EXERCISE AND PIOGLITAZONE FOR HIV-METABOLIC SYNDROMES

运动和吡格列酮治疗艾滋病毒代谢综合征

• 批准号: 7355267
• 负责人: KEVIN E YARASHESKI
• 金额: $ 1.39万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7355267
• 关键词: EXERCISE; PIOGLITAZONE; HIV; METABOLIC; SYNDROMES

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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。我们之前的研究已经研究了艾滋病毒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) 和脂肪重新分配的发病机制：皮下脂肪库中脂质和游离脂肪酸的脂肪分解和动员增加，导致其在肌肉中过度沉积和肝脏，导致血脂异常、胰岛素抵抗、肝葡萄糖输出增加，并可能导致内脏脂肪堆积。尚未确定有效的治疗方法。共识小组建议定期锻炼和饮食调整作为该综合征的主要治疗方法，药物干预措施作为次要治疗方法。在此修订后的申请中，我们建议测试有氧运动和举重运动训练以及口服胰岛素增敏剂（吡格列酮）作为治疗 HIV 相关 IGT 和脂肪重新分布的功效。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 + 吡格列酮对 40 名男性和 40 名 HIV 感染者和 IGT 感染者以及脂肪重新分布女性的疗效。我们将测量：胰岛素敏感性、葡萄糖处理率、肝葡萄糖生成率（高胰岛素血症、使用 6,6-[2H2]-葡萄糖的正常血糖钳夹）；全身和局部脂肪和肌肉含量（腹部和大腿的 1H-MRI 和 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、血清脂质谱以及治疗前和治疗 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，因为运动训练将激活肌肉中的 PPARα 表达，而吡格列酮将激活脂肪和肌肉中的 PPARγ 表达。我们预计该项目将提供直接证据，支持对艾滋病毒感染者和患有增加心血管疾病风险的代谢和拟人疾病的患者联合使用运动训练和吡格列酮。