We hypothesize that nutrient deprivation to the fetus results in fetal metabolic adaptations, including decreased insulin secretion, decreased insulin sensitivity, and increased protein breakdown, and that such metabolic adaptations limit fetal metabolic capacity to respond successfully to attempts at aggressive nutrient therapy. We will rest this hypothesis using our established model of chronic maternal hypoglycemia, and a new of maternal low-protein diet plus hypoaminoacidemia, to determine how chronic changes in maternal nutrient substrate concentrations and supply to the fetus lead to fetal nutrient deficit. Experiments will use our established methods of substrate and hormone clamps and Fick principle and tracer measurements to quantify fetal nutrient substrate entry, utilization, and oxidation rates. We also will measure insulin secretion in vivo and in vitro to determine possible mechanisms by which insulin secretion is inhibited, and we will quantify peripheral tissue glucose transporter mRNA and protein expression and protein localization to determine mechanisms that account for insulin resistance. Based on this information, we also will test how well these chronically nutrient deprived fetuses respond metabolically to increased nutrient supply, hypothesizing that: 1. rapid, high rates of glucose entry into the nutrient deprived fetus will produce excessive hypoxemia, acidosis, and lactate production; 2. rapid, high rates of entry of selected amino acids will produce a less than expected rate of their metabolism; 3. slow entry of glucose will normalize insulin secretion and insulin sensitivity, allowing increased glucose and amino acid metabolism; 4. slow entry of amino acids will normalize insulin secretion and insulin sensitivity, allowing increased glucose and amino acid metabolism. These will be the first fetal studies to determine how maternal low protein diet with and without hypoaminoacidemia, and alone and interactively with glucose deficit, leads to fetal nutrient deficit and potentially to limited rates of fetal growth, the first studies to determine the role of amino acid supply to the fetus in regulating fetal insulin secretion and insulin action, and the first studies to define in detail how re- introduction of previously deficient nutrients to the nutrient deprived fetus will affect fetal metabolism, providing essential data to plan future clinical trials of nutrient therapy of human fetal growth restriction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK052138-01A1
Application #
2395331
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Laughlin, Maren R
Project Start
1997-09-09
Project End
2001-08-31
Budget Start
1997-09-09
Budget End
1998-08-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
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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