Fetal Glucose and Amino Acid Deprivation

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Intrauterine growth restriction (IUGR) is a common disorder of pregnancy that disrupts fetal metabolism and growth, leading to marked increase in fetal, neonatal, and adult morbidity and mortality. Mechanisms for IUGR are inadequately understood, and there is confusion about how fetal metabolism is altered in IUGR, particularly regarding adaptations of substrate utilization capacity and insulin sensitivity. The goal of this program is to determine physiological, cellular, and molecular mechanisms underlying altered insulin action and substrate utilization in IUGR fetuses, with an aim to correcting the changes in utero. The proposed studies will test the hypothesis that the IUGR environment: a) increases glucose clearance and insulin sensitivity, and b) decreases amino acid metabolism by disrupting specific downstream cellular components insulin signaling cascades that lead to decreased protein synthesis and fetal growth. We will use in vivo and in vitro methods to test this hypothesis in our bovine model of IUGR produced by maternal during pregnancy. Specific aim 1 will determine if the capacity for plasma glucose and insulin to regulate fetal glucose utilization is increased and if changes in GLUT1 and 4 gene transcription, protein amount, and/or translocation account for altered glucose and/or insulin signal transduction that regulates glucose metabolism in skeletal muscle, including expression and phosphorylation of the Insulin Receptor, IRS-1, and PI3-kinase pathway, is increased in the IUGR fetus. Specific aim 3 will determine if the capacity for plasma amino acids and insulin to regulate amino acid utilization is diminished in IUGR fetuses. Specific aim 5 will determine if abnormal substrate utilization and/or insulin action discovered in Specific Aims 1-4 can be ameliorated by in vivo maternal and/or fetal infusions of glucose, amino acids, or insulin, thereby providing more rational therapeutic approaches to improve abnormal metabolism, development, and growth in fetuses with IUGR.