FETAL EFFECTS OF INSULIN AND GLUCOSE DEPRIVATION

这个项目的目标是更好地了解生理机制 这使得胎儿能够适应这种急性和慢性变化， 激素和代谢环境。 这项研究将特别侧重于 供应能量（葡萄糖）和蛋白质（氨基酸）底物。 建议的研究有两种形式：一。 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 诱导性低血糖;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 利用和生产，B）胎儿葡萄糖和胰岛素敏感性与 胎儿葡萄糖利用，c）胎儿葡萄糖和胰岛素敏感性与 胎儿氨基酸代谢，和d）胎儿葡萄糖和胰岛素敏感性 vs.胎儿畸形的来源和发生率。 二. 体外研究 将使用来自体内研究的动物的组织来确定： 胎儿胰岛素和葡萄糖对某些葡萄糖调节因子表达的影响 基因（糖原形成酶和葡萄糖转运蛋白）; B）影响 胎儿葡萄糖和胰岛素对肝细胞增生的影响 c）胎儿与胎儿发育的关系， 由葡萄糖和/或胰岛素缺乏和胎儿胰岛素样产生的生长 生长因子I和II。 方法将包括测量净养分基质通量的 胎儿使用菲克原则，定量的底物利用， 放射性和稳定同位素示踪母体、胎盘和胎儿 方法，评估底物和激素浓度对胎儿的影响 代谢使用底物和激素“钳”，细胞生理学技术 研究离体肝细胞、组织中的代谢和酶表达， 酶含量和活性分析、细胞和分子化学分析 解决糖调节蛋白的表达和糖代谢的技术 胰岛素样生长因子I和II与 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了解 营养素和激素的剥夺对胎儿产生胎儿生长 发育迟缓，发育迟缓的胎儿在能量方面的表现如何 蛋白质代谢，以及胎儿如何保持其生存能力， 能量、蛋白质和合成代谢激素供应减少。

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.