FETAL GLUCOSE AND AMINO ACID DEPRIVATION

我们假设胎儿缺乏营养会导致胎儿 代谢适应，包括胰岛素分泌减少， 胰岛素敏感性降低，蛋白质分解增加， 这种代谢适应限制了胎儿的代谢能力， 对积极的营养治疗有成功的反应。 我们 将使用我们建立的慢性疾病模型来验证这一假设。 产妇低血糖症，以及产妇低蛋白饮食加 低氨基酸血症，以确定如何在孕产妇慢性变化 营养底物浓度和胎儿的供应导致胎儿 营养缺乏 实验将使用我们建立的方法， 底物和激素钳和Fick原理及示踪剂 测量以量化胎儿营养基质进入，利用， 和氧化速率。 我们还将测量体内胰岛素分泌 并在体外确定胰岛素 分泌受到抑制，我们将定量外周组织葡萄糖 转运蛋白mRNA和蛋白表达及蛋白定位 以确定胰岛素抵抗的机制。 基于 根据这些信息，我们还将测试这些长期 营养缺乏的胎儿对增加的营养 供应，假设：1。 葡萄糖快速、高速率进入 进入营养缺乏的胎儿会产生过多的低氧血症， 酸中毒和乳酸产生; 2. 快速、高的入境率 选择的氨基酸将产生低于预期的速率， 代谢; 3. 葡萄糖缓慢进入将使胰岛素正常化 分泌和胰岛素敏感性，允许增加葡萄糖和 氨基酸代谢; 4. 氨基酸的缓慢进入将 使胰岛素分泌和胰岛素敏感性正常化， 增加葡萄糖和氨基酸代谢。 这将是 第一次胎儿研究，以确定如何产妇低蛋白饮食与 和无低氨基酸血症，单独和相互作用， 葡萄糖缺乏，导致胎儿营养不足，并可能 胎儿生长速度有限，第一次研究，以确定作用 氨基酸供应对胎儿胰岛素分泌的调节 和胰岛素的作用，以及第一个研究，以详细定义如何重新- 将以前缺乏的营养素引入营养素 剥夺胎儿将影响胎儿的代谢，提供必要的数据 计划未来人类胎儿营养治疗的临床试验 增长限制。

We hypothesize that nutrient deprivation to the fetus results in fetal metabolic adaptations, including decreased insulin secretion, decreased insulin sensitivity, and increased protein breakdown, and that such metabolic adaptations limit fetal metabolic capacity to respond successfully to attempts at aggressive nutrient therapy. We will rest this hypothesis using our established model of chronic maternal hypoglycemia, and a new of maternal low-protein diet plus hypoaminoacidemia, to determine how chronic changes in maternal nutrient substrate concentrations and supply to the fetus lead to fetal nutrient deficit. Experiments will use our established methods of substrate and hormone clamps and Fick principle and tracer measurements to quantify fetal nutrient substrate entry, utilization, and oxidation rates. We also will measure insulin secretion in vivo and in vitro to determine possible mechanisms by which insulin secretion is inhibited, and we will quantify peripheral tissue glucose transporter mRNA and protein expression and protein localization to determine mechanisms that account for insulin resistance. Based on this information, we also will test how well these chronically nutrient deprived fetuses respond metabolically to increased nutrient supply, hypothesizing that: 1. rapid, high rates of glucose entry into the nutrient deprived fetus will produce excessive hypoxemia, acidosis, and lactate production; 2. rapid, high rates of entry of selected amino acids will produce a less than expected rate of their metabolism; 3. slow entry of glucose will normalize insulin secretion and insulin sensitivity, allowing increased glucose and amino acid metabolism; 4. slow entry of amino acids will normalize insulin secretion and insulin sensitivity, allowing increased glucose and amino acid metabolism. These will be the first fetal studies to determine how maternal low protein diet with and without hypoaminoacidemia, and alone and interactively with glucose deficit, leads to fetal nutrient deficit and potentially to limited rates of fetal growth, the first studies to determine the role of amino acid supply to the fetus in regulating fetal insulin secretion and insulin action, and the first studies to define in detail how re- introduction of previously deficient nutrients to the nutrient deprived fetus will affect fetal metabolism, providing essential data to plan future clinical trials of nutrient therapy of human fetal growth restriction.