The long-term goal of this project is to identify and study the factor that regulate how maternal diabetes mellitus during pregnancy affects maternal, placental and fetal metabolism and fetal growth. This project will be carried out with 3 major objectives: 1) induce a diabetic state in pregnant sheep in order to measure the long-term consequences of maternal hyperglycemia on maternal glucose metabolism and on placental and fetal glucose, lactate, amino acid and O2 metabolism; 2) distinguish the role of the placenta from fetal factors in regulating fetal metabolism in relation to maternal hyperglycemia; 3) measure the long-term effects of selective changes of fetal insulin and glucose concentrations on fetal glucose, lactate, amino acid and oxygen metabolism. The maternal-placental-fetal metabolism and metabolic exchange will be quantified using techniques of umbilical and uterine blood flow measurement, chemical analyses of maternal arterial, uterine venous, umbilical arterial and umbilical venous blood, tracer methodology (radioisotopes, stable isotopes, mass spectrometry and nuclear magnetic resonance spectroscopy), glucose clamp methodology, and tissue incubations. These studies are important to diabetes mellitus in several respects: 1) they are unique in their ability to quantify metabolism in the mother, placenta and fetus simultaneously; 2) this ability will provide important information about how spontaneous and therapeutically induced changes in maternal glucose homeostasis affect both placental and fetal metabolism; 3) these studies will establish an original approach to measuring the effects of oxidative substrates and insulin levels on fetal amino acid metabolism, developing for the first time an in vivo approach to studying the integration of substrate and hormonal effects on fetal oxidative metabolism and fetal growth; 4) they will define the contribution of glucose carbon to fetal tissue accretion (including glycogen, lipid, and protein); 5) they will provide a unique examination of the development of fetal lipid deposition and metabolism; 6) they will provide a new approach to compare in vivo measurements of fetal metabolism with in vitro measures of cellular substrate metabolism.
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