Growth Hormone Releasing Hormone in Patients with HIV Lipodystrophy

HIV 脂肪营养不良患者的生长激素释放激素

• 批准号: 7642388
• 负责人: Takara Leah Stanley
• 金额: $ 5.67万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7642388
• 关键词: Abdomen; Address; Adipose tissue; Adverse effects; Affect; Alteplase; Area; Atherosclerosis; Body Composition; C-reactive protein; Cardiovascular system; Chronic Disease; DEXA; Data; Dose; Double-Blind Method; Dyslipidemias; Fatty acid glycerol esters; Feedback; Frequencies; General Population; HIV; HIV therapy; Health; Height; Hepatic; Inflammation; Insulin Resistance; Insulin-Like Growth Factor I; Investigation; Left; Life; Lipids; Lipodystrophy; Long-Term Effects; Magnetic Resonance Spectroscopy; Measures; Medial; Mediating; Metabolic; Morbidity - disease rate; OGTT; Obesity; Outcome; Patients; Phase III Clinical Trials; Physiologic pulse; Physiological; Placebos; Plasminogen Activator Inhibitor 1; Population; Proteins; Public Health; Randomized; Research; Sampling; Serum; Serum Markers; Somatotropin; Somatotropin-Releasing Hormone; Thick; Visceral; adiponectin; cardiovascular risk factor; design; hormone therapy; improved; inflammatory marker; insulin sensitivity; novel; prevent; public health relevance; subcutaneous; therapy duration; treatment duration; treatment effect

DESCRIPTION (provided by applicant): As HIV has evolved into a chronic disease, HIV-associated fat redistribution, or HIV lipodystrophy, has become a significant morbidity. Patients with HIV lipodystrophy have reduced growth hormone (GH) secretion, and GH therapy improves body composition in this population. Subcutaneous GH treatment does not mimic physiologic GH secretion, however, and consistently high levels of GH rather than pulsatile release may contribute to the side effects of GH therapy. Growth hormone releasing hormone (GHRH) is a novel therapy with potential to reduce visceral fat and improve markers of cardiovascular risk. GHRH augments endogenous pulsatile GH secretion and preserves negative feedback on somatotrophs by IGF-1. It may,therefore, be a more physiologically appropriate treatment for patients with HIV and fat redistribution. The first aim of this proposal is to compare the effects of GH and GHRH on GH pulsatility and insulin sensitivity. Twenty-five patients with HIV will receive either GH or GHRH daily for one week, followed by a one week observation period. At weeks 0, 1, and 2, patients will have frequent sampling to assess GH pulse dynamics, and insulin sensitivity will be measured using euglycemic hyperinsulinemic clamp. The hypothesis is that GHRH will augment GH pulse height and preserve pulse frequency, while GH will suppress GH pulsatility. Because of this difference, GH will cause greater insulin resistance than GHRH. The second aim is to investigate the long term effects of GHRH on body composition and cardiovascular health. Six months of GHRH therapy has been shown to reduce visceral fat by 15% in this population, but it is not known if this benefit will persist with longer duration of therapy. Further, the effect of GHRH on markers of cardiovascular risk is not well-characterized. In the proposed research, patients will be randomized to receive GHRH or placebo for 12 months. Endpoints will include changes in GH pulse dynamics, insulin sensitivity, intramyocellular lipid and hepatic fat using MR spectroscopy, carotid intimal medial thickness (CIMT), and inflammatory markers (adiponectin, C-reactive protein, tissue plasminogen activator, and plasminogen activator inhibitor-1). The hypothesis is that long-term GHRH therapy will improve body composition and cardiovascular health without adversely affecting insulin sensitivity. Public Health Relevance: This research will benefit public health in two important ways. First, GHRH is potentially an improved therapy for HIV-associated fat redistribution, and investigation of its use will benefit the growing number of patients with this condition. Second, understanding the mechanisms and metabolic consequences of this novel form of acquired lipodystrophy is relevant to treating obesity in the general population.

描述（由申请人提供）：随着艾滋病毒已演变成一种慢性疾病，艾滋病毒相关的脂肪重新分布或艾滋病毒脂肪营养不良已成为一种重要的发病率。患有 HIV 脂肪营养不良的患者生长激素 (GH) 分泌减少，GH 治疗可改善该人群的身体成分。然而，皮下 GH 治疗并不模仿生理 GH 分泌，持续高水平的 GH 而不是脉冲式释放可能会导致 GH 治疗的副作用。生长激素释放激素（GHRH）是一种新型疗法，有可能减少内脏脂肪并改善心血管风险标志物。 GHRH 增强内源性脉动 GH 分泌，并通过 IGF-1 保留对生长激素的负反馈。因此，对于艾滋病毒和脂肪重新分布的患者来说，这可能是一种生理上更合适的治疗方法。该提案的首要目的是比较 GH 和 GHRH 对 GH 脉动和胰岛素敏感性的影响。 25 名 HIV 感染者将在一周内每天接受 GH 或 GHRH，然后进行为期一周的观察期。在第 0、1 和 2 周，患者将频繁采样以评估 GH 脉冲动态，并使用正常血糖高胰岛素钳夹测量胰岛素敏感性。假设 GHRH 将增加 GH 脉冲高度并保持脉冲频率，而 GH 将抑制 GH 脉动。由于这种差异，GH 会比 GHRH 引起更大的胰岛素抵抗。第二个目标是研究 GHRH 对身体成分和心血管健康的长期影响。六个月的 GHRH 治疗已被证明可以使该人群的内脏脂肪减少 15%，但尚不清楚这种益处是否会随着治疗持续时间的延长而持续。此外，GHRH 对心血管风险标志物的影响尚不明确。在拟议的研究中，患者将被随机分配接受 GHRH 或安慰剂治疗 12 个月。终点将包括 GH 脉冲动态、胰岛素敏感性、肌细胞内脂质和肝脂肪（使用 MR 波谱）、颈动脉内膜中层厚度 (CIMT) 和炎症标志物（脂联素、C 反应蛋白、组织纤溶酶原激活剂和纤溶酶原激活剂抑制剂-1）的变化。假设长期 GHRH 治疗将改善身体成分和心血管健康，而不会对胰岛素敏感性产生不利影响。 公共健康相关性：这项研究将以两个重要方式有益于公共健康。首先，GHRH 可能是治疗 HIV 相关脂肪重新分布的一种改进疗法，对其使用的研究将使越来越多的患有这种疾病的患者受益。其次，了解这种新型获得性脂肪营养不良的机制和代谢后果与治疗普通人群的肥胖有关。