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Background: Serotonin (5-hydroxytryptamine, 5-HT) signaling is involved in neurodevelopment, mood regulation, energy metabolism, and other physiological processes. DNA methylation plays a significant role in modulating the expression of genes responsible for maintaining 5-HT balance, such as 5-HT transporter (SLC6A4), monoamine oxidase A (MAOA), and 5-HT receptor type 2A (HTR2A). Maternal metabolic health can influence long-term outcomes in offspring, with DNA methylation mediating these effects. We investigated associations between maternal metabolic parameters—pre-pregnancy body mass index (pBMI), gestational weight gain (GWG), and glucose tolerance status (GTS), i.e., gestational diabetes mellitus (GDM) versus normal glucose tolerance (NGT)—and cord blood methylation of SLC6A4, MAOA, and HTR2A in participants from our PlaNS birth cohort. CpG sites (15, 9, and 2 in each gene, respectively) were selected based on literature and in silico data. Methylation levels were quantified by bisulfite pyrosequencing. We also examined the stability of methylation patterns in these genes in circulating blood cells from birth to adolescence using longitudinal DNA methylation data from the ARIES database. Results: None of the 203 PlaNS mothers included in this study had preexisting diabetes, 99 were diagnosed with GDM, and 104 had NGT; all neonates were born at full term by planned Cesarean section. Methylation at most CpG sites differed between male and female newborns. SLC6A4 methylation correlated inversely with maternal pBMI and GWG, while methylation at HTR2A site -1665 correlated positively with GWG. None of the maternal metabolic parameters statistically associated with MAOA methylation. DNA methylation data in cord blood and peripheral blood at ages 7 and 15 years were available for 808 participants from the ARIES database; 4 CpG sites (2 in SLC6A4 and 2 in HTR2A) overlapped between the PlaNS and ARIES cohorts. A positive correlation between methylation levels in cord blood and peripheral blood at 7 and 15 years of age was observed for both SLC6A4 and HTR2A CpG sites. Conclusions: Methylation of 5-HT regulating genes in cord blood cells is influenced by neonatal sex, with maternal metabolism playing an additional role. Inter-individual variations present in circulating blood cells at birth are still pronounced in childhood and adolescence. [ABSTRACT FROM AUTHOR]

The non-classical human leucocyte antigen (HLA) class I molecule HLA-G is widely known to play a major role in feto-maternal tolerance. We tested the hypothesis that HLA-G expression is altered in placentas of women with gestational diabetes mellitus (GDM) in a specific pattern that depends on fetal sex. HLA-G expression was analysed in a total of 80 placentas (40 placentas from women with GDM and 40 healthy controls) by immunohistochemistry using the semi-quantitative immunoreactive score (IRS). Double immunofluorescence staining identified the cells expressing HLA-G in the decidua and allowed evaluation of the expression pattern. We found a significant (p < 0.001) reduction of HLA-G expression in extravillous cytotrophoblasts (EVTs) in the placentas of women with GDM as compared to the healthy controls and were able to demonstrate that this downregulation was not due to a loss of cell number, but to a loss of expression intensity. A special change in the cell pattern of EVTs was observed, with these cells showing an obvious decrease in HLA-G expression on their cell surface. No significant differences according to fetal sex were found. These data show a possible association between decreased HLA-G expression and presence of GDM and provide new insights into altered placental function in women with GDM. [ABSTRACT FROM AUTHOR]

Serotonin signaling plays an important role in regulating development and functions of the placenta. We hypothesized that metabolic disturbances associated with maternal obesity and/or gestational diabetes mellitus (GDM) affect placental serotonin homeostasis. Therefore, we examined the effects of high glucose (25 mM) and insulin (10 nM)—two hallmarks of maternal obesity and GDM—on mRNA expression of key regulators of serotonin homeostasis, including serotonin transporter (SERT), tryptophan hydroxylase 1 (TPH1), and monoamine oxidase A (MAOA), in the first-trimester trophoblast cell line ACH-3P, focusing on oxygen levels characteristic of early human placental development. Glucose downregulated expression of SERT and MAOA independently of oxygen level and upregulated expression of TPH1 at 6.5% oxygen but not at 2.5% oxygen. Compared to 6.5% oxygen, 2.5% oxygen upregulated SERT and downregulated TPH1 expression, with no effect on MAOA expression. Insulin upregulated SERT only at 2.5% oxygen but had no effect on TPH1 and MAOA expression. These results suggest that maternal metabolic alterations in early pregnancy may be a driving force for changes in placental serotonin homeostasis. [ABSTRACT FROM AUTHOR]

