Lachnospiraceae-derived butyrate mediates protection of high fermentable fiber against placental inflammation in gestational diabetes mellitus.

Inflammation-associated insulin resistance is a key trigger of gestational diabetes mellitus (GDM), but the underlying mechanisms and effective interventions remain unclear. Here, we report the association of placental inflammation (tumor necrosis factor-α) and abnormal maternal glucose metabolism in patients with GDM, and a high fermentable dietary fiber (HFDF; konjac) could reduce GDM development through gut flora-short-chain fatty acid-placental inflammation axis in GDM mouse model. Mechanistically, HFDF increases abundances of Lachnospiraceae and butyrate, reduces placental-derived inflammation by enhancing gut barrier and inhibiting the transfer of bacterial-derived lipopolysaccharide, and ultimately resists high-fat diet-induced insulin resistance. Lachnospiraceae and butyrate have similar anti-GDM and anti-placental inflammation effects, and they can ameliorate placental function and pregnancy outcome effects probably by dampening placental immune dysfunction. These findings demonstrate the involvement of important placental inflammation-related mechanisms in the progression of GDM and the great potential of HFDFs to reduce susceptibility to GDM through gut-flora-placenta axis.

Placenta-derived exosomal miR-135a-5p promotes gestational diabetes mellitus pathogenesis by activating PI3K/AKT signalling pathway via SIRT1.

Most people are aware of gestational diabetes mellitus (GDM), a dangerous pregnancy complication in which pregnant women who have never been diagnosed with diabetes develop chronic hyperglycaemia. Exosomal microRNA (miRNA) dysregulation has been shown to be a key player in the pathophysiology of GDM. In this study, we looked into how placental exosomes and their miRNAs may contribute to GDM. When compared to exosomes from healthy pregnant women, it was discovered that miR-135a-5p was elevated in placenta-derived exosomes that were isolated from the maternal peripheral plasma of GDM women. Additionally, we discovered that miR-135a-5p encouraged HTR-8/SVneo cell growth, invasion and migration. Further research revealed that miR-135a-5p activates HTR-8/SVneo cells' proliferation, invasion and migration by promoting PI3K/AKT pathway activity via Sirtuin 1 (SIRT1). The transfer of exosomal miR-135a-5p generated from the placenta could be viewed as a promising agent for targeting genes and pertinent pathways involved in GDM, according to our findings.

High TXNIP expression accelerates the migration and invasion of the GDM placenta trophoblast.

INTRODUCTION: Our previous study has proofed the glucose sensitive gene-thioredoxin-interacting protein (TXNIP) expression was up in the placenta of the patients with gestational diabetes mellitus (GDM), but the pathological mechanisms underlying abnormal TXNIP expression in the placenta of patients with GDM is completely unclear and additional investigations are required to explain the findings we have observed. In the present study, we simulated the high TXNIP expression via introducing the Tet-On "switch" in vitro, approximate to its expression level in the real world, to explore the following consequence of the abnormal TXNIP. METHODS: The expression and localization of TXNIP in the placenta of GDM patients and the health control was investigated via immunofluorescent staining, western blot and RT-qPCR. Overexpression of TXNIP was achieved through transfecting Tet-on system to the human trophoblastic cell line-HTR-8/Svneo cell. TXNIP knockout was obtained via CRISPR-Cas9 method. The cell phenotype was observed via IncuCyte Imaging System and flow cytometry. The mechanism was explored via western blot and RT-qPCR. RESULTS: The expression level of TXNIP in the GDM placenta was nearly 2-3 times higher than that in the control. The TXNIP located at trophoblastic cells of the placenta. When the expression of TXNIP was upregulated, the migration and invasion of the cells accelerated, but cell apoptosis and proliferation did not changed compared with the control group. Furthermore, the size of the TetTXNIP cells became larger, and the expression level of Vimentin and p-STAT3 increased in the TetTXNIP cells. All the changes mentioned above were opposite in the TXNIP-KO cells. CONCLUSIONS: Abnormal expression of TXNIP might be related to the impairment of the GDM placental function, affecting the migration and invasion of the placental trophoblast cells through STAT3 and Vimentin related pathway; thus, TXNIP might be the potential therapeutic target for repairing the placental dysfunction deficient in GDM patients.

