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相关的脂肪再分配或HIV脂肪营养不良已成为一种重要的发病率。HIV脂肪营养不良患者的生长激素（GH）分泌减少，GH治疗可改善该人群的身体成分。然而，皮下生长激素治疗不能模拟生理性生长激素分泌，持续高水平的生长激素而不是搏动释放可能会导致生长激素治疗的副作用。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增强内源性搏动GH分泌，并保留IGF-1对生长因子的负反馈。因此，对于患有HIV和脂肪再分配的患者来说，这可能是一种生理上更合适的治疗方法。本研究的第一个目的是比较GH和GHRH对GH搏动性和胰岛素敏感性的影响。25名HIV患者将在一周内每天接受GH或GHRH治疗，随后是一周的观察期。在第0、1和2周，患者将频繁取样以评估GH脉搏动态，并使用正糖高胰岛素钳测量胰岛素敏感性。假设GHRH会增加GH脉冲高度并保持脉冲频率，而GH会抑制GH脉动。由于这种差异，GH会比GHRH引起更大的胰岛素抵抗。第二个目的是研究GHRH对身体成分和心血管健康的长期影响。六个月的GHRH治疗已被证明可使这一人群的内脏脂肪减少15%，但不知道这种益处是否会随着治疗时间的延长而持续下去。此外，GHRH对心血管风险标志物的影响尚未得到很好的表征。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、细胞内脂质和肝脂肪的变化（使用磁共振光谱）、颈动脉内膜中间厚度（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）。假设是，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。

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.