Pregravid obesity is one of the major risk factors for pregnancy complications such as gestational diabetes mellitus (GDM) and an increased risk of cardiovascular events in children of affected mothers. However, the biological mechanisms that underpin these adverse outcomes are not well understood. High-density lipoproteins (HDLs) are antiatherogenic by promoting the efflux of cholesterol from macrophages and by suppression of inflammation. Functional impairment of HDLs in obese and GDM-complicated pregnancies may have long-term effects on maternal and offspring health. In the present study, we assessed metrics of HDL function in sera of pregnant women with overweight/obesity of the DALI lifestyle trial (prepregnancy BMI ≥ 29 kg/m2) and women with normal weight (prepregnancy BMI < 25 kg/m2), as well as HDL functionalities in cord blood at delivery. We observed that pregravid obesity was associated with impaired serum antioxidative capacity and lecithin–cholesterol acyltransferase activity in both mothers and offspring, whereas maternal HDL cholesterol efflux capacity was increased. Interestingly, functionalities of maternal and fetal HDL correlated robustly. GDM did not significantly further alter the parameters of HDL function and metabolism in women with obesity, so obesity itself appears to have a major impact on HDL functionality in mothers and their offspring. [ABSTRACT FROM AUTHOR]

Maternal diabetes and/or obesity in pregnancy are undoubtedly associated with later disease-risk in the offspring. The placenta, interposed between the mother and the foetus, is a potential mediator of this risk through epigenetic mechanisms, including DNA methylation. In recent years, multiple studies have identified differentially methylated CpG sites in the placental tissue DNA in pregnancies complicated by diabetes and obesity. We reviewed all published original research relevant to this topic and analysed our findings with the focus of identifying overlaps, contradictions, and gaps. Most studies focused on the association of gestational diabetes and/or hyperglycaemia in pregnancy and DNA methylation in placental tissue at term. We identified overlaps in results related to specific candidate genes, but also observed a large research gap of pregnancies affected by type 1 diabetes. Other unanswered questions relate to analysis of specific placental cell types and the timing of DNA methylation change in response to diabetes and obesity during pregnancy. Maternal metabolism is altered already in the first trimester involving structural and functional changes in the placenta, but studies into its effects on placental DNA methylation during this period are lacking and urgently needed. Foetal sex is also an important determinant of pregnancy outcome, but only few studies have taken this into account. Collectively, we provide a reference work for researchers working in this large and evolving field. Based on the results of the literature review, we formulate suggestions for future focus of placental DNA methylation studies in pregnancies complicated by diabetes and obesity. [ABSTRACT FROM AUTHOR]

Background Interactions between polymorphisms of the melatonin receptor 1B (MTNR1B) gene and lifestyle intervention for gestational diabetes have been described. Whether these are specific for physical activity or the healthy eating intervention is unknown. Objectives The aim was to assess the interaction between MTNR1B rs10830962 and rs10830963 polymorphisms and lifestyle interventions during pregnancy. Methods Women with a BMI (in kg/m2) of ≥29 (n  = 436) received counseling on healthy eating (HE), physical activity (PA), or both. The control group received usual care. This secondary analysis had a factorial design with comparison of HE compared with no HE and PA compared with no PA. Maternal outcomes at 24–28 wk were gestational weight gain (GWG), maternal fasting glucose, insulin, insulin resistance (HOMA-IR), disposition index, and development of GDM. Neonatal outcomes were cord blood leptin and C-peptide and estimated neonatal fat percentage. The interaction between receiving either the HE or PA intervention and genotypes of both rs10830962 and rs10830963 was assessed using multilevel regression analysis. Results GDM risk was increased in women homozygous for the G allele of rs10830962 (OR: 2.60; 95% CI: 1.34, 5.06) or rs10830963 (OR: 2.83; 95% CI: 1.24, 6.47). Significant interactions between rs10830962 and interventions were found: in women homozygous for the G allele but not in the other genotypes, the PA intervention reduced maternal fasting insulin (β: –0.16; 95% CI: –0.33, 0.02; P  = 0.08) and HOMA-IR (β: –0.17; 95% CI: –0.35, 0.01; P  = 0.06), and reduced cord blood leptin (β: –0.84; 95% CI: –1.42, –0.25; P  = 0.01) and C-peptide (β: –0.62; 95% CI: –1.07, –0.17; P  = 0.01). In heterozygous women, the HE intervention had no effect, whereas in women homozygous for the C allele, HE intervention reduced GWG (β: −1.6 kg; 95% CI: −2.4, −0.8 kg). No interactions were found. Conclusions In women homozygous for the risk allele of MTNR1B rs10830962, GDM risk was increased and PA intervention might be more beneficial than HE intervention for reducing maternal insulin resistance, cord blood C-peptide, and cord blood leptin. [ABSTRACT FROM AUTHOR]

