Physiological Importance of Growth Hormone Pulsatility

生长激素脉动的生理重要性

• 批准号: 7185148
• 负责人: CRAIG A JAFFE
• 金额: $ 42.09万
• 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/7185148
• 关键词: Acromegaly; Acute; Admission activity; Adult; Adverse effects; Affect; Age; Amino Acids; Animals; Biopsy; Blood; Bolus Infusion; Bone and Cartilage Funding; Breath Tests; CYP3A4 gene; Cartilage; Child; Clinical; Clinical Data; Continuous Infusion; Daily; Data; Endocrine; Enzymes; Erythromycin; Exposure to; Fatty Acids; Fatty acid glycerol esters; Female; Functional disorder; Gender; Growth; Hepatic; Hormone replacement therapy; Human; Hypopituitarism; Infusion procedures; Injection of therapeutic agent; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Investigation; Lipoprotein (a); Lipoproteins; Liver; Measurement; Measures; Mediator of activation protein; Messenger RNA; Metabolic; Methods; Muscle; Muscle Proteins; Needles; Nonesterified Fatty Acids; Osteogenesis; Palmitates; Patients; Pattern; Peripheral; Phosphorylation; Physiologic pulse; Physiological; Physiology; Production; Protein Biosynthesis; Proteins; Protocols documentation; Pulse taking; Randomized; Range; Rate; Rattus; Regulation; Relative (related person); Research Personnel; Rodent; Role; Running; STAT5A gene; Sampling; Serum; Somatotropin; Testing; Time; Tissue-Specific Gene Expression; Tissues; Western Blotting; Woman; base; bone; bone turnover; day; design; enzyme activity; fatty acid metabolism; fatty acid oxidation; glucose metabolism; growth hormone deficiency; improved; insulin sensitivity; intravenous glucose tolerance test; lipid metabolism; male; men; programs; research study; response; subcutaneous; uptake

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（由申请方提供）：已在动物中仔细研究了GH脉冲模式的作用。来自啮齿动物的大量数据表明，脉动和连续GH曲线具有非常不同的内分泌和代谢效应。相比之下，目前GH在人体中的临床应用是经验性的，不能再现GH释放的正常脉冲模式。儿童和成人对GH替代的次优反应可能与每日皮下注射GH获得的非生理性GH特征有关。我们以前已经表明，人类的生长激素分泌是性别特异性的，女性在一天中更连续地暴露于生长激素。此外，我们已经证明女性的肝脏CYP 3A 4活性高于男性，并且女性（连续）或男性（脉冲式）GH给药可以增加或降低CYP 3A 4活性。我们推测，脉冲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GH将增加CYP 3A 4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。我们将通过静脉注射GH（iv.）以两种不同的模式对15名男性和15名女性GH缺乏症患者进行研究。受试者将进入GCRC三次，接受为期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D5 W（对照）。第二次和第三次入院的顺序将随机接受静脉注射。GH连续输注或每6小时在20分钟内给予6次推注。将使用[13 C]-棕榈酸和[2 H3]-亮氨酸的静脉输注测量全身脂肪酸和氨基酸分布。将进行经皮针肌肉活组织检查，并测量[2 H3]-亮氨酸掺入。将使用血清IGF-I、红霉素呼气试验（CYP 3A 4）和脂蛋白的测量值确定每种治疗对肝脏的影响。将使用骨形成和再吸收标志物评估对骨的影响。将通过定量肌肉磷酸化STAT 5来研究STAT作为GH脉冲依赖性效应的介体的作用。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和病理生理的理解，并将有助于设计更有效的生长激素替代疗法。