Regulation of glucose homeostasis by small extracellular vesicles in normal pregnancy and in gestational diabetes

Abstract

The mechanisms underpinning maternal metabolic adaptations to a healthy pregnancy and in gestational diabetes mellitus (GDM) remain poorly understood. We hypothesized that small extracellular vesicles (sEVs) isolated from healthy pregnant women promote islet glucose‐stimulated insulin secretion (GSIS) and peripheral insulin resistance in nonpregnant mice and that sEVs from GDM women fail to stimulate insulin secretion and cause exacerbated insulin resistance. Small EVs were isolated from plasma of nonpregnant, healthy pregnant, and GDM women at 24‐28 weeks of gestation. We developed a novel approach in nonpregnant mice involving a mini‐osmotic pump for continuous 4‐day jugular venous infusion of sEVs and determined their effects on glucose tolerance in vivo and islets and skeletal muscle in vitro. Fasting insulin was elevated in mice infused with pregnant sEVs as compared to sEVs from nonpregnant and GDM women. Mice infused with sEVs from GDM women developed glucose intolerance. GSIS was increased in mice infused with healthy pregnancy sEVs compared to mice receiving nonpregnant sEVs. GSIS and muscle basal insulin signaling, and insulin responsiveness were attenuated in mice infused with GDM sEVs. sEVs represent a novel mechanism regulating maternal glucose homeostasis in pregnancy and we speculate that altered sEV content contributes to the development of GDM.

Gestational Diabetes Mellitus—Innovative Approach to Prediction, Diagnosis, Management, and Prevention of Future NCD—Mother and Offspring

“…These circulating particles, derived in pregnancy primarily from placenta and adipose tissue, “package” multiple potential protein and RNA molecules and transport them to specific sites. James-Allan et al ( 21 ) have demonstrated that specific small ECVs are associated with GDM and that infusion of human ECVs from GDM women produces both insulin resistance and reduced insulin secretion in rodents, reminiscent of the pathophysiology of GDM.…”

Extracellular vesicles and their potential role inducing changes in maternal insulin sensitivity during gestational diabetes mellitus

“…The increased activity of DPPIV can lead to cleavage of glucose‐dependent insulinotropic peptide (GIP) which decrease the pancreatic insulin secretion 146 . Also, our study in mice models infused with sEVs from GDM patients showed decreased glucose stimulated insulin secretion from islets compared to those receiving sEVs from normal healthy pregnancy 91 . These studies provide some insights into the role of EVs in the pathophysiology of GDM.…”

“…Furthermore, the role of these EVs in contributing to the inflammatory response, such as activation of monocytes and neutrophils in pregnancy disorders such as PE, has been studied 88,89 . Finally, another important downstream application of placental EVs is their functional effects in in vivo 21,90–92 . Rodents and non‐rodents have been used for studying the physiology of human pregnancy and related disorders, and the choice of the appropriate animal model is typically based on the research question.…”

“…There are several advantages and limitations associated with each model; however, discussion of these is beyond the scope of this review. Nonetheless, murine models are commonly used for the study of EVs in pregnancy 21,90–92 . For example, placental sEVs from human placental explant cultures were labelled with fluorescent dye and inoculated in pregnant mice, showing EV localization to lungs, liver and kidney.…”

“…sEVs from GDM patients can alter the insulin‐stimulated glucose uptake in skeletal muscle in vitro, indicating the effect of EVs in regulation of maternal insulin sensitivity 74 . Interestingly, mice which were continuously infused with sEVs enriched from GDM patients developed glucose intolerance and showed changes in the miRNA profile and insulin signalling in skeletal muscle tissues, most importantly, in the phosphorylation of IRS‐1 and Akt 91 …”