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: 7377224
• 负责人: KEVIN E YARASHESKI
• 金额: $ 9.87万
• 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: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7377224
• 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 agen (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 senstivity, 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 PPAR mRNA and protein expression, serum lipid profiles, and serum adiponectin levels before and at the end of 4 months of treatment. We hypothesize and exercise trainig + 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 PPAR expression in muscle and pioglitazone will activate PPAR 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.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。我们之前的研究已经检查了艾滋病毒携带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“脂毒性”假说来解释人类免疫缺陷病毒(HIV)中糖耐量受损(IGT)和脂肪再分布的发病机制：皮下脂肪库中脂类和游离脂肪酸的脂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、肝脏葡萄糖输出增加，并可能导致内脏脂肪堆积。目前还没有确定有效的治疗方法。共识小组建议将定期锻炼和饮食调整作为主要治疗措施，并将药物干预作为次要治疗措施。在这项修订的应用中，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相关性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HIV和IGT患者以及脂肪再分布患者中的疗效。我们将在治疗前和治疗4个月结束时测量：胰岛素敏感度、葡萄糖处理率、肝脏葡萄糖生成率(4hr-胰岛素改良6.6-[2H2]-葡萄糖耐量试验和最小造模)；全身和局部脂肪和肌肉含量(腹部和大腿的1H-MRI&DEXA)、比目鱼肌和肝脏的脂肪含量(1H-MRS)、肌肉和脂肪PPAR基因和蛋白的表达、血脂谱和血清脂联素水平。我们推测，在改善HIV感染者的胰岛素敏感性、降低内脏脂肪、肝脏和肌肉脂肪含量以及增加外周皮下脂肪含量方面，运动训练+吡格列酮将比单独使用吡格列酮更有效。我们假设联合治疗将更有效，因为运动训练将激活肌肉中PPAR的表达，而吡格列酮将激活脂肪和肌肉中PPAR的表达。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携带者和经历代谢和拟人化疾病增加心血管疾病风险的患者中的联合使用。