Abstract
Aims/hypothesisThe 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.MethodsPlacental 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.ResultsAll 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/interpretationThis is the first report of placental ER stress in GDM patients. Chemical chaperones and antioxidant vitamins represent potential therapeutic interventions for GDM.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-4040-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
Gestational diabetes mellitus (GDM) is a subtype of diabetes that arises de novo late in the second trimester or early in the third trimester of pregnancy
Low-grade endoplasmic reticulum (ER) stress is increased in GDM placentas Electron microscopy revealed mild to moderate dilatation of the ER cisternae, a hallmark of ER stress, in the syncytiotrophoblast of placentas from GDM pregnancies compared with normoglycaemic controls (Fig. 1a)
We provide the first evidence for the existence of placental ER stress in women with established GDM, as demonstrated by dilatation of ER cisternae in the syncytiotrophoblast and increased p-eukaryotic initiation factor 2 subunit α (eIF2α) and unspliced XBP-1 protein
Summary
Gestational diabetes mellitus (GDM) is a subtype of diabetes that arises de novo late in the second trimester or early in the third trimester of pregnancy. It represents a global health challenge, with incidences reaching 17.8% of total pregnancies [1]. Women with GDM are at increased risk of developing other complications of pregnancy, including pregnancy-induced hypertension and pre-eclampsia [2]. They have an increased lifetime risk for type 2 diabetes of approximately 30% [3]. GDM poses an increased risk of stillbirth, perinatal complications, macrosomia and growth restriction [4], and there is a greater predisposition to type 2 diabetes, obesity and metabolic and cardiovascular diseases later in life [5, 6]
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