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: 7621041
• 负责人: Joseph A. Vita
• 金额: $ 72.56万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7621041
• 关键词: 1-Phosphatidylinositol 3-Kinase; 5' -AMP-activated protein kinase; Accounting; Acute; Adipocytes; Adipose tissue; Adverse effects; Animals; Antioxidants; Area; Arterial Injury; Atherosclerosis; Atkins Diet; Bariatrics; Bed rest; Biological Markers; Biometry; Biopsy; Biopsy Specimen; Blood Vessels; Body Weight decreased; Boston; Carbohydrates; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion Molecules; Cells; Chronic; Clinical; Collection; Country; Cross-Sectional Studies; Data; Development; Dietary Intervention; Disease; Disease Progression; Economic Burden; Endocrinology; Epidemic; Event; Fatty acid glycerol esters; Functional disorder; Future; Gene Expression; Healed; Homeostasis; Human; Immune; Immunohistochemistry; Impairment; Individual; Inflammation; Inflammatory; Infusion procedures; Injury; Insulin; Insulin Resistance; Intra-abdominal; Invasive; Leukocytes; Levocarnitine Acetyl; Life Expectancy; Link; Lipids; Maintenance; Measures; Mediating; Medical; Medical center; Membrane Potentials; Metabolic; Metabolic syndrome; Metabolism; Metformin; Methodology; Mitochondria; Muscle; Nitric Oxide; Nitric Oxide Synthase; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated cardiovascular disease; Overweight; Oxidative Stress; Pathologist; Patients; Phenotype; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Physicians; Physiologic pulse; Polymerase Chain Reaction; Population; Prevention; Production; Protein Kinase; Public Health; Public Health Schools; Pulse taking; Range; Reactive Oxygen Species; Relative (related person); Research Design; Research Personnel; Research Priority; Risk; Signal Transduction; Site; Source; Staging; Stimulus; Sulfasalazine; Surgeon; Syndrome; Systemic disease; Techniques; Testing; Thioctic Acid; Time; Tissue Harvesting; Tissue Sample; Tissues; Universities; Vascular Diseases; Vascular remodeling; Vasodilator Agents; Visceral; Weight; Work; abdominal fat; adenylate kinase; adipokines; base; brachial artery; cardiovascular risk factor; cytokine; experience; healing; insight; insulin sensitivity; mitochondrial dysfunction; mitochondrial membrane; multidisciplinary; novel; nutrition; prevent; programs; response; secretory protein; social; subcutaneous; tonometry; translational study; weight loss intervention

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.

胰岛素抵抗综合征的患者，包括肥胖，代谢综合征和类型 2个糖尿病，明显增加了动脉粥样硬化的风险。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，包括失去内皮衍生的一氧化氮（NO）和 转化为促炎的表型，可能促进血管重塑和动脉粥样硬化。 一氧化氮合酶的胰岛素介导的激活取决于AKT/PI3激酶和可用性 线粒体衍生的活性氧。最近的研究表明这些信号传导机制 还取决于AMP依赖性蛋白激酶（AMP激酶）的活性。我们的初步数据表示 严格的床休息或短期脂质输注会在健康中产生急性胰岛素耐药性 与血管扩张函数的明显损害相关的受试者。使用此方法 提供了一个独特的机会，可以研究胰岛素抵抗的血管后果 患有更晚期疾病的患者存在混杂因素。这个项目将调查 在这些急性胰岛素抵抗状态下血管功能障碍的潜在机制 人类。在AIM 1中，我们将检验以下假设：AMP激酶的激活将钝化不良反应 通过测量基底和刺激的AMP激酶活性在血管功能上的胰岛素抵抗性 白细胞和肌肉以及确定是否通过预处理预防血管功能障碍 使用二甲双胍激活AMP激酶并增加胰岛素敏感性。在AIM 2中，我们将 研究线粒体功能障碍对胰岛素耐药性血管功能障碍的贡献 测量氧化应激和线粒体膜电位和ROS的全身标志物 白细胞生产。此外，我们将确定线粒体定向的抗氧化剂是否 lipoic酸和乙酰L-肉碱钝性血管功能障碍和胰岛素抵抗。在AIM 3中，我们将测试 NFICB激活有助于急性血管功能障碍的发展的假设 通过测量循环粘附分子，促炎性细胞因子和 脂肪因子。此外，我们将确定是否可以通过治疗预防血管功能障碍 与磺胺氨基氨酸一起抑制NFKAPPAB的激活。我们建议这些翻译研究将 提供有关胰岛素抵抗患者血管功能障碍机制的新见解， 将与肥胖症的预防和管理血管疾病有关， 代谢综合征和2型糖尿病。