EFFECTS OF GROWTH HORMONE THERAPY ON GLUCOSE AND PROTEIN METABOLISM IN CHILDR

生长激素治疗对儿童葡萄糖和蛋白质代谢的影响

• 批准号: 8356661
• 负责人: LUISA M RODRIGUEZ
• 金额: $ 0.16万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356661
• 关键词: Amino Acids; Child; Clinical Research; Diagnosis; Funding; Glucagon; Gluconeogenesis; Glucose; Grant; Growth; Hydroxybutyrates; Hypoglycemia; Isotopes; Leucine; Measures; National Center for Research Resources; Newly Diagnosed; Nonesterified Fatty Acids; Principal Investigator; Production; Protein Biosynthesis; Proteins; Proteolysis; Research; Research Infrastructure; Resources; Risk; Somatotropin; Source; Testing; Time; United States National Institutes of Health; Urea; cost; glucose metabolism; glucose production; glycogenolysis; growth hormone deficiency; hormone therapy; infancy; insulin sensitivity; lipid metabolism; oxidation; protein metabolism; r-hGH-M; response; stable isotope

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Children with growth hormone deficiency (GHD) have increased insulin sensitivity and may present with hypoglycemia during infancy. Treatment with recombinant human growth hormone (rhGH) reduces the risk for hypoglycemia and decreases insulin sensitivity. We hypothesize, that GHD causes a decrease in the fraction of glucose derived form gluconeogenesis and conversely glycogenolysis and insulin sensitivity will be increased, when GHD children are compared to healthy controls. We anticipate that total glucose production will be unaffected by rhGH therapy. Therefore, the GDH subjects treated with rhGH for 8 weeks will have an increase in the fraction of glucose derived form gluconeogenesis and a decrease in that form glycogenolysis and decreased insulin sensitivity. To test this hypothesis, 10 healthy and 10 GHD children will be studied using the stable isotope [U-13C] glucose and Mass Isotopes Distribution Analysis (MIDA). We will be specifically measuring the rate of glucose production, gluconeogenesis, glycogenolysis, insulin sensitivity and glucagon response after an overnight fast. In addition, we will measure changes in protein oxidation, proteolysis and fat metabolism using the stable isotopes [15N2] urea, [1-13C] leucine and concentrations of free fatty acids and b-hydroxybutyrate. The GHD group will be studied at the time of diagnosis and after 8 weeks of rhGH. HYPOTHESIS H1- The fraction of glucose derived from gluconeogenesis is decreased and that from glycogenolysis is increased in the post-absorptive state in untreated GHD children when compared to healthy children. H2- Treatment with rhGH will not change the overall glucose turnover but will normalize the abnormal partitioning of gluconeogenesis and glycogenolysis in GHD children. H3- GH replacement will reduce urea production and increase estimates of protein synthesis, thus optimizing the availability of amino acids for growth. H4-Untreated children with GHD after an overnight fast will have an increased glucagon challenge response that will decrease after 8 weeks of treatment with rhGH. SPECIFIC AIMS In healthy and newly diagnosed GHD children we will: 1. Measure the Glucose Production Rate (GPR) 2. Determine the fraction of glucose derived from gluconeogenesis and glycogenolysis 3. Estimate insulin sensitivity 4. Measure proteolysis and protein oxidation 5. Determine glucagon challenge response after an overnight fast. The above-mentioned parameters will be re-evaluated in the children with GHD after 8 weeks of rhGH therapy.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 摘要 患有生长激素缺乏症（GHD）的儿童胰岛素敏感性增加，并可能在婴儿期出现低血糖。重组人生长激素（rhGH）治疗可降低低血糖风险，降低胰岛素敏感性。 我们假设，当GHD儿童与健康对照组相比时，GHD导致来自血管生成的葡萄糖分数减少，相反糖原分解和胰岛素敏感性将增加。 我们预计总葡萄糖产量将不受rhGH治疗的影响。因此，用rhGH治疗8周的GDH受试者将具有源自糖原异生的葡萄糖分数的增加和糖原分解形式的减少以及胰岛素敏感性降低。为了检验这一假设，将使用稳定同位素[U-13 C]葡萄糖和质量同位素分布分析（MIDA）对10名健康儿童和10名GHD儿童进行研究。 我们将专门测量过夜禁食后的葡萄糖生成率、糖原生成率、糖原分解率、胰岛素敏感性和胰高血糖素反应率。此外，我们将使用稳定同位素[15 N2]尿素、[1- 13 C]亮氨酸以及游离脂肪酸和b-羟基丁酸盐的浓度来测量蛋白质氧化、蛋白质水解和脂肪代谢的变化。GHD组将在诊断时和rhGH治疗8周后进行研究。 假设 H1-与健康儿童相比，在未治疗的GHD儿童中，吸收后状态下来自糖原生成的葡萄糖分数减少，来自糖原分解的葡萄糖分数增加。 H2-rhGH治疗不会改变GHD儿童的总体葡萄糖周转，但会使GHD儿童的糖原生成和糖原分解的异常分配正常化。 H3- GH替代将减少尿素产生并增加蛋白质合成的估计，从而优化生长所需氨基酸的可用性。 H4-未经治疗的GHD儿童在过夜禁食后将具有增加的胰高血糖素激发反应，该反应将在用rhGH治疗8周后降低。 具体目标 对于健康和新诊断的GHD儿童，我们将： 1.测量葡萄糖生成速率（GPR） 2.测定来自糖原生成和糖原分解的葡萄糖分数 3.估计胰岛素敏感性 4.测量蛋白质水解和蛋白质氧化 5.测定空腹过夜后胰高血糖素激发反应。 在治疗8周后，对GHD患儿的上述指标进行重新评估。