title: Placental endoplasmic reticulum stress in gestational diabetes: the potential for therapeutic intervention with chemical chaperones and antioxidants.
abstract: The aim of this work was to determine whether placental endoplasmic reticulum (ER) stress may contribute to the pathophysiology of gestational diabetes mellitus (GDM) and to test the efficacy of chemical chaperones and antioxidant vitamins in ameliorating that stress in a trophoblast-like cell line in vitro.
  
  
  
  Placental samples were obtained from women suffering from GDM and from normoglycaemic controls and were frozen immediately. Women with GDM had 2 h serum glucose levels > 9.0 mmol/l following a 75 g oral glucose tolerance test and were treated with diet and insulin when necessary. Western blotting was used to assess markers of ER stress. To test the effects of hyperglycaemia on the generation of ER stress, a new trophoblast-like cell line, BeWo-NG, was generated by culturing in a physiological glucose concentration of 5.5 mmol/l (over 20 passages) before challenging with 10 or 20 mmol/l glucose.
  
  
  
  All GDM patients were well-controlled (HbA1c 5.86 ± 0.55% or 40.64 ± 5.85 mmol/mol, n = 11). Low-grade ER stress was observed in the placental samples, with dilation of ER cisternae and increased phosphorylation of eukaryotic initiation factor 2 subunit α. Challenge of BeWo-NG with high glucose activated the same pathways, but this was as a result of acidosis of the culture medium rather than the glucose concentration per se. Addition of chemical chaperones 4-phenylbutyrate and tauroursodeoxycholic acid and vitamins C and E ameliorated the ER stress.
  
  
  
  This is the first report of placental ER stress in GDM patients. Chemical chaperones and antioxidant vitamins represent potential therapeutic interventions for GDM.
authors.affiliation: Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
authors.forename: Hong-Wa
authors.initials: HW
authors.lastname: Yung
authors.affiliation: Department of Obstetrics and Gynecology, Oslo University Hospital, Ullevål and Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Patji
authors.initials: P
authors.lastname: Alnæs-Katjavivi
authors.affiliation: Centre for Maternal and Fetal Health, Institute of Human Development, University of Manchester, Manchester, UK.
authors.forename: Carolyn J P
authors.initials: CJ
authors.lastname: Jones
authors.affiliation: Institute of Nutrition, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Tatiana
authors.initials: T
authors.lastname: El-Bacha
authors.affiliation: Experimental and Clinical Research Center, a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité-Universitätsmedizin Berlin, Berlin, Germany.|Department of Obstetrics and Gynecology, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Berlin Institute of Health (BIH), Berlin, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Golic
authors.affiliation: Department of Obstetrics and Gynecology, Oslo University Hospital, Ullevål and Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Anne-Cathrine
authors.initials: AC
authors.lastname: Staff
authors.affiliation: Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK. gjb2@cam.ac.uk.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Burton
mesh_terms: D000138:Acidosis / Q000188:drug therapy; D000328:Adult; D000975:Antioxidants / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D016640:Diabetes, Gestational / Q000097:blood* / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D010654:Phenylbutyrates / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D015852:Eukaryotic Initiation Factor-2; D010654:Phenylbutyrates; D014810:Vitamin E; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; C075773:4-phenylbutyric acid; D005947:Glucose; D001205:Ascorbic Acid
keywords: Antioxidants; Chaperones; Endoplasmic reticulum stress; Gestational diabetes; Metabolic acidosis; Placenta; Trophoblast; Unfolded protein response