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.
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