Abstract
Gestational diabetes mellitus (GDM) is a unique form of glucose intolerance, in that it is transient and solely occurs in pregnancy. Pregnancies with GDM are at high risk of developing preeclampsia (PE), a leading cause of fetal and maternal morbidity or mortality. Since PE is associated with excessive activation of circulatory neutrophils and occurrence of neutrophil extracellular traps (NETs) in affected placentae, we examined these features in cases with GDM, as this could be a feature linking the two conditions. Our data indicate that neutrophil activity is indeed altered in GDM, exhibiting pronounced activation and spontaneous generation of NETs by isolated neutrophils in in vitro culture. In this manner, GDM may similarly affect neutrophil behavior and NET formation as witnessed in other forms of diabetes, with the addition of the physiological changes mediated by pregnancy. Since circulatory TNF-α levels are elevated in cases with GDM, a feature also observed in this study, we examined whether this pro-inflammatory cytokine contributed to neutrophil activation. By using infliximab, a clinically utilized TNF-α antagonist, we observed that the pro-NETotic effect of GDM sera was significantly reduced. We also detected pronounced neutrophil infiltrates in placentae from GDM cases. The occurrence of NETs in these tissues is suggested by the extracellular co-localization of citrullinated histones and myeloperoxidase. In addition, elevated neutrophil elastase (NE) mRNA and active enzymatic protein were also detected in such placentae. This latter finding could be important in the context of previous studies in cancer or diabetes model systems, which indicated that NE liberated from infiltrating neutrophils enters surrounding cells, altering cell signaling by the degradation of IRS1. These findings could potentiate the underlying inflammatory response process in GDM and possibly open an avenue for the therapeutic interventions in gestational hyperglycemia.
Highlights
Gestational diabetes mellitus (GDM) is a unique form of glucose intolerance exclusive to pregnancy and that by nature it is transient [1, 2]
As NETosis is altered in cases with Type 1 diabetes mellitus (T1DM) or Type 2 diabetes mellitus (T2DM), we examined this aspect in pregnancies affected by GDM, especially as such pregnancies are at increased risk of developing PE [9, 10]
In an exploratory examination of the NETotic activity of freshly isolated neutrophils in vitro, we observed that neutrophil extracellular traps (NETs) formation was significantly elevated in a case with GDM when compared to a matching second trimester sample (Figure 1A)
Summary
Gestational diabetes mellitus (GDM) is a unique form of glucose intolerance exclusive to pregnancy and that by nature it is transient [1, 2]. Since GDM may share some similarities with Type 2 diabetes mellitus (T2DM), such as insulin resistance or features of the metabolic syndrome, it has been suggested that GDM may be considered a pre-diabetic state or a momentary unmasking. Neutrophil Response in Gestational Diabetes of a T2DM-like condition [2]. The autoimmune component evident in Type 1 diabetes mellitus (T1DM) is not evident in GDM [1, 2]. Fueled by the pandemic in obesity and associated metabolic syndrome, GDM is rapidly becoming a global health-care concern, as it may significantly increase the incidence in T2DM due to the contribution of two parties, mother and child [3]. Neutrophils, termed polymorphonuclear neutrophil granulocytes (PMN), are currently experiencing a renaissance of scientific interest in a diverse array of human pathologies, largely due to their ability to form neutrophil extracellular traps (NETs) [14,15,16]
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