Associations of gestational diabetes and proton density fat fraction of vertebral bone marrow and paraspinal musculature in premenopausal women.

Background and objective: Fat content in bones and muscles, quantified by magnetic resonance imaging (MRI) as a proton density fat fraction (PDFF) value, is an emerging non-invasive biomarker. PDFF has been proposed to indicate bone and metabolic health among postmenopausal women. Premenopausal women with a history of gestational diabetes (GDM) carry an increased risk of developing type 2 diabetes and an increased risk of fractures. However, no studies have investigated the associations between a history of GDM and PDFF of bone or of paraspinal musculature (PSM), composed of autochthonous muscle (AM) and psoas muscle, which are responsible for moving and stabilizing the spine. This study aims to investigate whether PDFF of vertebral bone marrow and of PSM are associated with a history of GDM in premenopausal women. Methods: A total of 37 women (mean age 36.3 ± 3.8 years) who were 6 to 15 months postpartum with (n=19) and without (n=18) a history of GDM underwent whole-body 3T MRI, including a chemical shift encoding-based water-fat separation. The PDFF maps were calculated for the vertebral bodies and PSM. The cross-sectional area (CSA) of PSM was obtained. Associations between a history of GDM and PDFF were assessed using multivariable linear and logistic regression models. Results: The PDFF of the vertebral bodies was significantly higher in women with a history of GDM (GDM group) than in women without (thoracic: median 41.55 (interquartile range 32.21-49.48)% vs. 31.75 (30.03-34.97)%; p=0.02, lumbar: 47.84 (39.19-57.58)% vs. 36.93 (33.36-41.31)%; p=0.02). The results remained significant after adjustment for age and body mass index (BMI) (p=0.01-0.02). The receiver operating characteristic curves showed optimal thoracic and lumbar vertebral PDFF cutoffs at 38.10% and 44.18%, respectively, to differentiate GDM (AUC 0.72 and 0.73, respectively, sensitivity 0.58, specificity 0.89). The PDFF of the AM was significantly higher in the GDM group (12.99 (12.18-15.90)% vs. 10.83 (9.39-14.71)%; p=0.04) without adjustments, while the CSA was similar between the groups (p=0.34). Conclusion: A history of GDM is significantly associated with a higher PDFF of the vertebral bone marrow, independent of age and BMI. This statistical association between GDM and increased PDFF highlights vertebral bone marrow PDFF as a potential biomarker for the assessment of bone health in premenopausal women at risk of diabetes.

MicroRNA-195-5p facilitates endothelial dysfunction by inhibiting vascular endothelial growth factor A in gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a common disorder during pregnancy associated with endothelial dysfunction in the placental vasculature. MicroRNAs (miRNAs), which are short noncoding RNAs that modulate post-transcriptional gene expression, affect GDM progression. MiR-195-5p was reported to be a putative biomarker for GDM diagnosis, whose expression was markedly elevated in serum of GDM patients. Therefore, our study intended to explore whether miR-195-5p regulates endothelial cell dysfunction in GDM. Human placental microvascular endothelial cells (hPMECs) were treated with high concentration of glucose to establish an in vitro GDM model. The apoptosis, proliferation and angiogenesis of hPMECs were detected by flow cytometry analysis, CCK-8 assay and tube formation assay. The binding between vascular endothelial growth factor A (VEGFA) and miR-195-5p was verified by luciferase reporter assay. GDM mouse model was established by intraperitoneal injection of streptozocin. Cell apoptosis and the pathological changes in GDM mouse placenta tissues were evaluated by TUNEL staining and HE staining. Gene expression was detected by RT-qPCR. Protein levels were evaluated by western blotting. In this study, miR-195-5p knockdown promoted the proliferation and angiogenesis as well as inhibited the apoptosis of HG-treated hPMECs. MiR-195-5p targeted VEGFA, whose expression was downregulated in HG-treated hPMECs. VEGFA silencing antagonized the influence of miR-195-5p knockdown on the phenotypes of HG-treated hPMECs. Additionally, miR-195-5p inhibition decelerated cell apoptosis and improved pathological changes in GDM mouse placenta tissues. MiR-195-5p level was negatively correlated to VEGFA level in GDM mouse placenta tissues. Overall, miR-195-5p facilitates the endothelial cell dysfunction by inhibiting VEGFA in GDM.

