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.

Context Placental transport capacity influences fetal glucose supply. The syncytiotrophoblast is the transporting epithelium in the human placenta, expressing glucose transporters (GLUTs) and insulin receptors (IRs) in its maternal-facing microvillous plasma membrane (MVM) and fetal-facing basal plasma membrane (BM). Objective The objectives of this study were to (i) determine the expression of the insulin-sensitive GLUT4 glucose transporter and IR in the syncytiotrophoblast plasma membranes across gestation in normal pregnancy and in pregnancies complicated by maternal obesity, and (ii) assess the effect of insulin on GLUT4 plasma membrane trafficking in human placental explants. Design, Setting, and Participants Placental tissue was collected across gestation from women with normal body mass index (BMI) and mothers with obesity with appropriate for gestational age and macrosomic infants. MVM and BM were isolated. Main Outcome Measures Protein expression of GLUT4, GLUT1, and IR were determined by western blot. Results GLUT4 was exclusively expressed in the BM, and IR was predominantly expressed in the MVM, with increasing expression across gestation. BM GLUT1 expression was increased and BM GLUT4 expression was decreased in women with obesity delivering macrosomic babies. In placental villous explants, incubation with insulin stimulated Akt (S473) phosphorylation (+76%, P = 0.0003, n = 13) independent of maternal BMI and increased BM GLUT4 protein expression (+77%, P = 0.0013, n = 7) in placentas from lean women but not women with obesity. Conclusion We propose that maternal insulin stimulates placental glucose transport by promoting GLUT4 trafficking to the BM, which may enhance glucose transfer to the fetus in response to postprandial hyperinsulinemia in women with normal BMI.

Successful implantation and placentation are dependent on the interaction between decidual stromal cells (DSC) and extravillous trophoblast (EVT) cells. The extent of trophoblast invasion relies on communication between the placenta and maternal decidua. The cyclical process of decidualisation induces a transformation of endometrial fibroblasts to secretory DSC; these secreted products have many functions including the control of trophoblast invasion. Inadequate trophoblast invasion and remodelling of the uterine vessels (the spiral arteries) are associated with pregnancy disorders such as pre-eclampsia. Uterine artery Doppler resistance index (RI) in the first trimester of pregnancy can be used as a proxy measure of remodelling. DSC were isolated from pregnancies with normal (normal RI) or impaired (high RI) spiral artery remodelling. Following isolation, DSC were re-decidualised using cAMP and MPA and secretion of the decidualisation markers IGFBP-1 and prolactin assessed. We examined the impact of DSC-secreted factors on trophoblast cell function, using the EVT cell line SGHPL-4. We demonstrated that DSC exposed to decidual factors were able to re-decidualise in vitro and that the chemoattraction of trophoblasts by DSC is impaired in pregnancies with high RI. This study provides new insights into the role that DSC play in regulating EVT functions during the first trimester of pregnancy. This is the first study to demonstrate that DSC from pregnancies with impaired vascular remodelling in the first trimester secrete factors that inhibit the directional movement of trophoblast cells. This finding may be important in understanding aberrant trophoblast invasion in pregnancies where vascular remodelling is impaired.

The pathologies of the dangerous pregnancy complications pre-eclampsia (PE) and fetal growth restriction (FGR) are established in the first trimester of human pregnancy yet we know little of how this happens. Finely tuned interactions between maternal and placental cells are essential for pregnancy to progress without complications; however, the precise nature of this cross-talk and how it can go wrong are crucial questions that remain to be answered. This review summarises recent studies examining the role played by natural killer cells in regulating normal placentation and remodelling. Their involvement when it is impaired in PE/FGR pregnancies will additionally be discussed.

Small extracellular vesicles (sEVs) play a central role in cell-to-cell communication in normal physiology and in disease, including gestational diabetes mellitus (GDM) . The goal of this study was to test the hypothesis that chronic administration of sEVs isolated from GDM causes glucose intolerance in healthy pregnant mice. Small EVs were isolated from plasma between 24-28 weeks gestation from healthy pregnant women (controls) and GDM,  and infused intravenously for four days in late pregnant mice using a mini-osmotic pump. Subsequently in vivo glucose tolerance was assessed, muscle and adipose tissue insulin sensitivity and islet glucose stimulated insulin secretion (GSIS) was determined in vitro. Mice infused with sEVs from GDM developed glucose intolerance. Administration of sEVs from controls, but not sEVs from GDM women, stimulated islet GSIS and increased fasting insulin levels in pregnant mice. Neither infusion of sEVs from controls nor from GDM women affected muscle insulin sensitivity, placental insulin or mTOR signalling, placental and fetal weight. Moreover, these results were not associated with immunomodulatory effects as human sEVs do not activate mouse T-cells in vitro. We suggest that circulating sEVs regulate maternal glucose homeostasis in pregnancy and may contribute to the attenuated islet insulin secretion and more pronounced glucose intolerance in GDM as compared to healthy pregnancy.