Placental extracellular vesicles express active dipeptidyl peptidase IV; levels are increased in gestational diabetes mellitus

Neva Kandzija,Wei Zhang,Carolina Motta-Mejia,Vuyane Mhlomi,Jennifer Mcgowan-Downey,Tim James,Ana Sofia Cerdeira,Dionne Tannetta,Ian Sargent,Christopher W Redman,Claire C Bastie,Manu Vatish

doi:10.1080/20013078.2019.1617000

Abstract

ABSTRACTGestational diabetes mellitus (GDM) is the most common metabolic disorder in pregnancy and is characterized by insulin resistance and decreased circulating glucagon-like peptide-1 (GLP-1). GDM resolves rapidly after delivery implicating the placenta in the disease. This study examines the biological functions that cause this pathology. The placenta releases syncytiotrophoblast-derived extracellular vesicles (STB-EVs) into the maternal circulation, which is enhanced in GDM. Dipeptidyl peptidase IV (DPPIV) is known to play a role in type 2 diabetes by breaking down GLP-1, which in turn regulates glucose-dependent insulin secretion. STB-EVs from control and GDM women were analysed. We show that normal human placenta releases DPPIV-positive STB-EVs and that they are higher in uterine than paired peripheral blood, confirming placental origin. DPPIV-bound STB-EVs from normal perfused placentae are dose dependently inhibited with vildagliptin. DPPIV-bound STB-EVs from perfused placentae are able to breakdown GLP-1 in vitro. STB-EVs from GDM perfused placentae show greater DPPIV activity. Importantly, DPPIV-bound STB-EVs increase eightfold in the circulation of women with GDM. This is the first report of STB-EVs carrying a biologically active molecule that has the potential to regulate maternal insulin secretion.

Highlights

Gestational diabetes mellitus (GDM) is defined as glucose intolerance resulting in hyperglycaemia, with an onset or first recognition during pregnancy [1]
The syncytiotrophoblast-specific marker placental alkaline phosphatase (PLAP) was expressed in both MEDIUM/LARGE syncytiotrophoblast-derived extracellular vesicles (STB-extracellular vesicles (EVs)) and SMALL STB-EVs, confirming the placental origin of these two particle populations (Figure 1(d)); and the expression of exosome-specific marker syntenin was enriched in the SMALL STB-EVs fraction (Figure 1(d)), with marginal expression in MEDIUM/LARGE STB-EVs (Fig. S1)
We found that the normal human placenta releases STB-EVs that carry biologically active Dipeptidyl peptidase IV (DPPIV)

Summary

Introduction

Gestational diabetes mellitus (GDM) is defined as glucose intolerance resulting in hyperglycaemia, with an onset or first recognition during pregnancy [1]. In 2015, approximately 17.8 million of births were affected by GDM [2], with increasing prevalence directly linked to increasing risk factors (e.g. obesity) in women of reproductive age [3]. GDM causes short- and long-term complications for both mother and foetus. Women with GDM are at elevated risk for developing impaired glucose tolerance and type 2 diabetes later in life. It is reported that up to 70% of women with GDM develop type 2 diabetes within 5 years of delivery [4]. Children of women with GDM have increased lifetime risks of obesity and are more likely to have impaired glucose tolerance and diabetes in childhood and early adulthood [5,6]

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Conclusion