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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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导致糖异生衍生的葡萄糖部分减少，反之，糖原分解和胰岛素敏感性将增加。我们预计，重组人生长激素治疗不会影响总葡萄糖的产生。因此，接受重组生长激素治疗8周的GDH受试者将会有来自糖异生的葡萄糖部分增加，糖原分解的部分减少，胰岛素敏感性降低。为了验证这一假设，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。我们将专门测量隔夜禁食后葡萄糖生成、糖异生、糖原分解、胰岛素敏感性和胰升糖素反应的速率。此外，我们将使用稳定同位素[15N]尿素、[1-13C]亮氨酸以及游离脂肪酸和b-羟基丁酸酯浓度来测量蛋白质氧化、蛋白质分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。 未经治疗的GHD儿童在吸收后状态下，与健康儿童相比，来自糖异生的葡萄糖部分减少，而来自糖原分解的葡萄糖部分增加。重组人生长激素H2治疗不会改变糖代谢，但会使GHD儿童糖异生和糖原分解的异常分配恢复正常。H3-GH替代将减少尿素的产生，增加蛋白质合成的估计，从而优化生长所需的氨基酸的可获得性。H4--未经治疗的GHD儿童在隔夜禁食后将有更高的胰高血糖素挑战反应，该反应将在接受rhGH治疗8周后下降。 在健康和新诊断的GHD儿童中，我们将： 1.测定葡萄糖生成率(GPR)2.测定糖异生和糖原分解所得葡萄糖的比例3.测定胰岛素敏感性4.测定蛋白分解和蛋白质氧化5.测定隔夜禁食后高血糖素刺激反应。 在生长激素治疗8周后，对GHD患儿的上述指标进行重新评估。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. 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. 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.