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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且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。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 抽象的 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并降低胰岛素敏感性。 我们假设，当 GHD 儿童与健康对照相比时，GHD 会导致糖异生产生的葡萄糖比例减少，相反，糖原分解和胰岛素敏感性会增加。 我们预计总葡萄糖产量不会受到 rhGH 治疗的影响。因此，用rhGH治疗8周的GDH受试者将具有来自糖异生的葡萄糖部分的增加和来自糖原分解的部分的减少以及胰岛素敏感性的降低。为了检验这一假设，我们将使用稳定同位素 [U-13C] 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。 我们将专门测量禁食过夜后葡萄糖产生、糖异生、糖原分解、胰岛素敏感性和胰高血糖素反应的速率。此外，我们将使用稳定同位素[15N2]尿素、[1-13C]亮氨酸以及游离脂肪酸和b-羟基丁酸的浓度来测量蛋白质氧化、蛋白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，未经治疗的 GHD 儿童在吸收后状态下来自糖异生的葡萄糖分数减少，来自糖原分解的葡萄糖分数增加。 H2-rhGH 治疗不会改变总体葡萄糖周转率，但会使 GHD 儿童糖异生和糖原分解的异常分配正常化。 H3- GH 替代将减少尿素产量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 儿童在禁食一夜后，胰高血糖素激发反应会增加，而在使用 rhGH 治疗 8 周后，胰高血糖素激发反应会减弱。 具体目标 对于健康和新诊断的 GHD 儿童，我们将： 1. 测量葡萄糖生产率 (GPR) 2. 确定来自糖异生和糖原分解的葡萄糖分数 3. 估计胰岛素敏感性 4. 测量蛋白水解和蛋白质氧化 5. 确定禁食过夜后的胰高血糖素激发反应。 患有GHD的儿童在rhGH治疗8周后将重新评估上述参数。