Abstract
Gestational diabetes mellitus (GDM) is characterized by insulin resistance accompanied by low/absent beta-cell compensatory adaptation to the increased insulin demand. Although the molecular mechanisms and factors acting on beta-cell compensatory response during pregnancy have been partially elucidated and reported, those inducing an impaired beta-cell compensation and function, thus evolving in GDM, have yet to be fully addressed. MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs, which negatively modulate gene expression through their sequence-specific binding to 3′UTR of mRNA target. They have been described as potent modulators of cell survival and proliferation and, furthermore, as orchestrating molecules of beta-cell compensatory response and function in diabetes. Moreover, it has been reported that miRNAs can be actively secreted by cells and found in many biological fluids (e.g., serum/plasma), thus representing both optimal candidate disease biomarkers and mediators of tissues crosstalk(s). Here, we analyzed the expression profiles of circulating miRNAs in plasma samples obtained from n = 21 GDM patients and from n = 10 non-diabetic control pregnant women (24–33 weeks of gestation) using TaqMan array microfluidics cards followed by RT-real-time PCR single assay validation. The results highlighted the upregulation of miR-330-3p in plasma of GDM vs non-diabetics. Furthermore, the analysis of miR-330-3p expression levels revealed a bimodally distributed GDM patients group characterized by high or low circulating miR-330 expression and identified as GDM-miR-330high and GDM-miR-330low. Interestingly, GDM-miR-330high subgroup retained lower levels of insulinemia, inversely correlated to miR-330-3p expression levels, and a significant higher rate of primary cesarean sections. Finally, miR-330-3p target genes analysis revealed major modulators of beta-cell proliferation and of insulin secretion, such as the experimentally validated genes E2F1 and CDC42 as well as AGT2R2, a gene involved in the differentiation of mature beta-cells. In conclusion, we demonstrated that plasma miR-330-3p could be of help in identifying GDM patients with potential worse gestational diabetes outcome; in GDM, miR-330-3p may directly be transferred from plasma to beta-cells thus modulating key target genes involved in proliferation, differentiation, and insulin secretion.
Highlights
Gestational diabetes mellitus (GDM) is defined as any degree of carbohydrate intolerance, with onset or first recognition during second or third trimester of pregnancy [1]
Glucose homeostasis is maintained by a compensatory increase in insulin secretion, associated with hypertrophy and/or hyperplasia of β-cells [5]: it is supposed that several molecules, like placental hormones, play a central role in these adaptive changes [6], contributing to gene expression changes necessary to beta-cells in order to fulfill the compensatory request
All the patients performed a 75-g oral glucose tolerance test at 16–19 weeks or 24–28 weeks of pregnancy, and GDM was diagnosed if one of the three glucose concentrations measured was above the cutoff values, according to Italian guidelines
Summary
Gestational diabetes mellitus (GDM) is defined as any degree of carbohydrate intolerance, with onset or first recognition during second or third trimester of pregnancy [1]. Glucose homeostasis is maintained by a compensatory increase in insulin secretion, associated with hypertrophy and/or hyperplasia of β-cells [5]: it is supposed that several molecules, like placental hormones, play a central role in these adaptive changes [6], contributing to gene expression changes necessary to beta-cells in order to fulfill the compensatory request. Such compensatory phenomenon involves several specific beta-cell factors acting downstream these signaling molecules, such as the transcription factors MAFA and/or PDX1 whose expression strengthen and characterizes beta-cell phenotype maintenance [7, 8]
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