FETAL EFFECTS OF INSULIN AND GLUCOSE DEPRIVATION

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The goal of this project is to better understand physiologic mechanisms which permit the fetus to adapt to acute and chronic variations in this hormonal and metabolic milieu. The study will focus specifically on the supply of energy (glucose) and protein (amino acids) substrates. The proposed studies are in two forms: I. In vivo studies will use three fetal models (fetal hypoglycemia/hyperinsulinemia 20 to maternal insulin induced hypoglycemia; fetal hypoinsulinemia 20 to fetal pancreatectomy; fetal hypoinsulinemia 20 to fetal streptozotocin injection) and will test: a) maternal glucose and insulin sensitivity vs. maternal glucose utilization and production, b) fetal glucose and insulin sensitivity vs. fetal glucose utilization, c) fetal glucose and insulin sensitivity vs. fetal amino acid metabolism, and d) fetal glucose and insulin sensitivity vs. the sources and rates of fetal gluconeogenesis. II. In vitro studies will use tissues from animals studied in vivo to determine: a) the effects of fetal insulin and glucose on the expression of certain glucoregulatory genes (glycogen formation enzymes and glucose transporters); b) the effect of fetal glucose and insulin on hepatocellular gluconeogenesis and the expression of gluconeogenic enzymes, c) the relationship between fetal growth produced by glucose and/or insulin deficiency and fetal insulin-like growth factors I and II. Methodology will include measurement of net nutrient substrate flux to the fetus using the Fick principle, quantifications of substrate utilization in mother, placenta and fetus by radioactive and stable isotope tracer methods, assessment of substrate and hormone concentration effects on fetal metabolism using substrate and hormone "clamps", cell physiology techniques to study metabolism and enzyme expression in isolated hepatocytes, tissue analyses for enzyme contents and activities, cell and molecular chemistry techniques addressing the expression of glucoregulatory proteins and the relationship between insulin like growth factors I and II and hepatocellular metabolism in normal and growth retarded fetuses. Knowledge gained from this project will help our understanding about how nutrient and hormone deprivation to the fetus produce fetal growth retardation, how the growth retarded fetus behaves with respect to energy and protein metabolism, and how the fetus maintains its viability in the presence of reduced energy, protein, and anabolic hormone supply.