title: Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia.
abstract: Reduced fetal glucose supply, induced experimentally or as a result of placental insufficiency, produces an early activation of fetal glucose production. The mechanisms and substrates used to fuel this increased glucose production rate remain unknown. We hypothesized that in response to hypoglycemia, induced experimentally with maternal insulin infusion, the fetal liver would increase uptake of lactate and amino acids (AA), which would combine with hormonal signals to support hepatic glucose production. To test this hypothesis, metabolic studies were done in six late gestation fetal sheep to measure hepatic glucose and substrate flux before (basal) and after [days (d)1 and 4] the start of hypoglycemia. Maternal and fetal glucose concentrations decreased by 50% on d1 and d4 (P < 0.05). The liver transitioned from net glucose uptake (basal, 5.1 ± 1.5 μmol/min) to output by d4 (2.8 ± 1.4 μmol/min; P < 0.05 vs. basal). The [U-¹³C]glucose tracer molar percent excess ratio across the liver decreased over the same period (basal: 0.98 ± 0.01, vs. d4: 0.89 ± 0.01, P < 0.05). Total hepatic AA uptake, but not lactate or pyruvate uptake, increased by threefold on d1 (P < 0.05) and remained elevated throughout the study. This AA uptake was driven largely by decreased glutamate output and increased glycine uptake. Fetal plasma concentrations of insulin were 50% lower, while cortisol and glucagon concentrations increased 56 and 86% during hypoglycemia (P < 0.05 for basal vs. d4). Thus increased hepatic AA uptake, rather than pyruvate or lactate uptake, and decreased fetal plasma insulin and increased cortisol and glucagon concentrations occur simultaneously with increased fetal hepatic glucose output in response to fetal hypoglycemia.
authors.affiliation: Perinatal Research Center, Department of Pediatrics, Anschutz Medical Campus, University of Colorado, Aurora, Colorado.
authors.forename: Satya S
authors.initials: SS
authors.lastname: Houin
authors.affiliation: Perinatal Research Center, Department of Pediatrics, Anschutz Medical Campus, University of Colorado, Aurora, Colorado.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Rozance
authors.affiliation: Perinatal Research Center, Department of Pediatrics, Anschutz Medical Campus, University of Colorado, Aurora, Colorado.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Brown
authors.affiliation: Perinatal Research Center, Department of Pediatrics, Anschutz Medical Campus, University of Colorado, Aurora, Colorado.
authors.forename: William W
authors.initials: WW
authors.lastname: Hay
authors.affiliation: Perinatal Research Center, Department of Pediatrics, Anschutz Medical Campus, University of Colorado, Aurora, Colorado.
authors.forename: Randall B
authors.initials: RB
authors.lastname: Wilkening
authors.affiliation: Perinatal Research Center, Department of Pediatrics, Anschutz Medical Campus, University of Colorado, Aurora, Colorado stephanie.thorn@ucdenver.edu.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Thorn
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D002250:Carbon Radioisotopes; D004195:Disease Models, Animal; D004700:Endocrine System Diseases / Q000097:blood / Q000196:embryology* / Q000378:metabolism; D005260:Female; D005312:Fetal Blood; D005934:Glucagon / Q000097:blood; D005943:Gluconeogenesis; D018698:Glutamic Acid / Q000097:blood / Q000378:metabolism; D005998:Glycine / Q000097:blood / Q000378:metabolism; D006854:Hydrocortisone / Q000097:blood; D007003:Hypoglycemia / Q000097:blood / Q000196:embryology* / Q000378:metabolism; D007328:Insulin / Q000097:blood; D008099:Liver / Q000196:embryology* / Q000378:metabolism; D034561:Sheep, Domestic; D015854:Up-Regulation
chemical_list: D000596:Amino Acids; D001786:Blood Glucose; D002250:Carbon Radioisotopes; D007328:Insulin; D018698:Glutamic Acid; D005934:Glucagon; D005998:Glycine; D006854:Hydrocortisone
keywords: fetal; glucose; glucose production; hypoglycemia; liver