Physiological Importance of Growth Hormone Pulsatility

生长激素脉动的生理重要性

• 批准号: 6854525
• 负责人: CRAIG A JAFFE
• 金额: $ 41.67万
• 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/6854525
• 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中进行了仔细研究。来自啮齿类动物的大量数据表明，脉动型和连续型生长激素对内分泌和代谢的影响非常不同。相比之下，目前人类临床使用的生长激素是经验性的，并不能再现生长激素释放的正常搏动模式。儿童和成人对生长激素替代的次优反应可能与每日皮下注射生长激素获得的非生理性生长激素谱有关。我们之前已经表明，人类的生长激素分泌具有性别特异性，女性在一天中更持续地暴露于生长激素。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CYP3A4活性可以通过女性（连续）或男性（搏动）GH管理增加或降低。我们假设搏动和连续生长激素模式对人类肝脏和其他外周组织有不同的影响。我们预测连续生长激素会增加CYP3A4的活性和肝脏IGF-I的表达，而脉动生长激素会更有效地增加肌肉IGF-I、肌肉蛋白合成、脂肪酸氧化和骨转换。我们将通过对15名男性和15名女性GH缺乏症患者以两种不同的方式静脉注射GH来验证这一假设。受试者将被纳入GCRC三次，为期7天的对照或GH治疗。在第一次（对照组）入院时，他们将接受静脉注射D5W（对照组）。第二次和第三次入院的顺序将随机分配，接受静脉GH连续输注或每6小时注射6次，每次20分钟。全身脂肪酸和氨基酸配置将通过静脉输注[13C]-棕榈酸酯和[2H3]-柳氨酸来测量。将进行经皮穿刺肌肉活检，并测量GF-I mRNA和蛋白以及[2H3]-亮氨酸掺入量。每种治疗对肝脏的影响将通过血清igf - 1、红霉素呼气试验（CYP3A4）和脂蛋白的测量来确定。对骨的影响将通过骨形成和吸收的标志物来评估。STAT作为生长激素脉冲依赖性效应的中介的作用将通过量化肌肉磷酸化STAT5来研究。将评估胰岛素敏感性。这项研究的结果将增加我们对生长激素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生长激素替代疗法。