Diabetes in pregnancy is associated with adverse pregnancy outcomes including preterm birth. Although the mechanisms leading to these pregnancy complications are still poorly understood, aberrant angiogenesis and endothelial dysfunction play a key role. FKBPL and SIRT-1 are critical regulators of angiogenesis, however, their roles in pregnancies affected by diabetes have not been examined before in detail. Hence, this study aimed to investigate the role of FKBPL and SIRT-1 in pre-gestational (type 1 diabetes mellitus, T1D) and gestational diabetes mellitus (GDM). Placental protein expression of important angiogenesis proteins, FKBPL, SIRT-1, PlGF and VEGF-R1, was determined from pregnant women with GDM or T1D, and in the first trimester trophoblast cells exposed to high glucose (25 mM) and varying oxygen concentrations [21%, 6.5%, 2.5% (ACH-3Ps)]. Endothelial cell function was assessed in high glucose conditions (30 mM) and following FKBPL overexpression. Placental FKBPL protein expression was downregulated in T1D (FKBPL; p<0.05) whereas PlGF/VEGF-R1 were upregulated (p<0.05); correlations adjusted for gestational age were also significant. In the presence of GDM, only SIRT-1 was significantly downregulated (p<0.05) even when adjusted for gestational age (r=-0.92, p=0.001). Both FKBPL and SIRT-1 protein expression was reduced in ACH-3P cells in high glucose conditions associated with 6.5%/2.5% oxygen concentrations compared to experimental normoxia (21%; p<0.05). FKBPL overexpression in endothelial cells (HUVECs) exacerbated reduction in tubule formation compared to empty vector control, in high glucose conditions (junctions; p<0.01, branches; p<0.05). In conclusion, FKBPL and/or SIRT-1 downregulation in response to diabetic pregnancies may have a key role in the development of vascular dysfunction and associated complications affected by impaired placental angiogenesis. [ABSTRACT FROM AUTHOR]

Excess nutritional supply to the growing fetus, resulting from maternal diabetes and obesity, is associated with increased risks of fetal maldevelopment and adverse metabolic conditions in postnatal life. The placenta, interposed between mother and fetus, serves as the gateway between the two circulations and is usually considered to mediate maternal exposures to the fetus through a direct supply line. In this Perspective, however, we argue that the placenta is not an innocent bystander and mounts responses to fetal "signals of distress" to sustain its own adequate function and protect the fetus. We describe several types of protection that the placenta can offer the fetus against maternal metabolic perturbations and offer a theoretical model of how the placenta responds to the intrauterine environment in maternal diabetes and obesity to stabilize the fetal environment. Our approach supports growing calls for early screening and control of pregnancy metabolism to minimize harmful fetal outcomes. [ABSTRACT FROM AUTHOR]

