In a recent article published in Clinical Science, James-Allan et al. examined the effect of small extracellular vesicles (EVs) on glucose intolerance in pregnancy. This editorial commentary summarizes major findings from this study and discusses the impact on our understanding of the role of EVs in pregnancy

Gestational diabetes mellitus (GDM) is one of the most common medical complications in pregnancy with up to 20% of all pregnancies worldwide impacted [1]. It manifests in pregnancy due to reduced production of insulin or, more commonly, insulin resistance beyond that conventionally seen in pregnancy. Although the prevalence of GDM is increasing [2], the underlying cellular and molecular mechanisms driving its development remain elusive. One emerging area of interest is in the role of extracellular vesicles (EVs) as both biomarkers and vectors for intercellular communication in pregnancy [3]. EV levels, physicochemical properties, and molecular composition may all be altered in GDM and influence EV-mediated signaling [3]. A seminal paper by James-Allen et al. [4] showed that EVs from pregnant women promote insulin release in response to glucose in mice; a property that is not seen with EVs from non-pregnant women or women with GDM.

In a recent article published in Clinical Science, James-Allan et al. [5] further expanded on this work by examining the effects of EVs on glucose tolerance in pregnant mice. The authors focused specifically on a subpopulation of small EVs (sEVs) which are ∼50–150 nm in size and include exosomes (EVs produced through endosomal processes and fusion of multivesicular bodies with the plasma membrane) and microvesicles (formed by outward blebbing of the plasma membrane) [6]. The authors hypothesized that infusion of sEVs from women with GDM into healthy pregnant mice would induce glucose intolerance.

To test this hypothesis the authors employed an innovative approach of chronic infusion of EVs using osmotic minipumps in mice. In our experience, in vivo studies examining EV-related signaling generally employ intravenous or intraperitoneal injection which are less practical for studies on the chronic effects of EVs. As such, this approach could have far reaching consequences by advancing our understanding of the role of EVs in chronic conditions. After 4 days of EV administration, the authors assessed glucose intolerance in vivo as well as while muscle and adipose tissue insulin sensitivity, and islet glucose stimulated insulin secretion (GSIS) in vitro.

The authors observed glucose intolerance in mice exposed to sEVs from women with GDM when compared with untreated mice or those treated with sEVs from normal pregnancy. In addition, islet GSIS was increased in pregnant mice following infusion of sEVs from healthy pregnancies, but not those infused with GDM sEVs. Insulin signaling was also assessed in skeletal muscle and adipose tissue. Changes in adipose tissue insulin sensitivity or in fasting concentrations of circulating adiponectin were not observed in mice infused with sEVs isolated from normal or GDM pregnancies. Similarly, infusion of control and GDM sEVs did not also affect muscle insulin sensitivity, placental insulin or mammalian target of rapamycin signaling, and placental and fetal weight. Finally, the authors reported that infusion of EVs (from any source) was not associated with any T-cell immune response. The latter observation is consistent with a potential immune privilege of sEVs that has been suggested elsewhere [7].

Taken together these results suggest that EVs play a role in regulating glucose homeostasis in pregnancy and that this pathway may be dysregulated in GDM leading to more pronounced glucose intolerance (Figure 1). This would be a significant advance as much of the prior work relating to EVs in GDM has been associative [3,8–11] and, if confirmed, could set the stage for interventions that target EV-mediated effects on glucose handling in the pancreas.

Figure 1
Role of sEVs in glucose intolerance in pregnancy

Shown is the experimental design and major findings from James-Allen et al. [ 5]. sEVs from individuals with GDM recapitulate glucose intolerance and impaired GSIS in healthy pregnant mice.

Figure 1
Role of sEVs in glucose intolerance in pregnancy

Shown is the experimental design and major findings from James-Allen et al. [ 5]. sEVs from individuals with GDM recapitulate glucose intolerance and impaired GSIS in healthy pregnant mice.

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While such possibilities are exciting, a number of questions remain. First, it is worth noting that the authors did not track EV movement throughout the body as such, it is unclear how widely the sEVs distribute after release from the mini pump. One wonders, for example, if the failure to impact on skeletal muscle/adipose insulin signaling was due to a lack of a response or simply the fact that EVs did not reach these tissues. Second, the source of the EVs responsible for the effects is unclear. It has been estimated that 20% of sEVs in the maternal circulation at term are placental in origin with the remainder arising from maternal sources [12]. Assessing whether the effects of sEVs on glucose homeostasis are due to placental EVs would require separation of these populations. Third, the authors have focused specifically on sEVs. We recently reported that GDM increased circulating levels of endothelial of medium/large EVs with alterations in molecular composition [13]; however, it remains to be seen whether medium/large EVs have any impact on glucose homeostasis in pregnancy. Finally, it would be interesting to assess the effects of sEVs on maternal physiology beyond glucose handling. We, and others have shown that EVs can exert effects on vascular health, particularly in the context of diabetes [14] and one can speculate that GDM-mediated changes to EV formation and composition could contribute to maternal vascular dysfunction as well.

In summary, James-Allan et al. have established a novel method of utilizing chronic administration of human sEVs into pregnant mice. Using this model, the authors provide exciting evidence to suggest a role for sEVs in regulating maternal glucose homeostasis in GDM. This foundational work should lead to further mechanistic studies aimed at fully elucidating the significance of this signaling pathway in GDM pathogenesis and assessing its value as a therapeutic target.

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

The authors declare that there are no competing interests associated with the manuscript.

Agafe Bless Reyes: Conceptualization, Formal analysis, Writing—original draft, Writing—review & editing. Dylan Burger: Conceptualization, Resources, Supervision, Methodology, Writing—original draft, Project administration, Writing—review & editing.

EV

extracellular vesicle

GDM

gestational diabetes mellitus

GSIS

glucose stimulated insulin secretion

sEV

small EV

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