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

描述（由申请人提供）：过去6年，发达国家艾滋病相关发病率和死亡率显著下降，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，这种治疗进步所带来的热情已经被广泛报道的潜在有害代谢副作用所削弱，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相关脂肪营养不良综合征。我们实验室的一个主要目标是了解hiv相关代谢和形态异常的发病机制，并评估潜在的治疗方案，使用基于强化代谢病房评估的范式，其中每个受试者作为他或她自己的对照。在这些研究中，我们发现一定药理学剂量的生长激素（GH）可以减少总脂肪、躯干脂肪和内脏脂肪，并改善脂肪堆积的hiv感染男性的脂质谱。然而，生长激素也会损害胰岛素在肌肉和肝脏中的作用，从而限制了其潜在的治疗价值。我们现在建议评估一种使用胰岛素样生长因子- i （IGF-I）的新治疗策略，它已被证明可以减少脂肪和促进脂质氧化，同时提高胰岛素敏感性，在配方中，它与主要结合蛋白IGFBP-3络合，以提高生物利用度和安全性。我们假设igf - 1 /IGFBP-3将在HIV感染患者中实现脂肪动员和胰岛素增敏作用，从而提供比GH更好的治疗优势。在这个新的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，以评估三个月的IGF-I/IGFBP-3治疗对体脂肪含量和分布、瘦体和肌肉质量（DEXA和MRI）、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（间接量热法的正糖高胰岛素钳）、口服葡萄糖耐量、综合脂质和碳水化合物代谢（葡萄糖生成、糖异生、脂肪分解、新生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环境下影响糖脂代谢的机制。如果这项初步研究的结果是积极的，它们将为该药物的进一步研究提供基础，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.