INSULIN RESISTANCE AND CARDIOVASCULAR RISK FACTORS

胰岛素抵抗和心血管风险因素

• 批准号: 6798949
• 负责人: BRENT M EGAN
• 金额: $ 3.08万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6798949
• 关键词: angiotensins; baroreflex; cardiovascular disorder; clinical research; clinical trials; dietary sodium; disease /disorder proneness /risk; fatty acids; free radical oxygen; glucose tolerance test; human subject; hypertension; insulin sensitivity /resistance; low birth weight infant human; low salt diet; nuclear magnetic resonance spectroscopy; nutrition related tag; obesity; oxidative stress; plethysmography; protein isoforms; protein kinase C; vascular resistance; vascular smooth muscle; young adult human (21-34)

This K-24 application includes a mentoring plan and two research components which are linked together by the common theme of insulin resistance and cardiovascular risk factor clustering. In part 1 of the research plan, we plan to continue work under the current R01 and a subsequent competitive renewal to test the hypothesis that fatty acids and angiotensin induce a synergistic enhancement of oxidative stress in humans. The three specific aims are to determine (1) the effects of raising fatty acids and angiotensin singly and in combination on markers of platelet PKC activity and oxidative stress (2) the effects of a low NaCl diet, which raises plasma angiotensin II, on markers of oxidative stress in obese hypertensive patients during treatment, with an AT1 receptor antagonist compared to placebo 3) which protein kinase C (PKC) isoform isoform(s) are stimulated by oleic acid and lead to the generation of reactive oxygen species and activation of extracellular signal-regulated kinases in human aortic smooth muscle cells by using antisense oligonucleotides to specific PKCs. Each of these specific aims will be addressed using methods which are well established in our patient-oriented clinical and bench research. In part 2, with the support of this K-24 Award, we plan to extend the generalizability of our findings to the wider community and by addressing important gaps in the literature on low birth weight and cardiovascular risk. We will test the hypothesis that low birth weight contributes to cardiovascular risk and salt sensitivity in a biracial sample of young adults at two college campuses in South Carolina. Three specific aims will be addressed to determine the relationships of low birth weight (<2500 grams) to (1) metabolic components of insulin resistance (oral glucose tolerance test and dyslipidemia (NMR lipid profile) (2) hemodynamic components of the insulin resistance syndrome including laboratory and 24-hour ambulatory blood pressure (BP), baroreflex sensitivity (cross spectral analysis of systolic BP and heart rate), proximal and distal arterial compliance (HDI pulse-wave) and post-ischemic forearm vascular resistance (venous occlusion plethysmography). (3) Salt sensitivity defined by the differences in BP on 180 vs. 80 mmol/d NaCl diets. All of the mentoring activities, which would be supported by the K-24 Award, also relate to various facets of the insulin resistance syndrome. "Access to excess" calories and labor saving devices has produced an epidemic of obesity and cardiovascular risk factors related to insulin resistance. While lifestyle changes are important and the PI and his colleagues work diligently in this area most people are unable to normalize their risk through lifestyle changes alone. We believe that a better definition of the pathophysiological common denominators and key intracellular signaling events mediating these effects will provide the basis for novel therapeutic approaches to cardiovascular disease prevention.

这个K-24应用程序包括一个指导计划和两个研究组成部分，它们通过胰岛素抵抗和心血管风险因素聚类的共同主题联系在一起。在研究计划的第1部分中，我们计划在当前R 01和随后的竞争性更新下继续工作，以检验脂肪酸和血管紧张素诱导人体氧化应激协同增强的假设。这三个具体目的是确定（1）单独和联合增加脂肪酸和血管紧张素对血小板PKC活性和氧化应激标志物的影响（2）在治疗期间增加血浆血管紧张素II的低NaCl饮食对肥胖高血压患者氧化应激标志物的影响，3）其中蛋白激酶C（PKC）同种型同种型被油酸刺激并导致活性氧物质的产生和细胞外信号的激活，通过使用特异性PKCs的反义寡核苷酸在人主动脉平滑肌细胞中调节激酶。这些具体目标中的每一个都将使用在我们以患者为导向的临床和实验室研究中确立的方法来解决。在第2部分中，在K-24奖的支持下，我们计划将我们研究结果的普遍性扩展到更广泛的社区，并解决低出生体重和心血管风险文献中的重要空白。我们将在南卡罗来纳州的两所大学校园的年轻成年人的双胞胎样本中检验低出生体重有助于心血管风险和盐敏感性的假设。三个具体目标将被解决，以确定低出生体重的关系，（<2500克）至（1）胰岛素抵抗的代谢成分（口服葡萄糖耐量试验和血脂异常（NMR血脂谱）（2）胰岛素抵抗综合征的血流动力学成分，包括实验室和24小时动态血压（BP）、压力反射敏感性（收缩压和心率的交叉频谱分析）、近端和远端动脉顺应性（HDI脉搏波）和缺血后前臂血管阻力（静脉闭塞体积描记法）。(3)盐敏感性定义为180与80 mmol/d NaCl饮食的BP差异。所有的辅导活动，这将是由K-24奖的支持，也涉及到胰岛素抵抗综合征的各个方面。“获得多余的”热量和节省劳力的设备已经产生了肥胖症和与胰岛素抵抗相关的心血管危险因素的流行。虽然生活方式的改变很重要，PI和他的同事们在这方面努力工作，但大多数人无法仅通过改变生活方式来使他们的风险正常化。我们相信，更好地定义的病理生理学常见的致病因子和关键的细胞内信号转导事件介导这些影响将提供新的治疗方法，以预防心血管疾病的基础。