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

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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.