development of vascular dysfunction in acute insulin resistance by measuring circulating adhesion molecules, pro-inflammatory cytokines, and adipokines. In addition, we will determine whether vascular dysfunction can be prevented by treatment with sulfasalazine, which inhibits activation of NFkappaB. We suggest that these translational studies will provide new insights into the mechanisms of vascular dysfunction in patients with insulin resistance that will be relevant to the prevention and management of vascular disease in the setting of obesity, the metabolic syndrome, and Type 2 diabetes mellitus.