Extracellular Vesicles-New Players in Cell-to-Cell Communication in Gestational Diabetes Mellitus

Abstract

Research in extracellular vesicles (EVs) has contributed to a better understanding of physiological and pathophysiological conditions. Biologically active cargo, such as miRNAs and proteins, is critical in many different biological processes. In this context, pregnancy is one of the most complex physiological states, which needs a highly regulated system to ensure the correct nourishment and development of the baby. However, pre-existent maternal conditions and habits can modify the EV-cargo and dysregulate the system leading to pregnancy complications, with gestational diabetes mellitus (GDM) being one of the most reported and influential. Calcification and aging of muscle cells, protein modification in vascular control or variations in the levels of specific miRNAs are some of the changes observed or led by EV populations as adaptation to GDM. Interestingly, insulin sensitivity and glucose tolerance changes are not fully understood to date. Nevertheless, the increasing evidence generated has opened new possibilities in the biomarker discovery field but also in the understanding of cellular mechanisms modified and involved in GDM. This brief review aims to discuss some of the findings in GDM and models used for that purpose and their potential roles in the metabolic alterations during pregnancy, with a focus on insulin sensitivity and glucose tolerance.

Keywords: extracellular vesicles; gestational diabetes mellitus; glucose tolerance; insulin sensitivity; pregnancy complications.

Figure 1

Biomarker discovery in gestational diabetes mellitus (GDM). Pregnancy is a complex physiological state where, in 40 weeks, a sequence of adaptations take place in order to assure the correct nourishment and development of the baby. Currently, GDM affects a large proportion of mothers and its screening test takes place around week 24–28 of gestation. At this point, other pregnancy complications may be present (co-morbidities) putting at risk not just the baby (e.g., preterm birth) but also the mother. New guidelines and non-evidence based recommendations are trying to address this issue, advising new oral glucose tolerance test (OGTT) evaluation early in pregnancy. Nowadays, several research groups around the world are focused on identifying potential biomarkers for GDM in the early stages of pregnancy to support and optimise the resources needed for a successful outcome. This research uses different models and approaches to generate evidence. It can be used plasma samples containing molecules or components with a placental origin; placenta that can be used for perfusion or primary cell culture; or other adjacent structures such as umbilical cord to study interaction and other control points. In addition to these models, animals and immortalized cells have been used to test different conditions/drugs and to get a better understanding of cellular mechanisms involved in these pathological conditions. (Created with BioRender).

Figure 2

Findings related to extracellular vesicles and their role in insulin sensitivity and glucose tolerance. The standard procedure for the isolation of extracellular vesicles uses maternal plasma or serum as the source. From these samples, it is possible to isolate vesicles with a size between 30 and 100 nm. Interestingly, these vesicles contain miRNA and proteins as cargo, which have shown to be attractive options in the field of biomarker discovery. So far, these cargoes have been identified as critical elements for insulin resistance and glucose tolerance but also, at a higher level, processes involving muscular and adipose tissue. Other elements have been identified but further research is needed in order to reveal their function and relevance at a cellular level. (Created with BioRender).