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.
|Barry, James S; Rozance, Paul J; Brown, Laura D et al. (2016) Increased fetal myocardial sensitivity to insulin-stimulated glucose metabolism during ovine fetal growth restriction. Exp Biol Med (Maywood) 241:839-47|
|Brown, Laura D; Rozance, Paul J; Thorn, Stephanie R et al. (2012) Acute supplementation of amino acids increases net protein accretion in IUGR fetal sheep. Am J Physiol Endocrinol Metab 303:E352-64|
|Thorn, Stephanie R; Regnault, Timothy R H; Brown, Laura D et al. (2009) Intrauterine growth restriction increases fetal hepatic gluconeogenic capacity and reduces messenger ribonucleic acid translation initiation and nutrient sensing in fetal liver and skeletal muscle. Endocrinology 150:3021-30|
|Rozance, Paul J; Crispo, Michelle M; Barry, James S et al. (2009) Prolonged maternal amino acid infusion in late-gestation pregnant sheep increases fetal amino acid oxidation. Am J Physiol Endocrinol Metab 297:E638-46|
|Rozance, Paul J; Limesand, Sean W; Barry, James S et al. (2009) Glucose replacement to euglycemia causes hypoxia, acidosis, and decreased insulin secretion in fetal sheep with intrauterine growth restriction. Pediatr Res 65:72-8|
|Brown, Laura D; Rozance, Paul J; Barry, James S et al. (2009) Insulin is required for amino acid stimulation of dual pathways for translational control in skeletal muscle in the late-gestation ovine fetus. Am J Physiol Endocrinol Metab 296:E56-63|
|Rozance, Paul J; Limesand, Sean W; Barry, James S et al. (2008) Chronic late-gestation hypoglycemia upregulates hepatic PEPCK associated with increased PGC1alpha mRNA and phosphorylated CREB in fetal sheep. Am J Physiol Endocrinol Metab 294:E365-70|
|Wallace, Jacqueline M; Milne, John S; Aitken, Raymond P et al. (2007) Sensitivity to metabolic signals in late-gestation growth-restricted fetuses from rapidly growing adolescent sheep. Am J Physiol Endocrinol Metab 293:E1233-41|
|Rozance, Paul J; Limesand, Sean W; Zerbe, Gary O et al. (2007) Chronic fetal hypoglycemia inhibits the later steps of stimulus-secretion coupling in pancreatic beta-cells. Am J Physiol Endocrinol Metab 292:E1256-64|
|Hay, W W (2006) Early postnatal nutritional requirements of the very preterm infant based on a presentation at the NICHD-AAP workshop on research in neonatology. J Perinatol 26 Suppl 2:S13-8|
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