Circulating Exosomal miRNA Signature in Gestational Diabetes Mellitus Influences Glucose Metabolism in Placental Cells

There is increasing evidence that miRNA, which are enriched in small nanovesicles called exosomes, are important regulators of gene expression. In this study, we tested the hypothesis that circulating exosomes from womem with gestational diabetes mellitus (GDM) carry a specific set of miRNAs which regulate genes associated with placental glucose metabolism. Exosomes were isolated from plasma obtained from normal glucose tolerant women (NGT; n=12) and women with GDM (n=12) pregnancies at delivery by differential and buoyant density centrifugation. Exosomal RNA was extracted and an Illumina TrueSeq Small RNA kit was used to construct a small RNA library. Gene target identification and gene ontology analysis for miRNAs was performed using the Ingenuity pathway analysis (IPA). The effect of exosomes on glucose metabolism in placental cells was assessed using a human glucose metabolism array. In plasma, a total of 44 miRNAs were upregulated in exosomes from women with GDM compared to NGT pregnant women (p<0.005). IPA showed that exosomal miRNAs isolated from women with GDM regulates the expression of placental genes associated with the glycolytic pathway including 6-phosphofructokinase and phosphopyruvate hydratase. Interestingly, exosomes from women with GDM increases the expression of placental genes associated with glycolysis and decrease the expression of genes associated with pentose phosphate pathway. After integration of the miRNA and mRNA data, we identified 74 differentially expressed exosomal miRNAs associated with the modulation of 10 potential target mRNAs in placental cells, which are associated with glucose metabolism. This data suggests that circulating exosomes under diabetic conditions might modulate the placental metabolic state to enhance glycogen metabolism in GDM.