Gestational diabetes mellitus induces placental vasculopathies.

Gestational diabetes mellitus (GDM) poses significant long- and short-term risks to both the developing fetus and the mother. GDM can lead to maternal complications during pregnancy and increase the mother's risk of developing type 2 diabetes mellitus and cardiovascular disease later. The present study aimed to evaluate the maternal and fetal vasculopathies in the placenta of Saudi women with GDM. This prospective study examined 84 placentas from full-term pregnant women with no complications other than GDM; 40 placentas were collected from healthy women (controls), and 44 were collected from women diagnosed with GDM. The sampling took place in King Saud University Medical City, Riyadh, between January and August 2019. All placentas were histologically examined according to the Amsterdam Placental Workshop Group (2014, 2015). The results showed that the most common placental changes on the maternal side of the placenta in the GDM group were significant syncytial knots (77%), calcification (70%), villous agglutination (57%), decidual vasculopathy (43%), and retroplacental hemorrhage (34%). Placental infarction was the least common placental change in both groups. On the fetal side, vasculopathies included significant villous fibrinoid necrosis (70.5%), chorangiosis (50%), fibromuscular sclerosis (50%), and villous edema (38.6%). Significant villous fibrinoid necrosis, villous edema, and significant fibromuscular sclerosis were more prevalent in the GDM group. The present study concluded that gestational diabetes mellitus induces histopathological phenotypes in the full-term placenta. Increased decidual vasculopathy, syncytial knots, retroplacental hemorrhage, classification, villous agglutination, chorangiosis, villous edema, villous fibroid necrosis, and fibromuscular sclerosis may indicate GDM in the mother. Such findings in the placenta of a woman who has not been diagnosed with GDM increase the need for GDM examination in future pregnancies.

Downregulation of large-conductance Ca2+-activated K+ channels in human umbilical arterial smooth muscle cells in gestational diabetes mellitus.

AIMS: We investigated the changes in large-conductance Ca2+-activated K+ (BKCa) channels from human umbilical arterial smooth muscle cells experiencing gestational diabetes mellitus (GDM). MAIN METHODS: Whole-cell patch-clamp technique, arterial tone measurement, RT-PCR, Quantitative real-time PCR, western blot were performed in human umbilical arterial smooth muscle cells. KEY FINDINGS: Whole-cell BKCa current density was decreased in the GDM group compared with the normal group. The vasorelaxant effects of the synthetic BKCa channel activator NS-1619 (10 µM) were impaired in the GDM group compared with the normal group. Reverse-transcription polymerase chain reaction (RT-PCR), real-time RT-PCR, and western blot analyses suggested that the mRNA, total RNA, and protein expression levels of the BKCa channel were decreased in the GDM group relative to the normal group. In addition, the expression levels of protein kinase A and protein kinase G, which regulate BKCa channel activity, remained unchanged between the groups. Applying the BKCa channel inhibitor paxilline (10 µM) induced vasoconstriction and membrane depolarization of isolated umbilical arteries in the normal group but showed less of an effect on umbilical arteries in the GDM group. SIGNIFICANCE: Our results demonstrate for the first time impaired BKCa current and BKCa channel-induced vasorelaxation activities that were not caused by impaired BKCa channel-regulated protein kinases, but by decreased expression of the BKCa channels, in the umbilical arteries of GDM patients.

Regulatory role of Apelin-13-mediated PI3K/AKT signaling pathway in the glucose and lipid metabolism of mouse with gestational diabetes mellitus.

