FETAL GLUCOSE AND AMINO ACID DEPRIVATION

我们假设对胎儿的营养剥夺会导致胎儿 代谢适应，包括胰岛素分泌减少， 降低胰岛素敏感性，增加蛋白质分解，以及 这种代谢适应将胎儿的新陈代谢能力限制在 对积极的营养疗法的尝试做出成功的反应。我们 会用我们已建立的慢性病模型来验证这一假设吗？ 母体低血糖和一种新的母体低蛋白饮食 低氨基酸血症，以确定母体的慢性变化 营养底物浓度和对胎儿的供应导致胎儿 营养缺乏。实验将使用我们已建立的方法 底物和激素钳与菲克原理和示踪剂 量化胎儿营养底物进入、利用、 和氧化速率。我们还将测量体内胰岛素的分泌。 并在体外确定胰岛素可能的作用机制 分泌受到抑制，我们将对周围组织的葡萄糖进行量化 转运蛋白mRNA和蛋白的表达与蛋白定位 以确定导致胰岛素抵抗的机制。基座 在此信息上，我们还将测试这些长期的 营养缺乏的胎儿对营养增加的代谢反应 供应，假设：1.快速、高葡萄糖进入 进入营养匮乏的胎儿会产生过度的低氧血症， 酸中毒和乳酸的产生；2.快速、高进入率 选定的氨基酸将产生低于预期的其 代谢；3.缓慢进入葡萄糖会使胰岛素正常化。 分泌和胰岛素敏感性，允许增加血糖和 氨基酸代谢；4.氨基酸缓慢进入会 使胰岛素分泌和胰岛素敏感性正常化，允许 增加葡萄糖和氨基酸的代谢。这些将是 首次对胎儿进行研究以确定母亲如何通过低蛋白饮食 并且没有低氨基酸血症，并且单独和相互作用 葡萄糖缺乏，导致胎儿营养不足，并有可能 胎儿生长速度有限，首次研究确定其作用 胎儿的氨基酸供应在调节胎儿胰岛素分泌中的作用 和胰岛素的作用，以及第一个详细定义如何重新 将先前缺乏的营养引入到养分中 剥夺胎儿会影响胎儿新陈代谢，提供必要数据 计划未来人类胎儿营养疗法的临床试验 生长限制。

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.