Mechanisms of Vascular Dysfunction in Acute Insulin Resistance

急性胰岛素抵抗中血管功能障碍的机制

• 批准号: 7140900
• 负责人: Joseph A. Vita
• 金额: $ 67.09万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140900
• 关键词: acute disease /disorder; adenosine monophosphate; antioxidants; atherosclerosis; cardiovascular disorder epidemiology; cardiovascular disorder prevention; carnitine; chemoprevention; enzyme activity; gene expression; human subject; human therapy evaluation; insulin sensitivity /resistance; metformin; mitochondrial disease /disorder; nuclear factor kappa beta; patient oriented research; protein kinase; short chain fatty acid; sulfanilamides

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.

患有胰岛素抵抗综合征的患者，包括肥胖、代谢综合征和胰岛素抵抗综合征 2型糖尿病，动脉粥样硬化的风险明显增加。越来越多的工作表明 胰岛素有助于维持血管细胞稳态和局部胰岛素抵抗 具有病理作用，包括内皮源性一氧化氮 (NO) 生物活性的丧失和 转化为促炎表型，可能促进血管重塑和动脉粥样硬化。 胰岛素介导的一氧化氮合酶激活取决于 Akt/PI3 激酶以及 线粒体衍生的活性氧。最近的研究表明这些信号机制 还取决于 AMP 依赖性蛋白激酶（AMP 激酶）的活性。我们的初步数据表明 健康人一段时间的严格卧床休息或短期脂质输注会产生急性胰岛素抵抗 与血管舒张功能明显受损相关的受试者。使用该方法 提供了一个独特的机会来研究胰岛素抵抗的血管后果，而无需 患有更晚期疾病的患者中存在混杂因素。本项目将调查 解释急性胰岛素抵抗状态下血管功能障碍的潜在机制 人类。在目标 1 中，我们将测试 AMP 激酶的激活将减弱不利影响的假设 通过测量基础和刺激的 AMP 激酶活性来研究胰岛素抵抗对血管功能的影响 白细胞和肌肉，并确定预处理是否可以预防血管功能障碍 使用二甲双胍，它会激活 AMP 激酶并增加胰岛素敏感性。在目标 2 中，我们将 研究线粒体功能障碍对胰岛素抵抗中血管功能障碍的影响 测量氧化应激、线粒体膜电位和 ROS 的系统标志物 白细胞中的产生。此外，我们将确定线粒体定向抗氧化剂是否 硫辛酸和乙酰左旋肉碱可减弱血管功能障碍和胰岛素抵抗。在目标 3 中，我们将测试 NFicB 的激活有助于急性血管功能障碍的发生的假设 通过测量循环粘附分子、促炎细胞因子和胰岛素抵抗 脂肪因子。此外，我们将确定是否可以通过治疗来预防血管功能障碍 与柳氮磺吡啶一起使用，可抑制 NFkappaB 的激活。我们建议这些转化研究将 为胰岛素抵抗患者血管功能障碍的机制提供新的见解 将与肥胖背景下血管疾病的预防和管理相关， 代谢综合征和 2 型糖尿病。