OBJECTIVE: To investigate the regulatory mechanism of Apelin-13-mediated PI3K/AKT signaling pathway in the glucose and lipid metabolism of gestational diabetes mellitus (GDM) mouse. METHODS: GDM mice models were established and treated with Apelin-13 and/or PI3K/AKT inhibitor LY294002. Then, the indicators of glucose and lipid metabolism and the levels of inflammatory factors were detected. Besides, the levels of indicators of oxidative stress in the placenta of mice were measured. Western blotting was also carried out to determine the expression of PI3K/AKT pathway-related proteins in all groups. RESULTS: In comparison with the Control group, mice in the GDM group presented with the continuous increase in the level of FBG as the time went on, while FINS level decreased evidently. Besides, the fetus alive ratio in the GDM group was much lower with significant increased weight of fetal mouse and weight of placenta; the mice had significant decreased levels of IL-6, IL-1ß, TNF-α and MCP-1, and in the placenta, the levels of SOD, GPx, GSH and CAT were also reduced evidently, with significant downregulation of p-PI3K/PI3K and p-AKT/AKT. However, indicators above in the GDM mice treated with Apelin-13 had significant improvement as compared to those in the GDM group, and the improvement was reversed by LY294002 treatment. CONCLUSION: Apelin-13, possibly by activating the PI3K/AKT pathway, could improve the glucose and lipid metabolism, reduce the damage caused by oxidative stress and inflammatory reaction, and protect the pancreas islet, thereby improving the pregnancy outcome of GDM mice.

The Effect of Dietary Supplements on Oxidative Stress in Pregnant Women with Gestational Diabetes Mellitus: A Network Meta-Analysis.

BACKGROUND: Gestational diabetes mellitus (GDM) exacerbates the oxidative stress status of the pregnant women. Τo improve the oxidative stress status, several therapeutic interventions have been suggested. The aim of this network meta-analysis is to assess the effect of different dietary supplements on the oxidative stress status in pregnant women with GDM. METHODS: A network meta-analysis of randomized control trials was performed comparing the changes delta (Δ) in total antioxidant capacity (TAC) and concentration of malondialdehyde (MDA) as primary outcomes, following different therapeutic interventions with dietary supplements in pregnant women with GDM. Four electronic databases and grey literature sources were searched. The secondary outcomes were other markers of oxidative stress. RESULTS: The meta-analysis included 16 studies of 1173 women with GDM. Regarding ΔTAC: probiotics and omega-3 with vitamin E were superior to placebo/no intervention. Regarding ΔMDA: vitamin D with calcium, omega-3, vitamin D, omega-3 with vitamin E, magnesium with zinc and calcium, and probiotics were superior to placebo/no intervention. CONCLUSIONS: Administration of dietary supplements in women with GDM can be helpful in limiting the oxidative stress which develop in these pregnancies.

High total cholesterol and triglycerides levels increase arginases metabolism, impairing nitric oxide signaling and worsening fetoplacental endothelial dysfunction in gestational diabetes mellitus pregnancies.

Maternal physiological dyslipidemia (MPD) supports fetal development in human pregnancy. However, some women develop maternal supraphysiological dyslipidemia (MSPD: increased total cholesterol (TC) and triglycerides (TG) levels). MSPH is present in normal and also in gestational diabetes mellitus (GDM) pregnancies. MSPD and GDM associate with fetoplacental endothelial dysfunction, producing alterations in nitric oxide (NO)-L-arginine/arginase metabolism. Nevertheless, the effect of MSPD on GDM, and how this synergy alters fetoplacental endothelial function is unknown. Therefore, the aim of this study was to evaluate in human umbilical vein endothelial cells, the effects of MSPD in GDM and how these pathologies together affect the fetoplacental endothelial function. 123 women at term of pregnancy were classified as MPD (n = 40), MSPD (n = 35), GDM with normal lipids (GDM-MPD, n = 23) and with increased lipids (GDM-MSPD, n = 25). TC ≥291 mg/dL and TG ≥275 mg/dL were considered as MSPD. Endothelial NO synthase (eNOS), human cationic amino acid transporter 1 (hCat1), and arginase II protein abundance and activity, were assayed in umbilical vein endothelial cells. In MSPD and GDM-MSPD, TC and TG increased respect to MPD and GDM-MPD. eNOS activity was reduced in MSPD and GDM-MSPD, but increased in GDM-MPD compared with MPD. However, decreased tetrahydrobiopterin levels were observed in all groups compared with MPD. Increased hCat1 protein and L-arginine transport were observed in both GDM groups compared with MPD. However, the transport was higher in GDM-MSPD compared to GDM-MPD. Higher Arginase II protein and activity were observed in GDM-MSPD compared with MPD. Thus, MSPD in GDM pregnancies alters fetal endothelial function associated with NO metabolism.

