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

Abstract

Gestational 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.

Placental proteome abnormalities in women with gestational diabetes and large-for-gestational-age newborns

“…16 In particular, PRG2 and DPP-4, found to be upregulated in GDM/LGA placental proteome analysis, are both involved in pregnancy 17 18 and their dysregulation was shown to correlate with pregnancy-related disorders. 19 As PRG2 controls several growth factors activity, its upregulation may take part to the abnormal fetal size such as that observed in GDM/LGA, while the DPP-4 increase detected in placenta may account for some growth abnormalities as well as the dysregulated glycometabolic control in the new-borns, which have been shown in literature. 1 This may be of clinical interest given the availability of DPP-4 inhibitors.…”

Extracellular vesicles in normal pregnancy and pregnancy‐related diseases

“…The concentration of DPPIV + STBEVs in GDM maternal plasma is more than eightfold higher than that in normal pregnancies. Increased DPPIV biological activity is also demonstrated in STBEVs from GDM . A total of 78 exosomal proteins are differentially expressed in GDM compared to NGT.…”

Extracellular Vesicles in Feto–Maternal Crosstalk and Pregnancy Disorders

“…The involvement of placental hormones (PH) released from the human placenta has been associated with the development of insulin resistance and gestational diabetes mellitus (GDM). In such a context, higher levels of circulating small EVs and STBEV-EVs were detected in GDM patients when they were compared to healthy women [76,82]. It was also observed that the contribution of placental small EVs expressing PLAP as a placental marker was comparatively lower in GDM pregnancies.…”

“…Interestingly, normal human placenta releases STB-EVs that carry biologically active dipeptidyl peptidase IV (DPPIV), which plays a role in type 2 diabetes by breaking down glucagon-like peptide 1 (GLP-1), which in turn regulates glucose-dependent insulin secretion. Furthermore, STB-EVs from GDM perfused placentae showed greater dipeptidyl peptidase-4 (DPPIV) activity, and DPPIV-bound STB-EVs increase eightfold in the circulation of women with GDM [76]. It has been demonstrated that amnion epithelial cells (AECs) produce small EVs that interact with myometrial, decidual, and placental cells (BeWo).…”