The purpose of these two collaborative applications is to identify physiologic and basic mechanisms that are involved in the pathogenesis of insulin resistance, hypertriglyceridemia and body fat redistribution in people living with the human immunodeficiency virus (HIV) and receiving highly active antiretroviral therapy (HAART) including protease inhibitors (PI). The underlying hypothesis is that HIV infection and HAART/PI cause alterations in glucose and lipid metabolism in adipose tissue and skeletal muscle. Although one application focuses on abnormalities in skeletal muscle metabolism and the other on abnormalities in adipose tissue metabolism, the proposals are interactive and comprehensive. Both R01's will characterize patients based on glucose tolerance, serum triglyceride, and body fat distribution to identify uniform cohorts for detailed in vivo metabolic studies and cellular level tissue analyses. A Patient Recruitment and Clinical Management Core will recruit appropriate subjects from the ACTU and an extensive network of clinics and will be responsible for patient monitoring and safety. Both R01's will use sophisticated stable isotope tracer methods and the euglycemic-hyperinsulinemic pancreatic clamp procedure to evaluate whole-body and regional substrate kinetics in vivo, and will obtain muscle and adipose tissue samples for examining cellular mechanisms ex vivo. Studies from both R01's will be coordinated to maximize efficiency, avoid duplication, and minimize sample size and subject requirements by sharing study subjects, tissue samples and blood specimens. These studies will use several institutional resources including the General Clinical Research Center to assist in performing in vivo studies, the Mass Spectrometry Resource to assist with stable isotope enrichment and complex lipid analyses, and the Mallinckrodt Institute of Radiology to assist with dual energy x-ray absorptiometry and magnetic resonance scanning for adipose and muscle tissue mass and distribution, and for assessing muscle mitochondrial function. Each R01 involves both clinical and basic scientists, and the investigators have identified collaborators who can provide the resources and probes to evaluate cellular signaling and regulatory factors in-vitro, transgenic and null mouse models of lipid and muscle mitochondrial metabolism. These collaborative R01's take advantage of the considerable resources and research talent at Washington University to evaluate and characterize substrate kinetics and cellular defects responsible for the metabolic abnormalities associated with HIV infection and HAART.