MicroRNA-362-5p promotes the proliferation and inhibits apoptosis of trophoblast cells via targeting glutathione-disulfide reductase.

Gestational diabetes mellitus (GDM), a common complication of pregnancy, harms the health of pregnant women and fetuses. MicroRNAs (miRNAs) dysregulation in placenta is involved in GDM. Herein, we explored the roles of miR-362-5p in GDM. After high glucose (HG) treated HTR-8/SVneo cells, CCK-8 and flow cytometry were conducted to assess the capability of the proliferation and apoptosis, respectively. The data demonstrated that HG inhibited proliferation and induced apoptosis of HTR-8/SVneo cells. MiR-362-5p level was reduced in HG-treated cells and placenta tissues of GDM patients, measured by qPCR. Overexpressed miR-362-5p accelerated the proliferation and restrained apoptosis of HG-treated cells. Furthermore, glutathione-disulfide reductase (GSR) was verified as a target of miR-362-5p, through TargetScan database and dual-luciferase reporter assay. GSR was upregulated in GDM placenta tissues and was negatively regulated by miR-362-5p. Enforced GSR level abolished the effects of miR-362-5p overexpression on the proliferation and apoptosis of HTR-8/SVneo cells. Furthermore, miR-362-5p increased p-PI3K, p-AKT and bcl-2, while reduced bax and cleaved caspase3, which were abolished by GSR. In conclusion, miR-362-5p promoted cell proliferation and inhibited apoptosis via targeting GSR and activating PI3K/AKT pathway. The findings mentioned above suggested that miR-362-5p might be a therapy target of GDM.

Oestrogen receptor α in T cells controls the T cell immune profile and glucose metabolism in mouse models of gestational diabetes mellitus.

AIMS/HYPOTHESIS: The imbalance between maternal insulin resistance and a relative lack of insulin secretion underlies the pathogenesis of gestational diabetes mellitus (GDM). Alterations in T cell subtypes and increased levels of circulating proinflammatory cytokines have been proposed as potential mechanisms underlying the pathophysiology of insulin resistance in GDM. Since oestrogen modulates T cell immunity, we hypothesised that oestrogen plays a homeostatic role in visceral adipose tissue by coordinating T cell immunity through oestrogen receptor α (ERα) in T cells to prevent GDM. METHODS: Female CD4-cre ERαfl/fl (KO) mice on a C57BL/6 background with ERα ablation specifically in T cells, and ERαfl/fl (ERα-floxed [FL]) mice were fed 60 kJ% high-fat diet (HFD) for 4 weeks. Female mice mated with male BALB/c mice to achieve allogenic pregnancy and were maintained on an HFD to generate the GDM model. Mice were divided into four experimental groups: non-pregnant FL, non-pregnant KO, pregnant FL (FL-GDM) and pregnant KO (KO-GDM). GTTs and ITTs were performed on day 12.5 or 13.5 and 16.5 after breeding, respectively. On day 18.5 after breeding, mice were killed and T cell subsets in the gonadal white adipose tissue (gWAT) and spleen were analysed using flow cytometry. Histological examination was also conducted and proinflammatory gene expression in gWAT and the liver was evaluated. RESULTS: KO mice that mated with BALB/c mice showed normal fertility rates and fetal weights as compared with FL mice. Body and tissue weights were similar between FL and KO mice. When compared with FL-GDM mice, KO-GDM mice showed decreased insulin secretion (serum insulin concentration 15 min after glucose loading: 137.3 ± 18.3 pmol/l and 40.1 ± 36.5 pmol/l, respectively; p < 0.05), impaired glucose tolerance (glucose AUC in GTT: 2308.3 ± 54.0 mmol/l × min and 2620.9 ± 122.1 mmol/l × min, respectively; p < 0.05) and increased numbers of T helper (Th)17 cells in gWAT (0.4 ± 0.0% vs 0.8 ± 0.1%; p < 0.05). However, the contents of Th1 and regulatory T cells (Tregs) in gWAT remained similar between FL-GDM and KO-GDM. Glucose-stimulated insulin secretion was similar between isolated islets derived from FL and KO mice, but was reduced by IL-17A treatment. Moreover, the levels of proinflammatory gene expression, including expression of Emr1 and Tnfa in gWAT, were significantly higher in KO-GDM mice than in FL-GDM mice (5.1-fold and 2.7-fold, respectively; p < 0.01 for both). Furthermore, KO-GDM mice showed increased expression of genes encoding hepatokines, Ahsg and Fgf21 (both were 2.4-fold higher vs FL-GDM mice; p < 0.05 and p = 0.09, respectively), with no changes in inflammatory gene expression (e.g., Tnfa and Ifng) in the liver compared with FL-GDM mice. CONCLUSIONS/INTERPRETATION: Deletion of ERα in T cells caused impaired maternal adaptation of insulin secretion, changes in hepatokine profiles, and enhanced chronic inflammation in gWAT alongside an abnormal increase in Th17 cells. These results suggest that the ERα-mediated oestrogen signalling effects in T cells regulate T cell immunity and contribute to glucose homeostasis in pregnancy.

