Endoplasmic reticulum stress is increased in adipose tissue of women with gestational diabetes.

Stella Liong,Martha Lappas

doi:10.1371/journal.pone.0122633

Abstract

Maternal obesity and gestational diabetes mellitus (GDM) are two increasingly common and important obstetric complications that are associated with severe long-term health risks to mothers and babies. IL-1β, which is increased in obese and GDM pregnancies, plays an important role in the pathophysiology of these two pregnancy complications. In non-pregnant tissues, endoplasmic (ER) stress is increased in diabetes and can induce IL-1β via inflammasome activation. The aim of this study was to determine whether ER stress is increased in omental adipose tissue of women with GDM, and if ER stress can also upregulate inflammasome-dependent secretion of IL-1β. ER stress markers IRE1α, GRP78 and XBP-1s were significantly increased in adipose tissue of obese compared to lean pregnant women. ER stress was also increased in adipose tissue of women with GDM compared to BMI-matched normal glucose tolerant (NGT) women. Thapsigargin, an ER stress activator, induced upregulated secretion of mature IL-1α and IL-1β in human omental adipose tissue explants primed with bacterial endotoxin LPS, the viral dsRNA analogue poly(I:C) or the pro-inflammatory cytokine TNF-α. Inhibition of capase-1 with Ac-YVAD-CHO resulted in decreased IL-1α and IL-1β secretion, whereas inhibition of pannexin-1 with carbenoxolone suppressed IL-1β secretion only. Treatment with anti-diabetic drugs metformin and glibenclamide also reduced IL-1α and IL-1β secretion in infection and cytokine-primed adipose tissue. In conclusion, this study has demonstrated ER stress to activate the inflammasome in pregnant adipose tissue. Therefore, increased ER stress may contribute towards the pathophysiology of obesity in pregnancy and GDM.

Highlights

Gestational diabetes mellitus (GDM) is characterised as any degree of glucose intolerance with first recognition during pregnancy
This study, for the first time, demonstrates the inositol requiring enzyme 1 (IRE1) arm of the Endoplasmic reticulum (ER) stress pathway is increased in adipose tissue from obese pregnant women and women with GDM, as evidenced by the increased expression of ER stress proteins GRP78, IRE1α and/or XBP-1s
Activation of ER stress by thapsigargin in pregnant adipose tissues primed with LPS, poly(I:C) or TNF-α, induced IL-1β and IL-1α secretion but not transcription; an effect which was suppressed using inhibitors of pannexin-1 and caspase-1

Summary

Introduction

Gestational diabetes mellitus (GDM) is characterised as any degree of glucose intolerance with first recognition during pregnancy. Risk factors for GDM include advance maternal age, racial/ ethnic disparities, and obesity [1]. GDM is associated with substantial increased risks for both mother and infant [2,3,4]. Obesity is another significant public health concern, with a substantial.

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