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: 8145225
• 负责人: ROY J KIM
• 金额: $ 14.68万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145225
• 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; 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; High Density Lipoproteins; Homeostasis; Hormones; Human; Hypertriglyceridemia; In Vitro; Inflammation; Inflammatory; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Intervention; Label; 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; 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; glucose production; 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）： 项目概要：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（艾滋病毒）患者的生命。然而，这些药物的使用与由脂肪分布异常变化、血脂异常和葡萄糖稳态异常组成的综合征的发展相关。这些异常会增加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，并导致严重的心理困扰。增加皮下肥胖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-I（IGF-I）增加胰岛素敏感性，并且因为它防止细胞死亡，也可能减少脂肪组织的损失。本研究的目的是测试重组IGF-I在治疗HIV相关脂肪营养不良综合征中的疗效。具体目的是：（1）确定重组IGF-I对HIV脂肪代谢障碍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-I活性在介导脂肪分布变化和综合征代谢问题中的作用。48例患者将以双盲方式随机分配至安慰剂组或重组IGF-I组。将在基线和治疗24周后对患者进行评估。24周后，所有患者将接受积极治疗，直至第48周。评估包括血液样本以测量葡萄糖、胰岛素和脂蛋白;在0和24周时进行脂肪组织活检;以及在0、24周和48周时使用双能X射线吸收测定法和计算机断层扫描进行身体组成评估。患者还将在第0周和第24周再次接受高胰岛素钳夹。将分析脂肪组织的细胞凋亡和线粒体毒性变化。将进行体外实验以表征抗逆转录病毒药物如何抑制IGF-I信号传导的正常活性以及该途径与脂肪细胞凋亡的相互关系。 公共卫生关系：这项研究可能为治疗艾滋病毒护理中的一个常见和困难的问题提供一种新的策略，这种问题在全球范围内可能会增加。这项研究也可能增加我们对IGF-I激素在调节人体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其他疾病，如糖尿病和肥胖症。