FETAL GLUCOSE AND AMINO ACID DEPRIVATION

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Fetal growth restriction (FGR) from nutrient deprivation results in fetal metabolic adaptations including decreased insulin secretion and insulin sensitivity, and increased protein breakdown. These adaptations might limit fetal metabolic capacity to respond successfully to attempts at aggressive nutrient therapy. In this project, we will use our established FGR model of fetal glucose and insulin deficiency (with normoaminacidemia) from maternal hypoglycemia, and a new FGR model to be developed under Specific Aim #1 of maternal low-protein diet plus/minus hypoaminoacidemia (with normoglycemia), to test how well these FGR fetuses respond metabolically to increased nutrient supply. We will test 4 hypotheses: 1. rapid, high rates of glucose infusion into the FGR fetus will produce excessive hypoxemia, acidosis, and lactate production; 2. rapid, high rates of infusion of selected amino acids into the FGR fetus will produce less than expected rates of their metabolism; 3. slow introduction of glucose to the FGR fetus will normalize insulin secretion and insulin sensitivity, allowing increased glucose and amino acid metabolism; 4. slow introduction of amino acids to the FGR fetus will normalize insulin secretion and insulin sensitivity, allowing increased glucose and amino acid metabolism. 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. These will be the first studies to determine how amino acid supply to the fetus regulates fetal insulin secretion, and the first studies to define how reintroduction of previously deficient nutrients to the FGR fetus affects fetal metabolism, providing essential data to plan future clinical trials of nutrient therapy of human FGR.