Stromal Cell-Derived Factor (SDF) 2 and the Endoplasmic Reticulum Stress Response of Trophoblast Cells in Gestational Diabetes Mellitus and In vitro Hyperglycaemic Condition.

BACKGROUND AND AIM: The endoplasmic reticulum (ER) stress response and the unfolded protein response (UPR) are essential cellular mechanisms to ensure the proper functioning of ER in adverse conditions. However, activation of these pathways has also been associated with insulin resistance and cell death in pathological conditions such as diabetes mellitus. In the present study, we investigated whether stromal cell-derived factor 2 (SDF2)-an ER stress-responsive factor-is related to ER response in placental cells exposed to maternal gestational diabetes mellitus (GDM) or to a hyperglycaemic in vitro condition. OBJECTIVE: The study aimed to investigate the role of SDF2 in BeWo cells , a trophoblast cell line originating from choriocarcinoma , and in placental tissue under hyperglycaemic conditions. METHODS: Protein levels of SDF2 and UPR factors, glucose-related protein 78 (GRP78) and eukaryotic initiation factor 2 alpha (elF2 alpha) were evaluated in the placentae of pregnant women diagnosed with GDM and treated by diet-control (insulin was added when necessary). The mRNA expression of SDF2 and UPR factors CHOP and sXBP1 were assessed in cultured BeWo cells challenged with glucose and treated with or without insulin. RESULTS: SDF2 expression was increased in the placentae of GDM women treated with diet. However, its values were similar to those of normoglycemic controls when the GDM women were treated with insulin and diet. BeWo cells cultured with high glucose and insulin showed decreased SDF2 expression, while high glucose increased CHOP and sXBP1 expression, which was then significantly reverted with insulin treatment. CONCLUSION: Our findings extend the understanding of ER stress and SDF2 expression in placentae exposed to hyperglycaemia, highlighting the relevance of insulin in reducing the levels of ER stress factors in placental cells. Understanding the effect of ER stress partners such as SDF2 on signalling pathways involved in gestation, complicated by hyperglycaemia, is pivotal for basic biomedical research and may lead to new therapeutic possibilities.

RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy.

Successful pregnancies rely on adaptations within the mother1, including marked changes within the immune system2. It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy3. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK4,5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (Treg) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic Treg cells through RANK in a manner that depends on AIRE+ medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural Treg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of Treg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of Treg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of Treg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic Treg cells during pregnancy, and expand the functional role of maternal Treg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis.

The Impacts of Fish Oil and/or Probiotic Intervention on Low-Grade Inflammation, IGFBP-1 and MMP-8 in Pregnancy: A Randomized, Placebo-Controlled, Double-Blind Clinical Trial.

