Effects of Recombinant IGF-I in HIV Associated Metabolic Disease

描述(由申请人提供)： 项目概述：高效抗逆转录病毒药物大大延长了感染人类免疫缺陷病毒(HIV)患者的生命。然而，这些药物的使用与一种综合征的发展有关，该综合征包括脂肪分布的异常变化、血脂异常和糖稳态异常。这些异常增加了患糖尿病和心血管疾病的风险。皮下脂肪萎缩是抗逆转录病毒药物的常见并发症。脂肪萎缩是胰岛素抵抗和血脂异常的独立危险因素，并导致显著的心理痛苦。增加皮下脂肪和逆转该综合征的医学并发症的试验结果喜忧参半。胰岛素样生长因子-L(IGF-I)增加胰岛素敏感性，因为它防止细胞死亡，也可能减少脂肪组织的损失。本研究的目的是验证重组IGF-I治疗HIV相关性脂营养不良综合征的疗效。其具体目的是(1)确定重组IGF-I对HIV脂营养不良综合征患者皮下脂肪的影响；(2)确定IGF-I对血脂和血糖稳态的影响；以及(3)检测IGF-I活性在调节该综合征的脂肪分布变化和代谢问题中的作用。48名患者将被随机分为安慰剂组或重组IGF-I组，采用双掩蔽方式。患者将在基线和治疗24周后进行评估。24周后，所有患者都将接受积极治疗，直到48周。评估包括测量血糖、胰岛素和脂蛋白的血液样本；0周和24周的脂肪组织活检；以及0周、24周和48周的身体成分评估，使用双能X射线吸收测量仪和计算机断层扫描。患者还将在0周和24周再次接受高胰岛素钳夹治疗。脂肪组织将被分析细胞凋亡和线粒体毒性的变化。体外实验将被用来描述抗逆转录病毒药物如何抑制IGF-I信号的正常活性，以及这一途径与脂肪细胞凋亡的相互关系。 与公共卫生相关：这项研究可能为治疗艾滋病毒护理中常见和困难的问题提供一种新的战略，该问题可能会在全球范围内增加频率。这项研究还可能增加我们对IGF-I激素在调节人类脂肪组织数量和生物学特性方面的作用的理解。这可以帮助我们了解糖尿病和肥胖症等其他医学疾病。

DESCRIPTION (provided by applicant): Project Summary: Highly potent antiretroviral medications have greatly prolonged the lives of patients infected with the human immunodeficiency virus (HIV). However, the use of these medications is associated with development of a syndrome consisting of abnormal changes in fat distribution, dyslipidemia, and abnormal glucose homeostasis. These abnormalities increase the risk of diabetes and cardiovascular disease. Subcutaneous lipoatrophy is a common complication of antiretrovirals. Lipoatrophy is an independent risk factor for insulin resistance and dyslipidemia, and causes significant psychological distress. Trials to increase subcutaneous adiposity and reverse the medical complications of the syndrome have had mixed results. Insulin like growth factor-l (IGF-I) increases insulin sensitivity, and because it prevents cell death, might also reduce loss of fat tissue. The purpose of this study is to test the efficacy of recombinant IGF-I in the treatment of HIV associated lipodystrophy syndrome. The specific aims are to (1) Determine the effect of recombinant IGF-I on subcutaneous adiposity in patients with HIV lipodystrophy syndrome; (2) determine the effects of IGF-I on lipids and glucose homeostasis; and (3) examine the role of IGF-I activity in mediating the fat distribution changes and metabolic problems of the syndrome. Forty-eight patients will be randomized to either placebo or recombinant IGF-I, in double-masked fashion. Patients will be assessed at baseline and after 24 weeks of treatment. After 24 weeks, all patients will be given active therapy until week 48. Assessments includes blood samples to measure glucose, insulin, and lipoproteins; adipose tissue biopsy at 0 and 24 weeks; and body composition assessment at 0, 24 weeks, and 48 weeks, using dual energy x-ray absorptiometry and computed tomography. Patients will also undergo the hyperinsulinemic clamp at week 0 and again at week 24. Adipose tissue will be analyzed for changes in apoptosis and mitochondrial toxicity. In vitro experiments will be conducted to characterize how antiretrovirals inhibit normal activity of IGF-I signaling and the interrelationship of this pathway to adipocyte apoptosis. PUBLIC HEALTH RELEVANCE: This study could indicate a new strategy for treating a common and difficult problem in HIV care, one which may increase in frequency globally. The study may also increase our understanding of the role of the IGF-I hormone in regulating the amount and biological properties of human fat tissue. This could help us understand other medical conditions such as diabetes and obesity.