EXERCISE AND PIOGLITAZONE FOR HIV-METABOLIC SYNDROMES

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。我们之前的研究已经检查了艾滋病毒感染者代谢并发症的发病机制和潜在的治疗方法。我们采用代谢综合征X的“脂肪毒性”假说来解释HIV中糖耐量受损（IGT）和脂肪再分配的发病机制：皮下脂肪库中脂质和游离脂肪酸的脂肪分解和动员增加，导致它们在肌肉和肝脏中过度沉积，从而导致血脂异常、胰岛素抵抗、肝糖输出增加，并可能导致内脏脂肪堆积。目前还没有找到有效的治疗方法。共识小组建议定期运动和饮食调整作为主要治疗手段，药物干预作为次要治疗手段。在这个修订后的申请中，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和脂肪再分配治疗的有效性。我们提出了一项为期4个月的两组随机研究，评估吡格列酮和运动+吡格列酮在40名感染HIV和IGT和脂肪再分配的男性和女性中的疗效。我们将测量：胰岛素敏感性，葡萄糖处置率，肝脏葡萄糖生成率（高胰岛素，正血糖钳使用6,6-[2H2]-葡萄糖）；治疗4个月前和治疗结束时的全身和局部脂肪和肌肉含量（腹部、大腿和DEXA的1H-MRI）、比目鱼肌和肝脏脂质含量（1H-MRS）、肌肉和脂肪ppγ / α mRNA和蛋白表达、血脂谱和血清脂联素水平。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单独使用吡格列酮更有效。我们假设联合治疗会更有效，因为运动训练会激活肌肉中的ppar α表达，而吡格列酮会激活脂肪和肌肉中的ppar α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联合应用于艾滋病毒感染者和经历增加心血管疾病风险的代谢和拟人化疾病的人。

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.