BACKGROUND: We investigated the impact of fish oil and/or probiotics on serum and vaginal inflammatory and metabolic proteins and their relation to the onset of gestational diabetes mellitus (GDM). METHODS: Overweight/obese pregnant women received fish oil + placebo, probiotics + placebo, fish oil + probiotics or placebo + placebo from early pregnancy until six months postpartum (fish oil: 1.9 g docosahexaenoic acid and 0.22 g eicosapentaenoic acid; probiotics: Lactobacillus rhamnosus HN001 and Bifidobacterium animalis ssp. lactis 420, 1010 colony-forming units each). Serum high sensitivity C-reactive protein (hsCRP) and serum/vaginal (s/v) phosphorylated insulin-like growth factor binding-protein-1 (phIGFBP-1), IGFBP-1 and matrix metalloproteinase 8 (MMP-8) were analyzed. GDM was diagnosed according to 2 h 75 g OGTT. RESULTS: The intervention had no impact on the change in proteins during pregnancy. Nevertheless, s-MMP-8 decreased and s-IGFBP-1 increased more in obese than in overweight women in the fish oil + probiotics group, while a decrease in s-MMP-8 was seen in obese women and an increase was seen in overweight women in the probiotics + placebo group. The late pregnancy s-phIGFBP-1 was higher in women who developed GDM in fish oil + probiotics-group compared to fish oil + placebo-group. The concentrations of s-phIGFBP-1 (635.9 ± 315.3 ng/mL vs. 753.2 ± 335.1 ng/mL, p = 0.005) and s-IGFBP-1 (3.78 ± 0.72 ng/mL vs. 3.96 ± 0.69 ng/mL, p = 0.042) were lower in early pregnancy in women who developed GDM than in women remaining healthy. CONCLUSIONS: The intervention per se had no impact on the proteins, but obesity and GDM may modify the effect. IGFBPs may affect the development of GDM.

[Screening for gestational diabetes due to of the COVID-19 pandemic].

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a virus that causes coronavirus disease in 2019 (COVID-19). Currently, there is no evidence that pregnant women are more vulnerable to COVID-19. All concerns and anticipated risks are related to the potential impact of COVID-19 on perinatal outcomes, so pregnant women require special attention in relation to the preventive measures, diagnosis and treatment of a new coronavirus disease. Women with gestational diabetes mellitus (GDM) belong to the group of high perinatal risk and need timely medical assistance. During the COVID-19 pandemic, there is a necessity in temporary changes of approaches to diagnosing GSD and pregnancy care before and after delivery in women with GSD. The purpose of our review is to present and analyze all available GSD screening recommendations, updated and published in various countries in response to the coronavirus pandemic, at the time of publication of this article. It seems that there is no single universal strategy to achieve a reasonable balance. In this regard, it is necessary to develop new national algorithms for GSD screening, taking into account both demographic factors and the features and capabilities of our health system. We believe that the knowledge and experience achieved as a result of these changes will lead to the revision and improvement of national and international recommendations.

The effect of vascular complications of diabetes mellitus on human umbilical cord tissue and the number of Wharton Jelly's mesenchymal stem cells.

The current study investigated the change in umbilical cord tissue and the number of markers of Wharton's jelly mesenchymal stem cells (WJ-MSC) in pregnant women with gestational diabetes (GDM), with chronic diabetes who developed nephropathy as vascular complication (VC-PGDM), and healthy pregnant women as the control. The umbilical cords (UC) were investigated by the histomorphological method and the number of WJ-MSC were detected by flow-cytometry using the CD90, CD44, CD105, and CD73 markers in Wharton's jelly (WJ) isolated from fresh umbilical cords. The number of positive cells for CD 90, CD44, CD105, and CD73 were found to be elevated in the GDM group, whereas it was significantly diminished in the VC-PGDM group (p = 0.001, p = 0.001, p = 0.001, and p = 0.001). The only histopathological sign in the GDM group were an increased number of pores in the Wharton jelly. Artery wall thickness/cord diamater ratio was increased, which indicates an increase of the artery wall thickness in the VC- PGDM group (p = 0.039 and p = 0.048). The increase in umbilical cord diameter and number of Wharton jelly mesenchymal stem cells in babies of gestational diabetic mothers was considered as an effect of macrosomia seen in babies of mothers with gestational diabetes. Vasculopathy, a long-term complication of diabetes, is known to affect all tissues by causing marked lower perfusion and hypoxia, as well as a decrease in the MSC number in our study.

Dietary Total Antioxidant Capacity and Gestational Diabetes Mellitus: A Case-Control Study.

