Mechanisms of Arterial Dysfunction in Type 2 Diabetes Mellitus

2 型糖尿病动脉功能障碍的机制

• 批准号: 7029363
• 负责人: MARK A CREAGER
• 金额: $ 33.44万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7029363
• 关键词: I kappa B beta; atherosclerosis; clinical research; diabetic angiopathy; enzyme activity; free fatty acids; human subject; insulin; noninsulin dependent diabetes mellitus; nuclear factor kappa beta; protein kinase; vascular endothelium; vasodilation

Insulin contributes to the regulation of endothelial function and specifically to the production of nitric oxide (NO). In experimental models of insulin resistance, disturbances in insulin signaling lead to decreased production of NO, but this has not been established in patients with type 2 diabetes mellitus. Several potential mechanisms have emerged that may interfere with insulin signaling and consequently production of NO in patients with type 2 diabetes, including pro-inflammatory cytokines, increased concentrations of free fatty acids (FFA), and over-activity of the Rho kinase pathway. As NO is a potent anti-atherogenic molecule, preservation of NO bioactivity is an important goal in halting the development and progression of vascular disease in patients with type 2 diabetes. Accordingly, this proposal applies insights from basic biology to the clinical setting to define the mechanisms that impair vascular function and identify potential therapeutic targets that may improve vascular function in patients with type 2 diabetes. Each of the three specific aims will seek to determine mechanisms that inhibit insulin-mediated vasodilation in patients with type 2 diabetes by employing pharmacologic probes in placebo-controlled crossover trials. These will modulate FFA concentration (intralipid, acipimox), inhibit inflammation and NFKB activation via kB kinase p (salsalate), and inhibit Rho kinase activity (fasudil). Studies will employ a hyperinsulinemic, euglycemic clamp. Insulin-mediated endothelium-dependent vasodilation (by plethysmography and ultrasonography) and skeletal muscle glucose utilization (by [18F] FDG positron emission tomography) will be measured in vivo. Molecular measures of insulin-signaling (Akt and eNOS phosphorylation in biopsy specimens) will be measured ex vivo in skin biopsy specimens to investigate molecular signals that regulate vascular function. It is anticipated that findings from this investigation will uncover pathophysiologic mechanisms that account for abnormal vascular function and atherosclerosis in patients with type 2 diabetes and identify potential therapeutic targets to reduce the risk of adverse cardiovascular events.

胰岛素有助于调节内皮功能，特别是一氧化氮的产生 氧化物（NO）。在胰岛素抵抗的实验模型中，胰岛素信号传导的紊乱导致 减少NO的产生，但这在2型糖尿病患者中尚未建立。 已经出现了几种可能干扰胰岛素信号传导的潜在机制， 2型糖尿病患者NO的产生，包括促炎细胞因子， 游离脂肪酸（FFA）浓度和Rho激酶途径的过度活性。因为NO是一种强有力的 作为抗动脉粥样硬化的分子，保持NO的生物活性是阻止发展的一个重要目标。 和2型糖尿病患者血管疾病的进展。因此，本建议适用于 从基础生物学到临床环境的见解，以确定损害血管功能的机制 并确定可能改善2型糖尿病患者血管功能的潜在治疗靶点 糖尿病这三个具体目标中的每一个都将寻求确定抑制胰岛素介导的 2型糖尿病患者的血管舒张，采用安慰剂对照的药理学探针 交叉试验这些将调节FFA浓度（胰岛素，阿昔莫司），抑制炎症， 通过kB激酶p激活NF κ B（双水杨酯），并抑制Rho激酶活性（法舒地尔）。研究将采用 高胰岛素血正葡萄糖钳夹胰岛素介导的内皮依赖性血管舒张（通过 体积描记术和超声检查）和骨骼肌葡萄糖利用（[18F] FDG正电子 发射断层摄影术）将在体内测量。胰岛素信号传导的分子测量（Akt和eNOS 将在皮肤活检标本中离体测量磷酸化），以研究 调节血管功能的分子信号。预计这次调查的结果将 揭示导致血管功能异常和动脉粥样硬化的病理生理机制， 2型糖尿病患者，并确定潜在的治疗目标，以减少不良反应的风险， 心血管事件。