Short-chain fatty acids as novel therapeutics for gestational diabetes

in Journal of Molecular Endocrinology
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  • 1 Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia
  • 2 Mercy Perinatal Research Centre, Mercy Hospital for Women, Victoria, Australia

Correspondence should be addressed to M Lappas: mlappas@unimelb.edu.au
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Gestational diabetes mellitus (GDM) affects up to 16% of pregnant women and is associated with significant long-term health detriments for the mother and her offspring. Two central features of GDM are low-grade inflammation and maternal peripheral insulin resistance, therefore therapeutics which target these may be most effective at preventing the development of GDM. Short-chain fatty acids (SCFAs), such as butyrate and propionate, are metabolites produced from the fermentation of dietary fibre by intestinal microbiota. SCFAs possess anti-inflammatory, anti-obesity and anti-diabetic properties. Therefore, this study aimed to investigate the effect of SCFAs on inflammation and insulin signalling defects in an in vitro model of GDM. Human placenta, visceral adipose tissue (VAT) and s.c. adipose tissue (SAT) were stimulated with either the pro-inflammatory cytokine TNF or bacterial product lipopolysaccharide (LPS). The SCFAs butyrate and propionate blocked TNF- and LPS-induced mRNA expression and secretion of pro-inflammatory cytokines and chemokines in placenta, VAT and SAT. Primary human cells isolated from skeletal muscle were stimulated with TNF to assess the effect of SCFAs on inflammation-induced defects in the insulin signalling pathway. Butyrate and propionate were found to reverse TNF-induced increases in IRS-1 serine phosphorylation and decreases in glucose uptake. Butyrate and propionate exerted these effects by preventing ERK activation. Taken together, these results suggest that the SCFAs may be able to improve insulin sensitivity and prevent inflammation induced by sterile or bacterial inflammation. Future in vivo studies are warranted to investigate the efficacy and safety of SCFAs in preventing insulin resistance and inflammation associated with GDM.

Supplementary Materials

    • Supplementary Figure 1. Effect of SCFAs on IL6 and CCL2 secretion in FFAR2 and FFAR3 deficient trophoblast cells. (A,B) Human primary trophoblast cells were transfected with 50 nM siCONT, 50 nM FFAR2 or 50 nM FFAR3 for 72 h (n=3 patients). FFAR2 and FFAR3 mRNA expression was analysed by RT-qPCR and fold change was calculated relative to siCONT transfected cells. Data are mean  SEM with data points representing 3 individual experiments. (C,D) Human primary trophoblast cells were transfected with 50 nM siCONT, 50 nM FFAR2 or 50 nM FFAR3 for 48 h and then treated with 1 g/ml LPS in the absence or presence of 5 mM butyrate (But) or 10 mM propionate (Prop) for an additional 20 h (n=3 patients). The concentration of IL6 and CCL2 in the incubation medium was assayed by ELISA. Data are mean  SEM with data points representing 3 individual experiments.

 

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Sept 2018 onwards Past Year Past 30 Days
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