BACKGROUND: Elevated oxidative stress status has been reported among pregnant women with gestational diabetes mellitus (GDM). In diabetic condition, glucose and lipid peroxidation, and alteration in antioxidant defense lead to increased free radicals. The objective of this study was to investigate the association between dietary total antioxidant capacity (DTAC) and GDM. METHODS: This hospital-based case-control study was conducted in 463 pregnant women (healthy, n = 263; GDM, n = 200). Anthropometric indices, blood pressure, and biochemical analyses were measured. Dietary intake was assessed by the average of three 24-hour dietary intake records. DTAC was calculated by three indices: ferric reducing ability of plasma (FRAP), total radical-trapping antioxidant parameter (TRAP), and Trolox equivalent antioxidant capacity (TEAC). Multivariable logistic regression was performed to examine the relationship between DTAC and GDM risk in crude and adjusted models. RESULTS: The mean age and BMI were 28.33 ± 6.23 years and 29.67 ± 4.73 kg/m2, respectively. Total energy, protein, and selenium intakes were significantly higher in cases than controls (P < 0.05). Moreover, intakes of carbohydrate, vitamins C, B6, and A, manganese, fruits, fruit juices, vegetables, legumes, and FRAP were significantly lower in cases than controls (P < 0.05). The risk of gestational diabetes mellitus was 85% lower among those in the highest tertile of FRAP (OR: 0.15; 95% CI: 0.08-0.29). There was no significant association between the risk of GDM and TRAP (OR: 1.62; 95% CI: 0.94-2.79) as well as TEAC (OR: 1.56; 95% CI: 0.89-2.72). CONCLUSION: Pregnant women who were in the highest tertile of FRAP were at lower risk of GDM. However, larger prospective studies are needed to confirm our findings.

Gestational Diabetes Type 2: Variation in High-Density Lipoproteins Composition and Function.

Aims: Class A2 gestational diabetes mellitus (GDMA2) has short- and long-term effects on the mother and child. These may include abnormalities of placentation, damage to endothelial cells and cardiovascular disease. This research investigated the function and composition of high-density lipoproteins (HDL) among women with GDMA2 and their fetuses. Methods: Thirty pregnant women were recruited during admission for delivery. The function and expression of HDL, paraoxonase1 (PON1) and apolipoprotein A1 (APOA1) in the blood samples and the placental tissue were evaluated. The effect of HDL on migration of endothelial cells was measured in vitro. Results: Compared to normal pregnancy (NP), APOA1 in the maternal plasma of women with GDMA2 was decreased. More APOA1 and PON1 were released from HDL of women with GDMA2, compared to NP. Placental APOA1 and PON1 were decreased in GDMA2. For endothelial cells stimulated with TNFα, HDL cell migration was decreased when cells were evaluated with NP-HDL, as compared to GDMA2-HDL. Conclusions: GDMA2 affects the composition and function of HDL in plasma. Changes in HDL commonly seen in GDMA2 were observed in maternal and placental samples, but not in cord samples. These results might indicate a placental role in protecting the fetus by preserving the components and functions of HDL and require further investigation.

Mitochondrial dysfunction in the fetoplacental unit in gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a disease of pregnancy that is associated with d-glucose intolerance and foeto-placental vascular dysfunction. GMD causes mitochondrial dysfunction in the placental endothelium and trophoblast. Additionally, GDM is associated with reduced placental oxidative phosphorylation due to diminished activity of the mitochondrial F0F1-ATP synthase (complex V). This phenomenon may result from a higher generation of reactive superoxide anion and nitric oxide. Placental mitochondrial biogenesis and mitophagy work in concert to maintain cell homeostasis and are vital mechanisms securing the efficient generation of ATP, whose demand is higher in pregnancy, ensuring foetal growth and development. Additional factors disturbing placental ATP synthase activity in GDM include pre-gestational maternal obesity or overweight, intracellular pH, miRNAs, fatty acid oxidation, and foetal (and 'placental') sex. GDM is also associated with maternal and foetal hyperinsulinaemia, altered circulating levels of adiponectin and leptin, and the accumulation of extracellular adenosine. Here, we reviewed the potential interplay between these molecules or metabolic conditions on the mechanisms of mitochondrial dysfunction in the foeto-placental unit in GDM pregnancies.