Leptin Treatment of HIV-Associated Lipodystrophy

描述（申请人提供）：过去5年，发达国家艾滋病毒相关发病率和死亡率大幅下降，这一事件通常归因于高效抗逆转录病毒疗法的出现。然而，这种治疗进展所产生的热情已经被广泛报道的潜在有害的代谢副作用所缓和，包括胰岛素抵抗、血脂异常、外周和/或面部脂肪萎缩和中央/内脏脂肪堆积，这些发现让人想起X综合征，通常被称为HIV相关的脂肪代谢障碍综合征。我们实验室的一个主要目标是不仅要了解艾滋病毒相关的代谢和形态异常的发病机制，而且要评估新的治疗方法，使用一种基于密集的代谢病房评估的范例，其中每个受试者作为他或她自己的控制。本提案的目的是评估重组人瘦素的作用，瘦素是一种脂肪细胞衍生的激素，在患有脂肪营养不良的HIV感染患者中，在小鼠和人类脂肪营养不良模型中似乎具有显著的有益作用。将进行两项研究：在第一项研究中，我们将采用开放标签设计来评估瘦素替代疗法对12名同时患有低瘦素血症、高胰岛素血症和高胰岛素血症的HIV-脂肪代谢障碍患者的影响;在第二项研究中，我们将采用随机安慰剂对照设计，将我们对瘦素治疗疗效的研究扩展到40名非肥胖HIV阳性的糖尿病和脂肪代谢障碍患者。这两项研究旨在检验用瘦素治疗将：1）改善肝脏和外周胰岛素敏感性和总体碳水化合物代谢，如通过口服葡萄糖耐量试验、正常血糖高胰岛素钳夹和肝葡萄糖产生、糖原生成和糖原通量的稳定同位素示踪剂研究所测量的; 2）改善脂质代谢异常，如通过血浆脂质和脂蛋白水平以及全身脂解和从头肝脂肪生成和胆固醇生成的稳定同位素研究所测量的;和3）分别通过磁共振成像和光谱学测量，降低内脏脂肪、肝脏质量和肌细胞内脂质。为了评估瘦素对全身和局部脂肪和瘦肉组织分布的影响，我们还将进行全身双能X射线（DEXA）扫描。

DESCRIPTION (provided by applicant): The past 5 years have witnessed a dramatic reduction in HIV-associated morbidity and mortality in the developed world, an event that is generally attributed to the advent of highly active antiretroviral therapy. However, the enthusiasm generated by this therapeutic advance has been tempered by widespread reports of potentially deleterious metabolic side effects, including insulin resistance, dyslipidemia, peripheral and/or facial lipoatrophy, and central/visceral fat accumulation, findings reminiscent of syndrome X and commonly referred to as the HIV-associated lipodystrophy syndrome. A major goal of our laboratory has been to not only understand the pathogenesis of HIV-associated metabolic and morphologic abnormalities but also to evaluate novel therapies, using a paradigm based on intensive metabolic ward assessments in which each subject serves as his or her own control. The goal of the present proposal is to evaluate the effects of recombinant human leptin, an adipocyte-derived hormone that appears to have dramatic salutary effects in both murine and human models of lipodystrophy, in HIV-infected patients with lipodystrophy. Two studies will be performed: in the first, we will utilize an open-label design to evaluate the effects of leptin replacement therapy in 12 patients with HIV-lipodystrophy who are also hypoleptinemic, hyperinsulinemic, and hypertriglyceridemic; in the second we will utilize a randomized placebo-control design to extend our investigation of the efficacy of leptin treatment to a group of 40 non-obese HIV-positive patients with diabetes and lipodystrophy. These two studies are designed to test the hypotheses that treatment with leptin will: 1) improve hepatic and peripheral insulin sensitivity and overall carbohydrate metabolism as measured by oral glucose tolerance testing, a euglycemic hyperinsulinemic clamp and stable isotope tracer studies of hepatic glucose production, gluconeogenesis, and glycogen flux; 2) ameliorate abnormalities in lipid metabolism, as measured by plasma lipid and lipoprotein levels and stable isotope studies of whole-body lipolysis and de novo hepatic lipogenesis and cholesterolgenesis; and 3) decrease visceral adiposity, hepatic mass, and intramyocellular lipids, as measured by magnetic resonance imaging and spectroscopy, respectively. To evaluate the effects of leptin on whole-body and regional fat and lean tissue distribution, we will also perform whole-body dual-energy X-ray (DEXA) scanning.