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，特别是一氮的生产 氧化物（否）。在胰岛素耐药性的实验模型中，胰岛素信号传导中的干扰导致 NO的产生降低，但这尚未在2型糖尿病患者中确定。 已经出现了几种可能干扰胰岛素信号的潜在机制，因此 2型糖尿病患者的NO产生，包括促炎细胞因子，增加 游离脂肪酸（FFA）的浓度和Rho激酶途径的过度活性。因为没有强大的 抗动脉粥样硬化分子，无生物活性的保存是停止发展的重要目标 2型糖尿病患者血管疾病的进展。因此，此提案适用 从基本生物学到临床环境的见解，以定义损害血管功能的机制 并确定可能改善2型患者血管功能的潜在治疗靶标 糖尿病。三个特定目标中的每一个都将寻求确定抑制胰岛素介导的机制 通过在安慰剂对照中采用药理探针，使用药理学探针患者的血管舒张 跨界试验。这些将调节FFA浓度（脂质内，acipimox），抑制炎症和 NFKB通过Kb激酶P（salsalate）激活，并抑制Rho激酶活性（Fasudil）。研究将采用 高胰岛素，尤基糖夹。胰岛素介导的内皮依赖性血管舒张（通过 杂质学和超声检查）和骨骼肌葡萄糖利用率（通过[18F] FDG正电子 发射断层扫描）将在体内测量。胰岛素信号的分子测量（AKT和ENOS） 活检标本中的磷酸化）将在皮肤活检标本中的离体测量以研究 调节血管功能的分子信号。预计这项调查的发现将 发现病理生理机制，这些机制解释了异常血管功能和动脉粥样硬化 患有2型糖尿病的患者并识别潜在的治疗靶标，以降低不良风险 心血管事件。