Human placental exosomes in gestational diabetes mellitus carry a specific set of miRNAs associated with skeletal muscle insulin sensitivity

Abstract

There is increasing evidence that miRNAs, which are enriched in nanovesicles called exosomes, are important regulators of gene expression. When compared with normal pregnancies, pregnancies with gestational diabetes mellitus (GDM) are associated with skeletal muscle insulin resistance as well as increased levels of circulating placental exosomes. Here we investigated whether placental exosomes in GDM carry a specific set of miRNAs associated with skeletal muscle insulin sensitivity. Exosomes were isolated from chorionic villous (CV) explants from both women with Normal Glucose Tolerant (NGT) and GDM pregnancies. Using miRNA sequencing, we identified a specific set of miRNAs selectively enriched with exosomes and compared with their cells of origin indicating a specific packaging of miRNAs into exosomes. Gene target and ontology analysis of miRNA differentially expressed in exosomes secreted in GDM compared with NGT are associated with pathways regulating cell migration and carbohydrate metabolism. We determined the expression of a selected set of miRNAs in placenta, plasma, and skeletal muscle biopsies from NGT and GDM. Interestingly, the expression of these miRNAs varied in a consistent pattern in the placenta, in circulating exosomes, and in skeletal muscle in GDM. Placental exosomes from GDM pregnancies decreased insulin-stimulated migration and glucose uptake in primary skeletal muscle cells obtained from patients with normal insulin sensitivity. Interestingly, placental exosomes from NGT increase migration and glucose uptake in response to insulin in skeletal muscle from diabetic subjects. These findings suggest that placental exosomes might have a role in the changes on insulin sensitivity in normal and GDM pregnancies.

Extracellular vesicles in normal pregnancy and pregnancy‐related diseases

“…However, little is known about the role of EVs in metabolic regulation with regard to pregnancy. Nair et al demonstrate that placental exosomes from normal glucose tolerant (NGT) pregnant women are able to increase insulin‐induced glucose uptake in skeletal muscle from diabetic patients, suggesting placental exosomes may engage in the changes of insulin sensitivity in normal pregnancies. Recently, Jeyabalan and colleagues demonstrate that treatment with exosomes from adipose tissue (AT) of NGT pregnant women affects the expression of glucose metabolism‐related genes in placental cells.…”

“…Furthermore, ingenuity pathway analysis reveals the differential expression of mitochondrial function‐related proteins in AT exosomes of GDM . The work from Nair et al shows that placental exosomes are capable of modulating insulin‐stimulated migration and glucose uptake in primary skeletal muscle cells. Gene target and ontology analyses of differentially expressed miRNAs in GDM exosomes show that they are associated with pathways regulating cell migration and carbohydrate metabolism.…”

“…At 11‐14 weeks of gestation, the concentration of oral EVs is higher in asymptomatic women compared to controls with an AUC value of 0.81. Five metabolism‐related miRNAs, namely miR‐125a‐3p, miR‐99b‐5p, miR‐197‐3p, miR‐22‐3p and miR‐224‐5p, are consistently detected with high expression in skeletal muscle, placenta, placenta‐derived exosomes and circulating exosomes in GDM . Gillet et al have determined the miRNA profile of serum EVs in GDM at early pregnancies.…”

Exosomes and diabetes

“…Interestingly, incubation of HUVEC in hyperglycaemic conditions increased their release of exosomes, and these exosomes were able to mimic some of the effects of hyperglycaemia when added to control HUVEC, thus suggesting a role for exosomes in the development of endothelial dysfunction in GDM. In this regard, exosomes isolated from in vitro cultures of placenta explants from normal and GDM pregnancies show different miRNA profiles . Moreover, placental exosomes from GDM pregnancies decreased insulin‐stimulated glucose uptake in control primary human skeletal muscle cells, whereas exosomes from control pregnancies actually increased glucose uptake in primary skeletal muscle cells from diabetic patients …”

“…In this regard, exosomes isolated from in vitro cultures of placenta explants from normal and GDM pregnancies show different miRNA profiles . Moreover, placental exosomes from GDM pregnancies decreased insulin‐stimulated glucose uptake in control primary human skeletal muscle cells, whereas exosomes from control pregnancies actually increased glucose uptake in primary skeletal muscle cells from diabetic patients …”