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发现的艾滋病毒并发症， 在服用强效抗逆转录病毒药物的所有HIV感染者中，多达一半的人会受到影响 治疗，而且没有有效的治疗方法。症候群是 主要特征是脂肪重新分布，包括躯干肥胖，如 以及外周脂肪的减少。虽然该综合征的发病机制尚不清楚， 初步数据表明，这可能在一定程度上与蛋白酶抑制剂的治疗有关 该综合征的特征是空腹高胰岛素血症。然而， 以前没有对受影响患者的胰岛素动力学进行详细评估 目前尚不清楚该综合征的特征是否为 胰岛素抵抗本身。如果表现出胰岛素抵抗，就不得而知了。 是否由于肝脏中央胰岛素抵抗而导致的中枢性缺陷 过多的葡萄糖产生或外周，与葡萄糖减少有关 利用率。这一决心对于建立 对这一人群的胰岛素抵抗进行适当的治疗。一个假设 在这项建议中，胰岛素抵抗显著存在于 HIV-营养不良综合征与内脏腹部密切相关 这类患者的脂肪和脂肪酸产量增加。此外，干线 肥胖和游离脂肪酸(FFA)的产生增加被假设为 与外周血相比，主要导致肝脏胰岛素抵抗 抵抗。为了研究这些假说，胰岛素动力学和内脏 将比较患有和不患有HIV感染的患者的肥胖症 脂肪营养不良和健康对照。阿昔莫司的急性干预将是 研究确定FFA在胰岛素抵抗中的作用，以及 正常血糖钳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 将对男性和女性的动力学、身体成分和性类固醇水平进行比较 以确定女性在此综合征中的性别差异。 这项提案的第二个目标将是调查是否使用 胰岛素增敏剂二甲双胍可有效降低胰岛素 患有脂营养不良综合征的HIV感染患者的耐药性。这个 二甲双胍治疗HIV脂肪营养不良综合征的潜在好处是 两倍，包括减少长期心血管并发症和 HIV脂肪营养不良患者体内脂肪分布变化的逆转 综合症。 总而言之，这项提案将调查潜在的病理生理学 HIV脂营养不良综合征与Will的胰岛素抵抗机制 评估逆转患者胰岛素抵抗的新治疗策略 受这种综合症的影响。随着艾滋病毒患者寿命的延长， 成功的治疗方法可防止潜在的长期发病率与 胰岛素抵抗是慢性糖尿病新发人群的关键 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.