Cardiac Risk:Insulin Resistance, Hypertension, & PAI-1

心脏风险：胰岛素抵抗、高血压、

• 批准号: 6754426
• 负责人: abraham thomas
• 金额: $ 14.57万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6754426
• 关键词: angiotensin II; angiotensin receptor; angiotensinogen; atherosclerosis; cardiovascular disorder risk; clinical research; computed axial tomography; diabetes mellitus; diabetes mellitus genetics; gene environment interaction; genetic polymorphism; genotype; glucose clamp technique; human subject; hyperinsulinism; hypertension; insulin sensitivity /resistance; lipids; medical complication; myocardial infarction; obesity; patient oriented research; peptidyl dipeptidase A; phenotype; plasminogen activator inhibitors; renin angiotensin system

DESCRIPTION (provided by applicant): Patients with diabetes mellitus have an increased risk from cardiovascular morbidity and mortality that is similar to patients, without diabetes, who have had a previous myocardial infarction. Although many explanations for this increased risk have been proposed from studies, the risk for a specific individual is difficult to determine from these studies. Plasminogen activator inhibitor-1 (PAI-1) is an important peptide in the fibrinolytic-thrombotic pathway and elevated levels of PAI-1 have been shown to correlate with cardiovascular events, such as myocardial infarction. Thus, PAI-1 may be a marker for cardiovascular risk. The renin-angiotensin system (RAS) also has profound effects on the cardiovascular system and pharmacologic blockade of the RAS can affect cardiovascular disease. The RAS can also affect levels of greater insulin resistance and a more adverse lipid profile than other sub-groups. However, not every diabetic patient is at equal risk for cardiovascular events or for elevations in PAI-1 levels. Thus, there are environmental and genetic factors that predispose certain individuals to greater cardiovascular risk. A genetic predisposition compounded by adverse environmental factors may highlight those at greatest risk. Genetic polymorphisms in the RAS may increase the adverse cardiovascular risk in diabetic subjects by increasing PAI-1 plasma levels or by creating an adverse metabolic milieu. The studies highlighted in this proposal will categorize diabetic subjects by an intermediate phenotype of the RAS, first demonstrated in hypertensive subjects. The relationship of gene polymorphisms in the RAS and PAI-1 genes and intermediate phenotypes of PAI-1 levels, lipids, obesity, and insulin resistance will be determined. The knowledge of which genotypes and intermediate phenotypes predict a greater risk for cardiovascular risk in patients with diabetes may help identify those individuals at greatest risk, may be able to predict the risk for a specific individuals, and may also help define specific therapy to reduce that risk.

描述（由申请人提供）：糖尿病患者心血管发病和死亡的风险增加，与既往患有心肌梗塞的非糖尿病患者相似。 尽管研究对这种风险增加提出了许多解释，但很难从这些研究中确定特定个体的风险。 纤溶酶原激活剂抑制剂-1 (PAI-1) 是纤溶血栓途径中的重要肽，PAI-1 水平升高已被证明与心血管事件（例如心肌梗塞）相关。因此，PAI-1可能是心血管风险的标志物。肾素-血管紧张素系统 (RAS) 对心血管系统也有深远的影响，药物阻断 RAS 会影响心血管疾病。与其他亚组相比，RAS 还会影响更大的胰岛素抵抗水平和更不利的血脂状况。 然而，并非所有糖尿病患者都面临相同的心血管事件或 PAI-1 水平升高的风险。因此，环境和遗传因素会使某些人患上更大的心血管风险。遗传易感性加上不利的环境因素可能会突出那些风险最大的人。 RAS 基因多态性可能通过增加 PAI-1 血浆水平或产生不良代谢环境来增加糖尿病受试者的不良心血管风险。 该提案中强调的研究将根据 RAS 的中间表型对糖尿病受试者进行分类，该中间表型首次在高血压受试者中得到证实。将确定 RAS 和 PAI-1 基因中的基因多态性与 PAI-1 水平、脂质、肥胖和胰岛素抵抗的中间表型的关系。了解哪些基因型和中间表型预测糖尿病患者心血管风险更大的风险可能有助于识别那些风险最大的个体，可能能够预测特定个体的风险，还可能有助于确定特定的治疗方法以减少这种风险风险。