Our prior research has examined the pathogenesis and potential treatments for metabolic complications in people living with HIV. We have adopted the """"""""lipotoxicity"""""""" hypothesis for metabolic syndrome X to explain the pathogenesis of impaired glucose tolerance (IGT) and fat redistribution in HIV: increased lipolysis and mobilization of lipids and free fatty acids from subcutaneous adipose depots leads to their excessive deposition in muscle and liver which contributes to dyslipidemia, insulin resistance, increased hepatic glucose output, and possibly visceral fat accumulation. Effective treatments have not been identified. Consensus groups recommend regular exercise and dietary modifications as primary and pharmacologic interventions as secondary treatments for the syndromes. In this revised application, we propose to test the efficacy of aerobic and weight lifting exercise training and an oral insulin-sensitizing agent (pioglitazone) as treatments for HIV-associated IGT and fat redistribution. We propose a 4-month, 2-group randomized study to evaluate the efficacy of pioglitazone and exercise + pioglitazone in 40 men and 40 women living with HIV and IGT and fat redistribution. We will measure: insulin sensitivity, glucose disposal rate, hepatic glucose production rate (4hr-insulin modified 6,6-[2H2]-glucose tolerance test with minimal modeling); whole-body and regional fat and muscle content (1H-MRI of the abdomen and thigh & DEXA), soleus muscle and liver lipid content (1H-MRS), muscle and fat PPARgamma/alpha mRNA and protein expression, serum lipid profiles, and serum adiponectin levels before and at the end of 4 months of treatment. We hypothesize that exercise training + pioglitazone will be more effective than pioglitazone alone at improving insulin sensitivity, reducing visceral fat, liver and muscle lipid content, and increasing peripheral subcutaneous fat content in HIV-infected people. We hypothesize that combined treatment will be more effective because exercise training will activate PPARalpha expression in muscle and pioglitazone will activate PPARy expression in fat and muscle. We anticipate that this project will provide direct evidence that supports the combined use of exercise training and pioglitazone in people living with HIV and experiencing metabolic and anthropomorphic disorders that increase cardiovascular disease risk.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-AARR-B (03))
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Malozowski, Saul N
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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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
Schroeder, E Todd; He, Jiaxiu; Yarasheski, Kevin E et al. (2012) Value of measuring muscle performance to assess changes in lean mass with testosterone and growth hormone supplementation. Eur J Appl Physiol 112:1123-31
Smith, Gordon I; Reeds, Dominic N; Hall, Angela M et al. (2012) Sexually dimorphic effect of aging on skeletal muscle protein synthesis. Biol Sex Differ 3:11
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

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