EXERCISE AND PIOGLITAZONE FOR HIV-METABOLIC SYNDROMES

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。我们先前的研究已经检查了HIV感染者代谢并发症的发病机制和潜在治疗方法。我们采用代谢综合征X的“脂毒性”假说来解释HIV中葡萄糖耐量受损（IGT）和脂肪再分布的发病机制：增加的脂解和脂质和游离脂肪酸从皮下脂肪库的动员导致它们在肌肉和肝脏中的过度沉积，这导致血脂异常、胰岛素抵抗、肝葡萄糖输出增加以及可能的内脏脂肪蓄积。有效的治疗方法尚未确定。共识小组建议定期运动和饮食调整作为主要和药物干预作为综合征的次要治疗。在本修订申请中，我们建议测试有氧和举重运动训练以及口服胰岛素增敏剂（吡格列酮）作为HIV相关IGT和脂肪再分布治疗的有效性。我们提出了一项为期4个月的2组随机研究，以评估吡格列酮和运动+吡格列酮在40名男性和40名女性艾滋病毒感染者和IGT和脂肪再分布患者中的疗效。我们将测量：胰岛素敏感性，葡萄糖代谢率，肝葡萄糖生成率（高胰岛素血症，使用6，6-[2 H2]-葡萄糖的正葡萄糖钳夹）;全身和局部脂肪和肌肉含量（腹部和大腿的1H-MRI & DEXA）、比目鱼肌和肝脏脂质含量（1H-MRS）、肌肉和脂肪PPARgamma/alpha mRNA和蛋白质表达、血清脂质谱，治疗前和治疗4个月结束时的血清脂联素水平。我们假设运动训练+吡格列酮在改善HIV感染者的胰岛素敏感性、降低内脏脂肪、肝脏和肌肉脂质含量以及增加外周皮下脂肪含量方面比吡格列酮单药更有效。我们假设联合治疗将更有效，因为运动训练将激活肌肉中的PPARalpha表达，吡格列酮将激活脂肪和肌肉中的PPARgamma表达。我们预计，该项目将提供直接证据，支持运动训练和吡格列酮在艾滋病毒感染者和经历代谢和拟人化疾病的人中的联合使用，这些疾病会增加心血管疾病的风险。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 (hyperinsulinemic, euglycemic clamp using 6,6-[2H2]-glucose); 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 PPARgamma 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.