Background and objective: The maternal glucose-insulin axis is central for metabolic adaptations required for a healthy pregnancy. Metabolic changes in obese mothers in early pregnancy have been scantly described. Here we characterized the glucose-insulin axis in the first trimester of human pregnancy and assessed the effect of maternal obesity and fat mass. Methods: In this cross-sectional study, maternal blood samples (N = 323) were collected during voluntary pregnancy termination (gestational age 4+0–11+6 weeks) after overnight fasting. Smokers (N = 198) were identified by self-report and serum cotinine levels (ELISA). Maternal BMI (kg/m2) and serum leptin (ELISA) were used as proxy measures of obesity and maternal fat mass, respectively. BMI was categorized into under-/normal weight (BMI < 25.0 kg/m2), overweight (BMI 25.0–29.9 kg/m2) and obese (BMI ≥ 30.0 kg/m2), and leptin in tertiles (1st tertile: leptin < 6.80 ng/ml, 2nd tertile: leptin 6.80–12.89 ng/ml, 3rd tertile: leptin > 12.89 ng/ml). ISHOMA insulin sensitivity index was calculated from glucose and C-peptide (ELISA) serum concentrations. Analyses of covariance including multiple confounders were performed to test for differences in glucose, C-peptide and ISHOMA between gestational age periods, BMI and leptin groups. C-peptide and ISHOMA were log-transformed before analyses. Results: At weeks 7–9, fasting glucose and C-peptide levels were lower (P < 0.01 and P < 0.001, respectively) and insulin sensitivity higher (P < 0.001) than at weeks 4–6. Glucose levels were not significantly different between BMI or leptin categories. In contrast, C-peptide increased by 19% (P < 0.01) between the normal weight and the overweight group and by 39% (P < 0.001) between the overweight and obese group. In the leptin groups, C-peptide increased by 25% (P < 0.001) between the 1st and 2nd leptin tertile and by 15% (P < 0.05) between the 2nd and 3rd leptin tertile. ISHOMA decreased with higher BMI and fat mass. ISHOMA decreased by 18% (P < 0.01) between the normal weight and the overweight group and by 30% (P < 0.01) between the overweight and the obese group. In the leptin groups, ISHOMA decreased by 22% (P < 0.001) between the 1st and 2nd leptin tertile and by 14% (P < 0.05) between the 2nd and 3rd leptin tertile. Conclusions: At the group level, fasting glucose, C-peptide and insulin sensitivity dynamically change in the first trimester of human pregnancy. Maternal obesity is associated with higher C-peptide and lower insulin sensitivity at all periods in the first trimester of human pregnancy, while glucose is unaltered. These findings have implications for the timing of early gestational diabetes mellitus risk screening. [ABSTRACT FROM AUTHOR]

Summary: Objectives: To investigate the importance of time in pregnancy and neonatal sex on the association between maternal metabolic parameters and neonatal sum of skinfolds. Methods: This was a longitudinal, secondary analysis of the vitamin D and lifestyle intervention for gestational diabetes mellitus study, conducted in nine European countries during 2012 to 2015. Pregnant women with a pre‐pregnancy body mass index (BMI) of ≥29 kg/m2 were invited to participate. We measured 14 maternal metabolic parameters at three times during pregnancy: <20 weeks, 24 to 28 weeks, and 35 to 37 weeks of gestation. The sum of four skinfolds assessed within 2 days after birth was the measure of neonatal adiposity. Results: In total, 458 mother‐infant pairs (50.2% female infants) were included. Insulin resistance (fasting insulin and HOMA‐index of insulin resistance) in early pregnancy was an important predictor for boys' sum of skinfolds, in addition to fasting glucose and maternal adiposity (leptin, BMI and neck circumference) throughout pregnancy. In girls, maternal lipids (triglycerides and fatty acids) in the first half of pregnancy were important predictors of sum of skinfolds, as well as fasting glucose in the second half of pregnancy. Conclusions: Associations between maternal metabolic parameters and neonatal adiposity vary between different periods during pregnancy. This time‐dependency is different between sexes, suggesting different growth strategies. [ABSTRACT FROM AUTHOR]

