Mentored Patient-Oriented Research Career Development Aw

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PROPOSAL (Adapted from the applicant's abstract): Treatment of HIV-infected individuals with PIs is associated with changes in body fat distribution and metabolic disturbances similar to those seen in syndrome X. PI use has been variably associated with hypertriglyceridemia, insulin resistance including diabetes mellitus and the development of central obesity which is often accompanied by loss of fat from the extremities and buttocks. It is unclear how these complications relate to each other. Based on the experience of patients with syndrome X, it is highly probable that if these metabolic complications of PI therapy cluster, then they will in turn be associated with an increased risk of coronary artery disease. One hypothesis of this proposal is that patients who develop an increase in abdominal girth as well as those who develop hypertriglyceridemia without a clinically apparent change in body fat distribution will both have significantly more visceral fat and insulin resistance compared to controls. The investigators hypothesize that these changes represent one syndrome rather than several. To test this hypothesis, four groups of HIV-infected subjects will be compared: 1) PI-treated patients who have developed a "protease paunch;" 2) PI-treated patients with hypertriglyceridemia but no clinically apparent change in body fat distribution; 3) PI-treated patients free of these two complications; and 4) PI-naive patients. Body composition and visceral adiposity will be determined by dual energy X-ray absorptiometry (DEXA) and computerized tomography, respectively. Insulin sensitivity will be measured using the frequently sampled intravenous glucose test (FSIGT). A prospective study is also planned to test the hypothesis that, after the initiation of PI therapy, a decline in insulin sensitivity will predict the development of visceral fat accumulation and, therefore, may be casual in its development. This is a unique opportunity to study the development of visceral obesity and its relationship to insulin resistance. Finally, the investigators hypothesize that the decrease in peripheral adipose tissue associated with PI therapy is due to increased mobilization or decreased storage of triglycerides (TGs)in those depots. Other potential mechanisms of adipose tissue loss including apoptosis and dedifferentiation will also be studied. The loss of peripheral fat stores offer a unique opportunity to determine the genes involved in regulating adipose tissue mass and distribution in general.