FETAL EFFECTS OF INSULIN AND GLUCOSE DEPRIVATION

胰岛素和葡萄糖剥夺对胎儿的影响

• 批准号: 3842809
• 负责人: WILLIAM W HAY
• 金额: --
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3842809
• 关键词: aminoacid metabolism; bioenergetics; disease /disorder model; female; gel electrophoresis; gestational age; glucose metabolism; glucose transport; glycogenolysis; hormone regulation /control mechanism; hypoglycemia; insulin; insulin sensitivity /resistance; insulinlike growth factor; liver cells; liver metabolism; mother /embryo /fetus nutrition; northern blottings; nuclear runoff assay; nutrition related tag; pancreatectomy; pregnancy; prenatal growth disorder; sheep; streptozotocin

The goal of this project is to better understand physiologic mechanisms which permit the fetus to adapt to acute and chronic variations in this hormonal and metabolic milieu. The study will focus specifically on the supply of energy (glucose) and protein (amino acids) substrates. The proposed studies are in two forms: I. In vivo studies will use three fetal models (fetal hypoglycemia/hyperinsulinemia 20 to maternal insulin induced hypoglycemia; fetal hypoinsulinemia 20 to fetal pancreatectomy; fetal hypoinsulinemia 20 to fetal streptozotocin injection) and will test: a) maternal glucose and insulin sensitivity vs. maternal glucose utilization and production, b) fetal glucose and insulin sensitivity vs. fetal glucose utilization, c) fetal glucose and insulin sensitivity vs. fetal amino acid metabolism, and d) fetal glucose and insulin sensitivity vs. the sources and rates of fetal gluconeogenesis. II. In vitro studies will use tissues from animals studied in vivo to determine: a) the effects of fetal insulin and glucose on the expression of certain glucoregulatory genes (glycogen formation enzymes and glucose transporters); b) the effect of fetal glucose and insulin on hepatocellular gluconeogenesis and the expression of gluconeogenic enzymes, c) the relationship between fetal growth produced by glucose and/or insulin deficiency and fetal insulin-like growth factors I and II. Methodology will include measurement of net nutrient substrate flux to the fetus using the Fick principle, quantifications of substrate utilization in mother, placenta and fetus by radioactive and stable isotope tracer methods, assessment of substrate and hormone concentration effects on fetal metabolism using substrate and hormone "clamps", cell physiology techniques to study metabolism and enzyme expression in isolated hepatocytes, tissue analyses for enzyme contents and activities, cell and molecular chemistry techniques addressing the expression of glucoregulatory proteins and the relationship between insulin like growth factors I and II and hepatocellular metabolism in normal and growth retarded fetuses. Knowledge gained from this project will help our understanding about how nutrient and hormone deprivation to the fetus produce fetal growth retardation, how the growth retarded fetus behaves with respect to energy and protein metabolism, and how the fetus maintains its viability in the presence of reduced energy, protein, and anabolic hormone supply.

该项目的目标是更好地了解生理机制 这使得胎儿能够适应急性和慢性的变化 荷尔蒙和代谢环境。 该研究将特别关注 供应能量（葡萄糖）和蛋白质（氨基酸）底物。 拟议的研究有两种形式： I. 体内研究将使用三种 胎儿模型（胎儿低血糖/高胰岛素血症20至母体胰岛素 诱发低血糖；胎儿低胰岛素血症20至胎儿胰腺切除术； 胎儿低胰岛素血症20至胎儿链脲佐菌素注射）并将测试： a) 母体葡萄糖和胰岛素敏感性与母体葡萄糖的比较 利用和产生，b) 胎儿葡萄糖和胰岛素敏感性与胎儿葡萄糖和胰岛素敏感性对比 胎儿葡萄糖利用率，c) 胎儿葡萄糖和胰岛素敏感性对比 胎儿氨基酸代谢，以及 d) 胎儿葡萄糖和胰岛素敏感性 与胎儿糖异生的来源和速率。 二. 体外研究 将使用体内研究的动物组织来确定：a) 效果 胎儿胰岛素和葡萄糖对某些葡萄糖调节表达的影响 基因（糖原形成酶和葡萄糖转运蛋白）； b) 效果 胎儿葡萄糖和胰岛素对肝细胞糖异生的影响 糖异生酶的表达，c）胎儿之间的关系 葡萄糖和/或胰岛素缺乏和胎儿胰岛素样生长引起的生长 生长因子 I 和 II。 方法将包括测量净营养底物通量 胎儿使用菲克原理，定量底物利用率 放射性和稳定同位素示踪剂对母亲、胎盘和胎儿的影响 方法，评估底物和激素浓度对胎儿的影响 使用底物和激素“钳”进行新陈代谢，细胞生理学技术 研究离体肝细胞、组织的代谢和酶表达 酶含量和活性、细胞和分子化学分析 解决葡萄糖调节蛋白表达的技术和 胰岛素样生长因子I和II之间的关系 正常和生长迟缓胎儿的肝细胞代谢。 从这个项目中获得的知识将有助于我们理解如何 胎儿的营养和激素剥夺会导致胎儿生长 发育迟缓，生长迟缓的胎儿在能量方面的表现 和蛋白质代谢，以及胎儿如何在体内维持其活力 能量、蛋白质和合成代谢激素供应减少。