Background: To investigate longitudinal associations of maternal glucose/HbA1c and insulin dose with birthweight-related outcomes in women with type 1 diabetes.Methods: We performed a cohort study including 473 pregnant women with type 1 diabetes with singleton pregnancies. We investigated maternal self-monitored blood glucose (SMBG, mmol/L), HbA1c (%, mmol/mol) and insulin dose (IU/kg/day) in the three trimesters as potential independent variables, while adjusting for potential confounders. Outcomes of interest were birthweight, birthweight SD score, neonatal length, weight/length index, ponderal index and placental weight. Multiple linear regression analysis was performed with separate analyses for SMBG and HbA1c .Results: Maternal glucose and insulin dose were independently associated with birthweight-related outcomes. In the main analysis, in the first trimester most associations were positive for insulin dose, in the second the associations were positive for glucose and inverse for insulin while in the third there were no associations. Most sensitivity analyses produced consistent results. In a sensitivity analysis splitting the first trimester in two periods, positive associations of maternal insulin with birthweight-related outcomes were observed in weeks 0+ to 6+.Conclusions: Early in pregnancy in women with type 1 diabetes, maternal insulin dose is positively associated with birthweight-related outcomes, whereas in the second trimester, a positive association with SMBG emerges and the association with maternal insulin becomes inverse. If confirmed in other cohorts, these results would have implications in the management of women with type 1 diabetes. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs), small non-coding RNAs, have emerged as important, epigenetic regulators of endothelial function. Metabolic disturbances such as diabetes alter miRNA expression. In adults, the miRNA transcriptome as well as endothelial function differ between the sexes. Here, we hypothesized that metabolic disturbances associated with gestational diabetes (GDM) alter miRNA signatures in feto-placental endothelial cells (fpEC), dependent on fetal sex. We isolated human primary fpEC after normal and GDM-complicated pregnancies with male and female neonates and screened for differential miRNA expression using next-generation miRNA sequencing. To test for miRNAs commonly regulated in fpEC of female and male progeny, data were stratified for fetal sex and maternal body mass index (BMI). Analyses were also performed separately for female and male fpEC, again accounting for maternal BMI as covariate. Potential biological pathways regulated by the altered set of miRNAs were determined using mirPath software. Maternal GDM altered 26 miRNA signatures when male and female fpEC were analyzed together. Separate analysis of male versus female fpEC revealed 22 GDM affected miRNAs in the females and only 4 in the males, without overlap. Biological functions potentially modulated by the affected miRNAs related to 'Protein Processing in Endoplasmic Reticulum' and 'Proteoglycans in Cancer'. Maternal GDM alters miRNA signatures in fpEC, and biological functions affected by these miRNAs relate to well-known adverse functional consequences of diabetes on endothelium. GDM effects were highly dependent on fetal sex with miRNA signatures in female fpEC being more susceptible to metabolic derangements of GDM than miRNAs in male fpEC. [ABSTRACT FROM AUTHOR]

The placenta plays a key role in sustaining fetal growth and development. Due to its position between mother and fetus, it is exposed to changes in the intrauterine environment in both circulations. The relative influence of changes in those circulations depends on the period of gestation. Early in pregnancy, maternal influences prevail and may affect the complex biological processes characteristic for this pregnancy period, such as placentation, early cell differentiation, and spiral artery remodeling. It is still unclear whether the placenta early in pregnancy is a friend or foe for the fetus. Later in pregnancy, when the fetal circulation is gradually establishing, fetal signals gain importance in regulating placental structure and function. Many of the placental alterations seen at term of pregnancy are the result of fetoplacental interactions often driven by fetal signals associated with maternal diabetes or obesity. These alterations, such as hypervascularization or enhanced cholesterol removal from placental endothelial cells, can be regarded as adaptations to maintain homeostasis at the fetoplacental interface and, thus, to protect the fetus. However, extreme conditions such as poorly controlled diabetes or pronounced obesity may exceed placental homeostatic capacity, with potentially adverse consequences for the fetus. Thus, in late pregnancy, the placenta acts mostly as a friend as long as the environmental perturbations do not exceed placental capacity for mounting adaptive responses. [ABSTRACT FROM AUTHOR]

Objective: Risk factors are widely used to identify women at risk for gestational diabetes mellitus (GDM) without clear distinction by pregnancy period or oral glucose tolerance test (OGTT) time points. We aimed to assess the clinical risk factors for Hyperglycemia in pregnancy (HiP) differentiating by these two aspects. Design and methods: Nine hundred seventy-one overweight/obese pregnant women, enrolled in the DALI study for preventing GDM. OGTTs were performed at =19 + 6, 24-28 and 35-37 weeks (IADPSG/WHO2013 criteria). Women with GDM or overt diabetes at one time point did not proceed to further OGTTs. Potential independent variables included baseline maternal and current pregnancy characteristics. Statistical analysis: Multivariate logistic regression. Results: Clinical characteristics independently associated with GDM/overt diabetes were at =19 + 6 weeks, previous abnormal glucose tolerance (odds ratio (OR): 3.11; 95% CI: 1.41-6.85), previous GDM (OR: 2.22; 95% CI: 1.20-4.11), neck circumference (NC) (OR: 1.58; 95% CI: 1.06-2.36 for the upper tertile), resting heart rate (RHR, OR: 1.99; 95% CI: 1.31-3.00 for the upper tertile) and recruitment site; at 24-28 weeks, previous stillbirth (OR: 2.92; 95% CI: 1.18-7.22), RHR (OR: 3.32; 95% CI: 1.70-6.49 for the upper tertile) and recruitment site; at 35-37 weeks, maternal height (OR: 0.41; 95% CI: 0.20-0.87 for upper tertile). Clinical characteristics independently associated with GDM/overt diabetes differed by OGTT time point (e.g. at =19 + 6 weeks, NC was associated with abnormal fasting but not postchallenge glucose). Conclusion: In this population, most clinical characteristics associated with GDM/overt diabetes were non-modifiable and differed by pregnancy period and OGTT time point. The identified risk factors can help define the target population for future intervention trials. [ABSTRACT FROM AUTHOR]

