INSULIN RESISTANCE IN THE HIV LIPODYSTROPHY SYNDROME

描述（申请人摘要） 脂肪营养不良综合征是一种新认识的艾滋病并发症， 这影响了多达一半的艾滋病毒感染者， 治疗，并且没有有效的治疗方法。该综合征是 主要表现为脂肪再分布，包括躯干肥胖， 以及外周脂肪减少。虽然该综合征的机制尚不清楚， 初步数据表明， 该综合征的特征是空腹高胰岛素血症。然而，在这方面， 对受影响患者的胰岛素动力学的详细评估以前没有 已执行，并且尚不清楚该综合征的特征是否为 胰岛素抵抗本身如果显示胰岛素抵抗， 缺陷是否是中心性的，由于中心性肝胰岛素抵抗， 葡萄糖生成过多或外周，与葡萄糖减少相关 利用率这一决心对于建立 胰岛素抵抗的适当治疗。一个假设 在这个建议中，在糖尿病患者中存在显著的胰岛素抵抗， HIV-脂肪营养不良综合征与内脏腹部 脂肪和增加的脂肪酸产生。此外，Trunk 肥胖和游离脂肪酸（FFA）产生增加被假设为 与外周胰岛素抵抗相比， 阻力为了研究这些假设，胰岛素动力学和内脏 肥胖将在两个艾滋病毒感染的患者进行比较， 脂肪代谢障碍和健康对照。阿昔莫司的急性干预将是 研究FFA在胰岛素抵抗中的作用， 正葡萄糖钳夹将用于区分肝脏和外周 HIV脂肪营养不良患者的胰岛素抵抗。此外，胰岛素 动力学，身体成分和性类固醇水平将在男性和 女性来确定这种综合征的性别差异。 本建议的第二个目的是调查使用 胰岛素增敏剂二甲双胍可有效降低胰岛素 HIV感染者脂肪营养不良综合征的耐药性。的 二甲双胍治疗HIV脂肪营养不良综合征的潜在益处是 包括减少长期心血管并发症， 逆转HIV脂肪营养不良患者体内脂肪分布的变化 综合征 总之，本提案将研究潜在的病理生理学 HIV脂肪营养不良综合征的胰岛素抵抗机制 评估一种新的治疗策略，以逆转患者的胰岛素抵抗 受这种综合症的影响。随着艾滋病毒感染者寿命的延长， 成功的治疗，以防止潜在的长期发病率相关的 胰岛素抵抗对于新出现的慢性 感染但免疫稳定的患者群体。

DESCRIPTION (Applicant's abstract) The lipodystrophy syndrome is a newly recognized complication of HIV disease, which affects up to half of all HIV-infected patients on potent antiretroviral therapy, and for which there is no effective therapy. The syndrome is characterized primarily by fat redistribution, including truncal obesity, as well as peripheral fat loss. Although the mechanism of the syndrome is unknown, and may relate in part to protease inhibitor therapy, preliminary data suggest that the syndrome is characterized by fasting hyperinsulinemia. However, detailed evaluation of insulin dynamics in affected patients has not previously been performed, and it is unknown whether the syndrome is characterized by insulin resistance per se. If insulin resistance is shown, it is not known whether the defect is central, due to central hepatic insulin resistance and excessive glucose production or peripheral, related to diminished glucose utilization. This determination is critical for the establishment of appropriate therapy for insulin resistance in this population. One hypothesis in this proposal is that significant insulin resistance exists in the HIV-Iipodystrophy syndrome and is closely associated with visceral abdominal fat and increased fatty acid production in such patients. Furthermore, truncal adiposity and increased free fatty acid (FFA) production is hypothesized to result in primarily hepatic insulin resistance, compared to peripheral resistance. To investigate these hypotheses, insulin dynamics and visceral adiposity will be compared in both HIV-infected patients with and without lipodystrophy and healthy controls. Acute intervention with acipimox will be investigated to determine the role of FFA in the insulin resistance, and euglycemic clamp will be used to differentiate between hepatic and peripheral insulin resistance in patients with HIV lipodystrophy. Furthermore, insulin dynamics, body composition and sex steroid levels will be compared in men and women to determine gender differences in this syndrome. The second aim of this proposal will be to investigate whether the use of an insulin sensitizing agent, metformin, will effectively reduce insulin resistance in HIV-infected patients with the lipodystrophy syndrome. The potential benefits of metformin therapy in the HIV lipodystrophy syndrome are two-fold and include reduction in long-term cardiovascular complications and reversal in the changes in body fat distribution in the HIV lipodystrophy syndrome. In summary, this proposal will investigate the potential pathophysiologic mechanisms of insulin resistance in the HIV lipodystrophy syndrome and will evaluate a novel therapeutic strategy to reverse insulin resistance in patients affected by this syndrome. As HIV patients are living longer, development of successful therapies to prevent potential long-term morbidity associated with insulin resistance is critical for the emerging population of chronically infected, but immunologically stable, population of patients.