This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.HIV-1 protease inhibitors (PI) have increased life expectancy in the HIV-infected. Recently, there have been reports of abnormal glucose and lipid metabolism, endothelial dysfunction, elevated levels of non-traditional vascular risk factors as well as even reports of cardiac events in HIV-infected patients receiving PI. However, it remains to be defined if the heightened vascular risk is due to PI alone, HIV infection alone, or an interaction between the two. Recent preliminary data from our laboratory suggest that in HIV-negative non-obese subjects, the PI indinavir (IDV) induces endothelial dysfunction as well as insulin resistance (IR). This proposal will attempt to dissect out the role of IDV in the absence of HIV-infection in induction of IR, the sites of IDV-induced IR, as well as endothelial dysfunction, and evaluate the role of IR in IDV-induced endothelial dysfunction. We will study insulin sensitivity, endothelial function, lipid parameters, newly recognized vascular risk factors and the possible cellular basis for the IR in healthy HIV-negative non-obese subjects before and after 4 weeks of IDV, and the effect of improved insulin sensitivity on the above parameters before and after 4 weeks of co-administration of IDV and the insulin sensitizer, rosiglitazone in a similar group of subjects. We will test the following hypotheses in our subjects: 1) IDV induces IR at the level of muscle, fat and liver. 2) IDV induces endothelial dysfunction. 3) IDV induces changes in qualitative lipid parameters and non-traditional vascular risk factors, thus pointing to these factors as possible bases for the endothelial dysfunction. 4) Rosiglitazone will improve IR as well as endothelial dysfunction.
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