Can IGF-I /IGFBP-3 Reverse Central Fat Accumulation?

描述（由申请人提供）：过去6年，发达国家的HIV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（HAART）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，脂肪萎缩和中央脂肪堆积，这些发现让人想起代谢综合征X，通常被称为HIV相关的脂肪营养不良综合征。我们实验室的一个主要目标是了解艾滋病毒相关的代谢和形态异常的发病机制，并评估潜在的治疗方案，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。在这些研究中，我们发现，药理学剂量的生长激素（GH）减少总，躯干和内脏脂肪，并改善脂肪堆积的HIV感染男性的血脂谱。然而，GH也损害了肌肉和肝脏中的胰岛素作用，从而限制了其潜在的治疗价值。我们现在建议使用胰岛素样生长因子-I（IGF-I）评估一种新的治疗策略，该治疗策略已被证明可以减少脂肪并增强脂质氧化，同时改善胰岛素敏感性，在该制剂中，IGF-I与其主要结合蛋白IGFBP-3复合，以提高生物利用度和安全性。我们假设IGF-I/IGFBP-3将在HIV感染患者中实现脂肪动员和胰岛素增敏作用，从而提供优于GH的治疗优势。在这项新的R21申请中提出的原理验证研究中，我们将进行密集的代谢病房研究，以评估IGF-I/IGFBP-3治疗三个月对体脂含量和分布以及瘦体重和肌肉质量的影响（DEXA和MRI），肌细胞内脂质水平（质子光谱），胰岛素介导的葡萄糖摄取和处置（正葡萄糖高胰岛素钳夹间接测热法）、口服葡萄糖耐量、综合脂质和碳水化合物代谢（葡萄糖产生、脂肪生成、脂肪分解、从头脂肪生成的稳定同位素研究）和血浆脂质和脂蛋白水平。这些研究将提供关于这种新型治疗方法的有效性和安全性的全面信息，以及它在HIV感染和HAART背景下影响葡萄糖和脂质代谢的机制。 如果这项初步研究的结果是积极的，他们将提供一个理由，进一步研究这种药物，包括随机，双盲，安慰剂对照试验。

DESCRIPTION (provided by applicant): The past 6 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 (HAART). However, the enthusiasm generated by this therapeutic advance has been tempered by widespread reports of potentially deleterious metabolic side effects, including insulin resistance, dyslipidemia, lipoatrophy, and central fat accumulation, findings reminiscent of metabolic syndrome X and commonly referred to as HIV-associated lipodystrophy syndrome. A major goal of our laboratory has been to understand the pathogenesis of HIV-associated metabolic and morphologic abnormalities and evaluate potential therapeutic options, using a paradigm based on intensive metabolic ward assessments in which each subject serves as his or her own control. In such studies we found that a pharmacologic dose of growth hormone (GH) reduced total, trunk and visceral fat and improved lipid profiles in HIV-infected men with fat accumulation. However, GH also impaired insulin action in both muscle and liver, thus limiting its potential therapeutic value. We now propose to evaluate a novel treatment strategy using insulin-like growth factor-I (IGF-I), which has been shown to reduce fat and enhance lipid oxidation while improving insulin sensitivity, in a formulation in which it is complexed to its major binding protein, IGFBP-3, to enhance bioavailability and safety. We hypothesize that IGF-I/IGFBP-3 will achieve both fat-mobilizing and insulin-sensitizing effects in patients with HIV infection and thus provide a therapeutic advantage over GH. In the proof-of-principle study proposed in this new R21 application, we will perform intensive metabolic ward studies to evaluate the effect of three months of treatment with IGF-I/IGFBP-3 on body fat content and distribution and lean body and muscle mass (DEXA and MRI), intramyocellular lipid levels (proton spectroscopy), insulin-mediated glucose uptake and disposal (euglycemic hyperinsulinemic clamp with indirect calorimetry), oral glucose tolerance, integrated lipid and carbohydrate metabolism (stable isotope studies of glucose production, gluconeogenesis, lipolysis, de novo lipogenesis), and plasma lipid and lipoprotein levels. These studies will provide comprehensive information on the efficacy and safety this novel therapeutic approach as well as the mechanisms by which it impacts glucose and lipid metabolism in the setting of HIV infection and HAART. Should the results of this preliminary study be positive, they would provide a rationale for further studies of this agent, including a randomized, double-blind, placebo-controlled trial.