INSULIN RESISTANCE AND CARDIOVASCULAR RISK FACTORS

这个K-24应用程序包括一个指导计划和两个研究组件，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。在研究计划的第一部分中，我们计划在当前的R01和随后的竞争性更新下继续工作，以测试脂肪酸和血管紧张素诱导人类氧化应激协同增强的假设。三个具体目的是确定(1)单独或联合提高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)低NaCl饮食提高血浆血管紧张素II对治疗期间肥胖高血压患者氧化应激标志物的影响。3)油酸刺激蛋白激酶C （PKC）异构体异构体，通过使用特异性PKC的反义寡核苷酸，导致人主动脉平滑肌细胞中活性氧的产生和细胞外信号调节激酶的激活。这些具体目标中的每一个都将使用我们以患者为导向的临床和实验研究中建立的方法来解决。在第二部分中，在K-24奖的支持下，我们计划通过解决文献中关于低出生体重和心血管风险的重要空白，将我们的发现推广到更广泛的社区。我们将在南卡罗莱纳的两所大学校园中对年轻人的双种族样本进行测试，以验证低出生体重会导致心血管风险和盐敏感性的假设。确定低出生体重（<2500克）与：(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（核磁共振脂质谱）；(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光谱分析）；近端和远端动脉顺应性（HDI脉搏波）和缺血后前臂血管阻力（静脉闭塞容积描记）。(3)盐敏感性由180 mmol/d和80 mmol/d NaCl饲粮的BP差异定义。所有由K-24奖支持的指导活动也涉及胰岛素抵抗综合征的各个方面。“获得过量”的卡路里和节省劳力的设备已经造成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，而且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使其风险正常化。我们相信，更好地定义病理生理共同点和介导这些作用的关键细胞内信号事件将为心血管疾病预防的新治疗方法提供基础。

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.