Growth Hormone Releasing Hormone in Patients with HIV Lipodystrophy

描述（由申请人提供）：由于HIV已演变为一种慢性疾病，HIV相关的脂肪再分布或HIV脂肪营养不良已成为一种重要的发病率。HIV脂肪营养不良患者生长激素（GH）分泌减少，GH治疗可改善这一人群的身体组成。然而，皮下GH治疗不能模拟生理GH分泌，并且持续高水平的GH而不是脉冲释放可能导致GH治疗的副作用。生长激素释放激素（GHRH）是一种新的治疗方法，具有减少内脏脂肪和改善心血管风险标志物的潜力。GHRH增强内源性脉冲GH分泌，并通过IGF-1保持对生长激素的负反馈。因此，它可能是一种更适合HIV和脂肪再分布患者的生理治疗方法。该建议的第一个目的是比较GH和GHRH对GH脉动性和胰岛素敏感性的影响。25名HIV患者将每天接受GH或GHRH治疗一周，随后是一周的观察期。在第0、1和2周，将对患者进行频繁采样以评估GH脉冲动力学，并使用正常血糖高胰岛素钳夹法测量胰岛素敏感性。假设GHRH将增加GH脉冲高度并保持脉冲频率，而GH将抑制GH脉动性。由于这种差异，GH将导致比GHRH更大的胰岛素抵抗。第二个目的是研究GHRH对身体成分和心血管健康的长期影响。在这一人群中，6个月的GHRH治疗已被证明可减少15%的内脏脂肪，但尚不清楚这种益处是否会随着治疗时间的延长而持续。此外，GHRH对心血管风险标志物的影响尚未得到充分表征。在拟议的研究中，患者将随机接受GHRH或安慰剂治疗12个月。终点将包括GH脉冲动力学、胰岛素敏感性、使用MR波谱的肌细胞内脂质和肝脂肪、颈动脉内膜中层厚度（CIMT）和炎症标志物（脂联素、C反应蛋白、组织纤溶酶原激活物和纤溶酶原激活物抑制剂-1）的变化。假设长期GHRH治疗将改善身体组成和心血管健康，而不会对胰岛素敏感性产生不利影响。 公共卫生相关性：这项研究将在两个重要方面有益于公共卫生。首先，GHRH可能是一种改善HIV相关脂肪再分布的疗法，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，了解这种新形式的获得性脂肪代谢障碍的机制和代谢后果与治疗普通人群中的肥胖症有关。

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.