MECHANISMS UNDERLYING CARDIOVASCULAR RISKS IN DIABETES

糖尿病心血管风险的潜在机制

• 批准号: 2762410
• 负责人: GORDON H WILLIAMS
• 金额: $ 28.14万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2762410
• 关键词: ACE inhibitors; angiotensin /renin /aldosterone hypertension; angiotensin II; angiotensinogen; blood pressure; clinical research; diabetes mellitus genetics; diabetic angiopathy; disease /disorder proneness /risk; fibrinolysis; gene expression; genetic markers; genetic polymorphism; genetic susceptibility; hemodynamics; human subject; hyperglycemia; hyperinsulinism; kidney; low salt diet; nutrition related tag; peptidyl dipeptidase A; plasminogen activator inhibitors

The overall hypothesis to be tested in this investigation is that in diabetes mellitus (DM), it is hyperinsulinemia and hyperglycemia in combination with differences in the specific alleles of the genes of the renin-angiotensin and PAI-1 systems that predispose the individual to vascular complications. The hypothesis is based on studies that have shown that the renin-angiotensin system (RAS) profoundly influences vascular responsiveness, cardiovascular remodeling, and plasminogen activator-inhibitor-1 (PAI-1) production. Further, aldosterone can modify the actions of the RAS on these target tissues, e.g., it modulates AngII receptor expression, enhances collage formation and fibrosis and modifies PAI-1 production. Hyperglycemia and insulin also can modify these systems. Therefore, the investigators feel that RAS, hyperinsulinemia and hyperglycemia all may play substantial roles in mediating the adverse vascular (pressor, cardiac and atherosclerotic) complications in diabetes mellitus (DM). In addition, variations in the occurrence of these complications may be secondary not only to the control of glucose and the level of exogenous and/or endogenous insulin, but also to variations in the function of critical genes in the diabetic population. To evalulate the hypothesis, the investigator will address four Specific Aims: 1) to determine the relationship between angiotensinogen (AGT) genotype and hypertension in DM; 2) to test the hypothesis that variation in the pressor and hemodynamic responses to AngII in DM is mediated by variations in the genetic environment, specifically, the AGT and angiotensin converting enzyme (ACE) genes; 3) to determine the relationships between PAI-1 levels and insulin resistance and its response to insulin and AngII and to correlate these with PAI-1 and AGT genotypes; and 4) to access the influence of hyperglycemia on vascular function and PAI-1 levels To accomplish these goals, the investigator proposes to study normal subjects and patients with DM in the controlled environment of a General Clinical Research Center. Pressor and renal hemodynamic responses will be determined. The responsiveness of PAI-1 to AngII and insulin infusions, low salt diet and ACE inhibition will be assessed. Each subject's alleles at the AGT, ACE and PAI-1 loci will be determined. It is anticipated that the results of these studies will clarify the potential role of the RAS and hyperglycemia in mediating the vascular and atherosclerotic (via its effect on PAI-1 production and release) complications of DM. An additional benefit derived from these studies will be to provide clues as to the role of variations in the genetic environment of the systems noted on the variable expression of these complications as indicated by changes in surrogate markers. With this information, specific preventive and therapeutic measures could then be tested as to their efficacy in retarding the development of these complications.

在本研究中要检验的总体假设是 糖尿病（DM），是高胰岛素血症和高血糖 结合在特定基因的特定等位基因的差异 肾素 - 血管紧张素和PAI-1系统，使个人易于 血管并发症。 该假设是基于具有的研究 表明肾素 - 血管紧张素系统（RAS）深刻影响 血管反应能力，心血管重塑和纤溶酶原 激活剂抑制剂1（PAI-1）产生。 此外，醛固酮可以 修改RAS对这些靶组织的作用，例如 调节Angii受体表达，增强拼贴的形成和 纤维化并修饰PAI-1的产生。高血糖和胰岛素也 可以修改这些系统。因此，调查人员认为Ras， 高胰岛素血症和高血糖均可能在 介导不良血管（压力，心脏和动脉粥样硬化） 糖尿病并发症（DM）。 另外， 这些并发症的发生不仅可能是次要的 控制葡萄糖以及外源和/或内源性胰岛素的水平， 但同时糖尿病中关键基因功能的功能也有所不同 人口。 为了评估该假设，研究者将解决 四个具体目标：1）确定 DM中的血管紧张素原（AGT）基因型和高血压； 2）测试 假设施加和血流动力学反应的变化 DM中的AngII是由遗传环境中的变化介导的， 具体而言，AGT和血管紧张素转化酶（ACE）基因； 3） 确定PAI-1水平与胰岛素之间的关系 抗药性及其对胰岛素和ANGII的反应，并将其关联 与PAI-1和AGT基因型； 4）访问 血管功能和PAI-1水平的高血糖以完成这些 目标，研究人员建议研究正常受试者和患者 在一般临床研究的受控环境中使用DM 中心。 将确定压力和肾脏血流动力学反应。 PAI-1对ANGII和胰岛素输注的反应性，低盐 饮食和ACE抑制作用将进行评估。 每个主题的等位基因 将确定AGT，ACE和PAI-1基因座。 预计 这些研究的结果将阐明RA和 介导血管硬化和动脉粥样硬化的高血糖（通过其 对DM的PAI-1产生和释放并发症的影响。 一个 这些研究获得的其他好处将是提供线索 关于变化在系统遗传环境中的作用 在这些并发症的可变表达中注意，如 替代标记的变化。 有了这些信息， 然后可以测试预防和治疗措施 延迟这些并发症发展的功效。