Physiological Importance of Growth Hormone Pulsatility

生长激素脉动的生理重要性

• 批准号: 7017736
• 负责人: CRAIG A JAFFE
• 金额: $ 41.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7017736
• 关键词: SDS polyacrylamide gel electrophoresis; bioperiodicity; biopsy; bone development; bone metabolism; breath tests; clinical research; colorimetry; cytochromes; endocrine disorder; enzyme linked immunosorbent assay; fatty acid metabolism; gas chromatography mass spectrometry; gender difference; gene expression; hormone biosynthesis; hormone metabolism; human subject; injection /infusion; insulin sensitivity /resistance; insulinlike growth factor; liver function; muscle function; polymerase chain reaction; somatotropin; western blottings

DESCRIPTION (provided by applicant): The role of GH pulse pattern has been carefully studied in animals. Extensive data from rodents demonstrate that pulsatile and continuous GH profiles have very different endocrine and metabolic effects. In contrast, the present clinical use of GH in humans is empiric and does not reproduce the normal pulsatile pattern of GH release. Suboptimal responses to GH replacement in children and adults might relate to non-physiological GH profiles obtained by daily subcutaneous GH injections. We have previously shown that GH secretion in humans is gender-specific, with woman having more continuous exposure to GH throughout the day. Moreover, we have demonstrated that woman have higher hepatic CYP3A4 activity than do men and that CYP3A4 activity can be increased or decreased by female (continuous) or male (pulsatile) GH administration. We hypothesize that pulsatile and continuous GH patterns have differential effects on the liver and other peripheral tissues in humans. We predict that continuous GH will increase the activity of CYP3A4 and the expression of hepatic IGF-I whereas the pulsatile GH will more effectively increase muscle IGF-I, muscle protein synthesis, fatty acid oxidation and bone turnover. We will test this hypothesis by administering GH intravenously (iv.) in two different patterns to 15 men and 15 women with GH deficiency. Subjects will be admitted to the GCRC three times for 7 days of control or GH treatment. During the first (control) admission, they will receive an iv. infusion of D5W (control). The order of the second and third admissions will be randomized to receive either iv. GH as a continuous infusion or as 6 boluses given over 20 min every 6 h. Whole body fatty acid and amino acid disposition will be measured using iv infusions of [13C]-palmitate and [2H3]-Ieucine. Percutaneous needle muscle biopsies will be performed and ]GF-I mRNA and protein and [2H3]-Ieucine incorporation measured. The effect of each treatment on the liver will determined using measurements of serum IGF-I, erythromycin breath test (CYP3A4) and lipoproteins. The effects on bone will be assessed using markers of bone formation and resorption. A role for STAT as a mediator of pulse-dependent effects of GH will be investigated by quantifying muscle phosphorylated STAT5. Insulin sensitivity will be assessed. The results of this study will add to our understanding of the physiology and pathophysiology of GH action and will help in designing more effective means of GH replacement therapy.

描述（由申请人提供）：GH 脉冲模式的作用已在动物身上进行了仔细研究。来自啮齿动物的大量数据表明，脉冲式和连续式 GH 曲线具有截然不同的内分泌和代谢作用。相比之下，目前 GH 在人类中的临床使用是经验性的，不能重现 GH 释放的正常脉动模式。儿童和成人对 GH 替代的反应欠佳可能与每日皮下 GH 注射获得的非生理 GH 谱有关。我们之前已经表明，人类的 GH 分泌具有性别特异性，女性全天更连续地接触 GH。此外，我们已经证明，女性比男性具有更高的肝脏 CYP3A4 活性，并且女性（连续）或男性（脉冲）GH 给药可以增加或减少 CYP3A4 活性。我们假设脉动和连续 GH 模式对人类的肝脏和其他外周组织有不同的影响。我们预测，连续 GH 将增加 CYP3A4 的活性和肝脏 IGF-I 的表达，而脉冲 GH 将更有效地增加肌肉 IGF-I、肌肉蛋白质合成、脂肪酸氧化和骨转换。我们将通过以两种不同的方式向患有 GH 缺乏症的 15 名男性和 15 名女性静脉注射 GH 来检验这一假设。受试者将三次进入 GCRC 进行 7 天的对照或 GH 治疗。在第一次（对照）入院期间，他们将接受静脉注射。输注 D5W（对照）。第二次和第三次入院的顺序将随机分配以接受 iv 治疗。 GH 连续输注或每 6 小时 20 分钟内推注 6 次。将使用静脉输注[13C]-棕榈酸酯和[2H3]-亮氨酸来测量全身脂肪酸和氨基酸分布。将进行经皮针肌肉活检并测量]GF-1 mRNA和蛋白质以及[2H3]-亮氨酸掺入。每种治疗对肝脏的影响将通过血清 IGF-I、红霉素呼气试验 (CYP3A4) 和脂蛋白的测量来确定。将使用骨形成和吸收的标记物来评估对骨的影响。将通过量化肌肉磷酸化 STAT5 来研究 STAT 作为 GH 脉冲依赖性效应调节剂的作用。将评估胰岛素敏感性。这项研究的结果将增进我们对 GH 作用的生理学和病理生理学的理解，并将有助于设计更有效的 GH 替代疗法。