PLASMA FREE FATTY ACIDS, ENDOTHELIAL DYSFUNCTION, AND THE ROLE OF NOS PATHWAY

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。本项目在有2型糖尿病(DM2)家族史(FH+)和无(FH-)家族史的健康非糖尿病志愿者中探索了游离脂肪酸诱导的胰岛素抵抗损害NO生成和促进内皮功能障碍的体内机制。我们通过正常血糖、高胰岛素钳夹实验、体积描记术和缺血后血流介导的扩张法(BART)和一氧化氮合酶(NOS)途径的化学方法来评估胰岛素刺激的葡萄糖处理对血管内皮功能的影响。我们研究了两组健康受试者：(1)DM2的FH+和(2)DM2的FH-。实验方案包括4次访问。就诊1包括病史、体格检查、心电图和实验室检查(血细胞计数、化学发光蛋白、血脂、尿液分析、微量白蛋白/肌酐比值)。访视2包括75克口服葡萄糖耐量试验(OGTT)和身体阻抗测量。就诊3和就诊4分别为进入GCRC输注20%Intralipid/肝素和甘油(对照组)(随机顺序，相隔4-6周)。在输液过程中，抽取血样检测血浆内皮功能标志物(ADMA、精氨酸、瓜氨酸、精氨酸酶活性、亚硝酸盐、硝酸盐)、游离脂肪酸、血糖和胰岛素水平。在输液后4小时进行体积描记。在开始输液后24小时进行BART，然后进行2小时的正常血糖高胰岛素钳夹。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project explores in vivo mechanisms by which free fatty acid-induced insulin resistance impairs NO generation and promotes endothelial dysfunction in healthy non-diabetic volunteers with (FH+) and without (FH-) family history of type 2 diabetes mellitus (DM2). We assess the whole body insulin-stimulated glucose disposal by euglycemic hyperinsulinemic clamp studies, the endothelial function by plethysmography and post-ischemic flow mediated dilatation (BART) and chemistry of the NOS pathway. We study 2 groups of healthy subjects: (1) FH+ of DM2 and (2) FH- of DM2. The experimental protocol includes 4 visits. Visit 1 consists of medical history, physical examination, ECG and laboratory tests (CBC, CMP, lipids urine analysis, microalbumin/creatinine ratio). Visit 2 consists of a 75-gram oral glucose tolerance test (OGTT) and body impedance measurement. Visit 3 and 4 consist of admission to the GCRC for infusion of Intralipid 20%/heparin and Glycerol (control) respectively (random order, 4-6 weeks apart). During the infusion, blood samples are drawn to check plasma endothelial function markers (ADMA, arginine, citrulline, arginase activity, nitrite, nitrate), FFA, glucose and insulin levels. Plethysmography is performed 4 hours into the infusion. BART is performed 24 hour after starting the infusion, followed by a 2-hour euglycemic hyperinsulinemic clamp.