The purpose of these 2 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 issue 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 form 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 we 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059531-02
Application #
6382004
Study Section
Special Emphasis Panel (ZHL1-CSR-A (M2))
Program Officer
Jones, Teresa L Z
Project Start
2000-09-15
Project End
2005-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$342,954
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Cade, William Todd; Overton, Edgar Turner; Mondy, Kristin et al. (2013) Relationships among HIV infection, metabolic risk factors, and left ventricular structure and function. AIDS Res Hum Retroviruses 29:1151-60
Cade, W Todd; Reeds, Dominic N; Overton, E Turner et al. (2013) Pilot study of pioglitazone and exercise training effects on basal myocardial substrate metabolism and left ventricular function in HIV-positive individuals with metabolic complications. HIV Clin Trials 14:303-12
Cade, W Todd; Reeds, Dominic N; Overton, E Turner et al. (2011) Effects of human immunodeficiency virus and metabolic complications on myocardial nutrient metabolism, blood flow, and oxygen consumption: a cross-sectional analysis. Cardiovasc Diabetol 10:111
Yarasheski, Kevin E; Scherzer, Rebecca; Kotler, Donald P et al. (2011) Age-related skeletal muscle decline is similar in HIV-infected and uninfected individuals. J Gerontol A Biol Sci Med Sci 66:332-40
Chen, Fabian; Lam, Raymond; Shaywitz, David et al. (2011) Evaluation of early biomarkers of muscle anabolic response to testosterone. J Cachexia Sarcopenia Muscle 2:45-56
Yarasheski, Kevin E; Cade, W Todd; Overton, E Turner et al. (2011) Exercise training augments the peripheral insulin-sensitizing effects of pioglitazone in HIV-infected adults with insulin resistance and central adiposity. Am J Physiol Endocrinol Metab 300:E243-51
Richmond, Scott R; Carper, Michael J; Lei, Xiaoyong et al. (2010) HIV-protease inhibitors suppress skeletal muscle fatty acid oxidation by reducing CD36 and CPT1 fatty acid transporters. Biochim Biophys Acta 1801:559-66
Cade, W T; Reeds, D N; Mondy, K E et al. (2010) Yoga lifestyle intervention reduces blood pressure in HIV-infected adults with cardiovascular disease risk factors. HIV Med 11:379-88
Zhang, Sheng; Carper, Michael J; Lei, Xiaoyong et al. (2009) Protease inhibitors used in the treatment of HIV+ induce beta-cell apoptosis via the mitochondrial pathway and compromise insulin secretion. Am J Physiol Endocrinol Metab 296:E925-35
Flint, Oliver P; Noor, Mustafa A; Hruz, Paul W et al. (2009) The role of protease inhibitors in the pathogenesis of HIV-associated lipodystrophy: cellular mechanisms and clinical implications. Toxicol Pathol 37:65-77

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