This K23 application proposes a 5-year mentored training and research plan to develop expertise in the clinical trial design, assessment, and analysis of HIV-related metabolic complications as they relate to the development and progression of endothelial dysfunction and insulin resistance. Didactic training will include coursework that is part of the Clinical Research Career Development Program at Washington University and the curriculum at St. Louis University's School of Public Health. A primary goal of this proposal is to develop a better understanding of the characteristics, natural history, cardiovascular risk, and pathogenesis of insulin resistance and endothelial dysfunction in persons on highly active antiretroviral therapy (HAART). Another goal of this proposal is to test the use of a peroxisome proliferator activated receptor gamma (PPARgamma) agonist in the therapy of these complications, thus supporting the hypothesis that PPARgamma dysregulation has an important role in the pathogenesis of insulin resistance and endothelial dysfunction in HIV-infected persons. To meet these goals, this proposal has the following specific aims: 1) Determine the temporal relationship between endothelial dysfunction and insulin resistance in HIV infected patients on HAART and its significance in terms of cardiovascular risk, 2) Evaluate the effects of a PPAR? agonist and HMG-CoA reductase inhibitor on regulation of insulin resistance, endothelial dysfunction, and biomarkers of inflammation in HIV-infected patients on HAART. Hypotheses for specific aim 1 will be tested using a 3-year prospective observational study of patients on HAART. Cardiovascular disease, worsening insulin resistance, and body fat changes will be measured by cardiac CT/carotid doppler, fasting insulin/oral glucose tolerance testing, and DEXA/CT, respectively. Hypotheses for specific aim 2 will be tested using a 48-wk. crossover trial of atorvastatin+pioglitazone vs. atorvastatin alone. Changes in insulin sensitivity/glucose disposal and body fat changes will be measured with IV glucose tolerance testing and DEXA, respectively. For both studies, brachial artery reactivity testing will be used to measure endothelial function as a surrogate for cardiovascular risk. Inflammatory biomarkers will be evaluated as surrogates for cardiovascular risk insulin resistance. The candidate will receive specific training and guidance by an exemplary mentor and faculty advisory committee and will have the full support of Washington University's outstanding research environment. This award will help fulfill the candidate's long-term career objective of becoming an independent researcher in the field of HIV-related metabolic complications.
