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Placental endoplasmic reticulum stress in gestational diabetes: the potential for therapeutic intervention with chemical chaperones and antioxidants.

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Yung, Hong-Wa 
Alnæs-Katjavivi, Patji 
Jones, Carolyn JP 
El-Bacha, Tatiana 
Golic, Michaela 


AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: This is the first report of placental ER stress in GDM patients. Chemical chaperones and antioxidant vitamins represent potential therapeutic interventions for GDM.



Antioxidants, Chaperones, Endoplasmic reticulum stress, Gestational diabetes, Metabolic acidosis, Placenta, Trophoblast, Unfolded protein response, Acidosis, Adult, Antioxidants, Ascorbic Acid, Blood Glucose, Blotting, Western, Cell Line, Diabetes, Gestational, Endoplasmic Reticulum Stress, Eukaryotic Initiation Factor-2, Female, Glucose, Humans, Phenylbutyrates, Phosphorylation, Placenta, Pregnancy, Taurochenodeoxycholic Acid, Unfolded Protein Response, Vitamin E

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Springer Science and Business Media LLC
Wellcome Trust (084804/Z/08/Z)
This study was supported by a grant from the Wellcome Trust (084804/2/08/Z). TE-B was supported by a Newton Advanced Fellowship awarded to TE-B and GJB from the Academy of Medical Sciences, and by the Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro.