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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本项目探讨了在体内机制，游离脂肪酸诱导的胰岛素抵抗损害NO的产生，促进内皮功能障碍的健康非糖尿病志愿者（FH+）和（FH-）2型糖尿病（DM 2）家族史。 我们通过正常血糖高胰岛素钳夹研究评估全身胰岛素刺激的葡萄糖处置，通过体积描记术和缺血后血流介导的扩张（BART）和NOS通路的化学来评估内皮功能。 我们研究了2组健康受试者：（1）DM 2的FH+和（2）DM 2的FH-。 实验方案包括4次访视。访视1包括病史、体格检查、ECG和实验室检查（CBC、CMP、血脂尿分析、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。访视3和访视4包括分别进入GCRC输注Intraperoid 20%/肝素和甘油（对照）（随机顺序，间隔4-6周）。在输注期间，抽取血液样品以检查血浆内皮功能标志物（ADMA、精氨酸、瓜氨酸、脱氢酶活性、亚硝酸盐、硝酸盐）、FFA、葡萄糖和胰岛素水平。体积描记术在输注后4小时进行。开始输注后24小时进行BART，然后进行2小时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.