Expression of Natural Cytotoxicity Receptors on and Intracellular Cytokine Production by NK Cells in Women with Gestational Diabetes Mellitus

Abstract

Gestational diabetes mellitus (GDM) is characterized by glucose intolerance that is caused by metabolic changes during pregnancy, and is considered a risk factor for the occurrence of DM in future. There are studies that reported changes in the cytokine in women with GDM. The concentration of serum IFN-γ and adiponectin decreased, while serum leptin, IL-6, IL-10, and TNF-α increased in GDM women when compared to that in healthy pregnant women. 16 17 Placenta and adipose tissues from patients with GDM released higher amounts of TNF-α in response to high glucose than that from normal pregnant women.18 Plasma TNF-α were reported to be low during the first and second trimester, but it increased during late pregnancy, and was inversely correlated with the insulin sensitivity. 19, 20 However, the relationship between GDM and the functions of NK cells in pregnant women has not been clarified so far. The purpose of this study was to evaluate the expression of peripheral blood NK (pNK) cell surface markers (CD16, NKp46, and NKp30) and the percentage of cytokine (IFN-γ, TNF-α, TGF-β, and VEGF) producing pNK cells in women with / without GDM at 12 weeks of pregnancy. 2 Materials and Methods Study SubjectsWe designed a prospective study and patients from Hirosaki University Hospital were recruited for this study between July 2014 and March 2015. This study was approved by the local ethics committee, and signed informed consent forms were obtained from all study subjects. Blood samples were collected during routine blood tests for prenatal check-up at 12weeks of gestation.Thirty-four Japanese women (GDM (n=7), non-GDM (n=27)) with singleton pregnancy were included. All GDM patients were diagnosed at 12 to 16 weeks of gestation. Pregnant women with multi-fetal gestations, pre-gestational diabetes, and overt diabetes were excluded, while pregnant women with impaired glucose tolerance before the onset of pregnancy were included in this study. Maternal and neonatal characteristics are shown in Table 1. Two-hour-glucose level of 75-g OGTT in GDM group was significantly higher than that in the non-GDM group.There were no complications reported in the newborn infants (such as macrosomia, shoulder dystocia, and hypoglycemia) in both the GDM and non-GDM groups and there were no pregnant women suffering from PE in both the GDM and non-GDM groups. Screening of GDMAll pregnant women were subjected to a two-step screening method for GDM. This screening method is based on the Guideline for Obstetrical Practice in Japan 2014. 21 Briefly, women who had a random plasma glucose level of ≥95mg/dl at 12 weeks of gestation were subjected to 75-g OGTT after fasting overnight. Diagnosis of GDM was based on the criteria of one or more abnormal values [fasting ≥92mg/dl (5.1mmol/l), such as 1 hour ≥180mg/dl (10.0mmol/l) or 2 hour ≥153mg / dl (8.5mmol/l)] reported for the subjects. Pregnant women, not diagnosed as GDM at 12 weeks of screening, were again subjected to random blood glucose measurement at 3 28 weeks of gestation. Women with random...

Impaired Treg and NK cells profile in overweight women with gestational diabetes mellitus

“…Hara et al found lower number of circulating NK cells in GDM, but did not analyze the percentage of cell subpopulations according to the level of CD56 expression. In contrast and in line with our results, Chiba et al observed higher percentage of CD56 dim cells and lower of NK CD56 bright cells in pregnant women with GDM.…”

Expression of natural cytotoxicity receptors and cytokine production on endometrial natural killer cells in women with recurrent pregnancy loss or implantation failure, and the expression of natural cytotoxicity receptors on peripheral blood natural killer cells in pregnant women with a history of recurrent pregnancy loss

“…In conclusion, we have demonstrated the importance of NKp46 in reproduction. We have reported decreased expression of NKp46 in peripheral blood in women with previous reproductive failures, such as RPL and implantation failure, in peritoneal fluid in women with pelvic endometriosis, and in peripheral blood in pregnant women with gestational diabetes mellitus . These studies suggest that regulation of NKp46 expression in various types of NK cells may be one of the key factors in reproductive failure.…”

“…We have reported decreased expression of NKp46 in peripheral blood in women with previous reproductive failures, such as RPL and implantation failure, 16,26,27,34,35 in peritoneal fluid in women with pelvic endometriosis, 36 and in peripheral blood in pregnant women with gestational diabetes mellitus. 37 These studies suggest that regulation of NKp46 expression in various types of NK cells may be one of the key factors in reproductive failure. Additionally, analysis of NKp46 expression may be a useful tool to investigate and diagnose reproductive failures, such as RPL and implantation failure.…”

Unveiling the pathophysiology of gestational diabetes: Studies on local and peripheral immune cells

“…The authors suggest that hyperglycaemia leads to an inflammatory condition associated with increased expression of cytotoxic cells. Chiba et al in a prospective study showed higher percentages of cytotoxic NK, lower frequencies of cytokine‐secreting NK cells and NKCD56 bright /NKp46 + in the diabetic patients compared to the controls. They also found increased IFN‐γ‐ and TNF‐α‐producing CD56 + cells and decreased TGF‐β and VEGF‐producing CD56 + cells in GDM patients.…”