title: Limited capacity for glucose oxidation in fetal sheep with intrauterine growth restriction.
abstract: Intrauterine growth-restricted (IUGR) fetal sheep, produced by placental insufficiency, have lower oxygen concentrations, higher lactate concentrations, and increased hepatic glucose production that is resistant to suppression by insulin. We hypothesized that increased lactate production in the IUGR fetus results from reduced glucose oxidation, during basal and maximal insulin-stimulated conditions, and is used to support glucose production. To test this, studies were performed in late-gestation control (CON) and IUGR fetal sheep under basal and hyperinsulinemic-clamp conditions. The basal glucose oxidation rate was similar and increased by 30-40% during insulin clamp in CON and IUGR fetuses (P < 0.005). However, the fraction of glucose oxidized was 15% lower in IUGR fetuses during basal and insulin-clamp periods (P = 0.05). IUGR fetuses also had four-fold higher lactate concentrations (P < 0.001) and lower lactate uptake rates (P < 0.05). In IUGR fetal muscle and liver, mRNA expression of pyruvate dehydrogenase kinase (PDK4), an inhibitor of glucose oxidation, was increased over fourfold. In IUGR fetal liver, but not skeletal muscle, mRNA expression of lactate dehydrogenase A (LDHA) was increased nearly fivefold. Hepatic expression of the gluconeogenic genes, phosphoenolpyruvate carboxykinase (PCK)1, and PCK2, was correlated with expression of PDK4 and LDHA. Collectively, these in vivo and tissue data support limited capacity for glucose oxidation in the IUGR fetus via increased PDK4 in skeletal muscle and liver. We speculate that lactate production also is increased, which may supply carbon for glucose production in the IUGR fetal liver.
authors.affiliation: Perinatal Research Center, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Brown
authors.affiliation: Perinatal Research Center, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Rozance
authors.affiliation: Perinatal Research Center, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Bruce
authors.affiliation: Perinatal Research Center, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Friedman
authors.affiliation: Perinatal Research Center, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: William W
authors.initials: WW
authors.lastname: Hay
authors.affiliation: Perinatal Research Center, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado stephanie.wesolowski@ucdenver.edu.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Wesolowski
mesh_terms: D000818:Animals; D005260:Female; D005317:Fetal Growth Retardation / Q000662:veterinary*; D005333:Fetus / Q000378:metabolism*; D005786:Gene Expression Regulation; D005943:Gluconeogenesis / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007773:Lactates / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D011247:Pregnancy; D012756:Sheep
chemical_list: D007328:Insulin; D007773:Lactates; D005947:Glucose
keywords: fetal; glucose oxidation; glucose production; liver; muscle