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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK035836-04
Application #
3234096
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1985-09-01
Project End
1991-08-31
Budget Start
1988-09-01
Budget End
1989-08-31
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Manco-Johnson, Marilyn J; Hacker, Michele R; Jacobson, Linda J et al. (2009) Pharmacokinetics of protein C and antithrombin in the fetal lamb: a model to predict human neonatal replacement dosing. Neonatology 95:279-85
Hay Jr, William W (2006) Placental-fetal glucose exchange and fetal glucose metabolism. Trans Am Clin Climatol Assoc 117:321-39; discussion 339-40
Hay Jr, William W (2006) Recent observations on the regulation of fetal metabolism by glucose. J Physiol 572:17-24
Manco-Johnson, Marilyn J; Jacobson, Linda J; Hacker, Michele R et al. (2002) Development of coagulation regulatory proteins in the fetal and neonatal lamb. Pediatr Res 52:580-8
Aldoretta, P W; Carver, T D; Hay Jr, W W (1998) Maturation of glucose-stimulated insulin secretion in fetal sheep. Biol Neonate 73:375-86
Young, D A; Zerbe, G O; Hay Jr, W W (1997) Fieller's theorem, Scheffe simultaneous confidence intervals, and ratios of parameters of linear and nonlinear mixed-effects models. Biometrics 53:838-47
Gresores, A; Anderson, S; Hood, D et al. (1997) Separate and joint effects of arginine and glucose on ovine fetal insulin secretion. Am J Physiol 272:E68-73
Carver, T D; Anderson, S M; Aldoretta, P W et al. (1996) Effect of low-level basal plus marked ""pulsatile"" hyperglycemia on insulin secretion in fetal sheep. Am J Physiol 271:E865-71
Hay Jr, W W (1995) Metabolic interrelationships of placenta and fetus. Placenta 16:19-30
Turbow, R M; Curran-Everett, D; Hay Jr, W W et al. (1995) Cerebral lactate metabolism in near-term fetal sheep. Am J Physiol 269:R938-42

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