Effects of Recombinant IGF-I in HIV Associated Metabolic Disease

重组 IGF-I 在 HIV 相关代谢疾病中的作用

• 批准号: 7555252
• 负责人: ROY J KIM
• 金额: $ 14.68万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7555252
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Adult; Affect; Aftercare; Anti-Retroviral Agents; Apoptosis; Attenuated; Biological; Biopsy; Blood specimen; Body Composition; CREB1 gene; Cardiovascular Diseases; Caring; Cell Death; Characteristics; Cholesterol Ester Transfer Proteins; Complication; DNA Nucleotidylexotransferase; Detection; Development; Diabetes Mellitus; Dyslipidemias; Esterified Fatty Acids; Etiology; Fasting; Fatty Acids; Fatty acid glycerol esters; Frequencies; Functional disorder; Gene Expression; Glucose; Glycerol; HIV; HIV-Associated Lipodystrophy Syndrome; Hepatic; High Density Lipoprotein Cholesterol; Homeostasis; Hormones; Human; Hypertriglyceridemia; In Vitro; Inflammation; Inflammatory; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Intervention; Label; Life; Limb structure; Link; Lipids; Lipoatrophy; Lipodystrophy; Lipolysis; Lipoproteins; Liver; Masks; Measurement; Measures; Mediating; Mediation; Medical; Metabolic; Metabolic Diseases; Mitochondria; Mitochondrial DNA; Muscle; Nonesterified Fatty Acids; Nucleosomes; Obesity; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Placebos; Principal Investigator; Production; Property; Randomized; Recombinant Insulin-Like Growth Factor; Recombinants; Research Personnel; Risk Factors; Role; Sampling; Series; Serum; Signal Pathway; Signal Transduction; Somatomedins; Somatotropin; Specimen; Syndrome; Testing; Therapeutic; Thigh structure; Tissues; Toxic effect; Triglycerides; Very low density lipoprotein; Very low density lipoprotein cholesterol; Virus Diseases; X-Ray Computed Tomography; antiretroviral therapy; blood glucose regulation; cytokine; diabetes risk; efficacy testing; glucose disposal; glucose output; improved; insulin sensitivity; mRNA Expression; medical complication; mitochondrial dysfunction; prevent; programs; psychological distress; public health relevance; reconstitution; research study; subcutaneous

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.

描述（由申请人提供）： 项目摘要：高度有效的抗逆转录病毒药物大大延长了感染人类免疫缺陷病毒（HIV）的患者的寿命。但是，这些药物的使用与综合征的发展有关，该综合征包括脂肪分布，血脂异常和异常葡萄糖稳态的异常变化。这些异常增加了糖尿病和心血管疾病的风险。皮下脂蛋白是抗逆转录病毒的常见并发症。脂质是胰岛素抵抗和血脂异常的独立危险因素，并引起严重的心理困扰。提高皮下肥胖并扭转综合征的医学并发症的试验结果不同。胰岛素像生长因子-L（IGF-I）一样，会提高胰岛素敏感性，并且由于它可以防止细胞死亡，因此也可能减少脂肪组织的损失。这项研究的目的是测试重组IGF-I在治疗HIV相关脂肪营养不良综合征的疗效。具体目的是（1）确定重组IGF-I对HIV脂肪营养综合征患者皮下肥胖的影响； （2）确定IGF-I对脂质和葡萄糖稳态的影响； （3）检查IGF-1活性在介导综合征的脂肪分布变化和代谢问题中的作用。四十八名患者将以双掩盖的方式随机分为安慰剂或重组IGF-I。将在基线和治疗24周后评估患者。 24周后，将对所有患者进行主动治疗，直到第48周。评估包括测量葡萄糖，胰岛素和脂蛋白的血液样本； 0和24周的脂肪组织活检；使用双能X射线吸收仪和计算机断层扫描，在0、24周和48周时的身体组成评估。患者还将在第0周和第24周再次接受高胰岛素夹。将分析脂肪组织的细胞凋亡和线粒体毒性的变化。将进行体外实验，以表征抗逆转录病毒抑制IGF-I信号的正常活性以及这种脂肪细胞凋亡途径的相互关系。 公共卫生相关性：这项研究可能表明一种新的策略来治疗艾滋病毒护理中常见和困难的问题，该问题可能会在全球范围内增加。这项研究还可能增加我们对IGF-I激素在调节人脂肪组织的数量和生物学特性中的作用的理解。这可以帮助我们了解其他医疗状况，例如糖尿病和肥胖症。