Background: Process evaluation is an essential part of designing and assessing complex interventions. The vitamin D and lifestyle intervention study (DALI) study is testing different strategies to prevent development of gestational diabetes mellitus among European obese pregnant women with a body mass index ≥29 kg/m2. The intervention includes guidance on physical activity and/or healthy eating by a lifestyle coach trained in motivational interviewing (MI). The aim of this study was to assess the process elements: reach, dose delivered, fidelity and satisfaction and to investigate whether these process elements were associated with changes in gestational weight gain (GWG).Methods: Data on reach, dose delivered, fidelity, and satisfaction among 144 participants were collected. Weekly recruitment reports, notes from meetings, coach logs and evaluation questionnaires (n = 110) were consulted. Fidelity of eight (out of twelve) lifestyle coach practitioners was assessed by analysing audio recorded counselling sessions using the MI treatment integrity scale. Furthermore, associations between process elements and GWG were assessed with linear regression analyses.Results: A total of 20% of the possible study population (reach) was included in this analysis. On average 4.0 (of the intended 5) face-to-face sessions were delivered. Mean MI fidelity almost reached 'expert opinion' threshold for the global scores, but was below 'beginning proficiency' for the behavioural counts. High variability in quality of MI between practitioners was identified. Participants were highly satisfied with the intervention, the lifestyle coach and the intervention materials. No significant associations were found between process elements and GWG.Conclusion: Overall, the intervention was well delivered and received by the study population, but did not comply with all the principles of MI. Ensuring audio recording of lifestyle sessions throughout the study would facilitate provision of individualized feedback to improve MI skills. A larger sample size is needed to confirm the lack of association between process elements and GWG.Trial Registration: ISRCTN registry: ISRCTN70595832 ; Registered 12 December 2011. [ABSTRACT FROM AUTHOR]

Placentas from gestational diabetes mellitus (GDM) are often hypervascularized; however, participation of vascular endothelial growth factor (VEGF) and its receptors in this placental adaptation is unclear. We aimed to test whether changes in phosphorylation of tyrosine 951 or tyrosine 1175 (pY951 or pY1175) of the vascular endothelial growth factor receptor 2 (KDR) are associated with the proangiogenic state observed in placentas from GDM. We obtained placental samples from women with normal pregnancies (n = 24) or GDM (n = 18). We measured the relative expression of markers for endothelial cell number (CD31, CD34), VEGF, vascular endothelial growth factor receptor 1 (Flt-1), KDR, pY951 and pY1175 of KDR in placental homogenate. Immunohistochemistry of placental blood vessels were performed using CD34. Proliferation and migration of human umbilical vein endothelial cells (HUVEC) obtained from normal pregnancy and GDM were determined in absence or presence of conditioned medium (CM) harvested from GDM or normoglycemic HUVEC cultures. GDM was associated with more CD31 and CD34 protein compared to normal pregnancy. High number, but reduced area of placental blood vessels was found in GDM. Reduced Flt-1 levels (mRNA and protein) are associated with reduced KDR mRNA, but higher KDR protein levels in placentas from GDM. No significant changes in Y951-or Y1175-phosphorylation of KDR in placentas from GDM were found. GDM did not alter proliferation of HUVECs, but enhanced migration. Conditioned medium harvested from GDM HUVEC cultures enhanced KDR protein amount, tube formation capacity and cell migration in HUVEC isolated from normoglycemic pregnancies. The data indicate that GDM is associated with reduced expression of Flt-1 but high pro-migratory activation of KDR reflecting a proangiogenic state in GDM. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that gestational diabetes mellitus (GDM) alters the DNA methylation pattern of the fetal serotonin transporter gene (SLC6A4), and examined the functional relevance of DNA methylation for regulation of the SLC6A4 expression in the human placenta. The study included 50 mother-infant pairs. Eighteen mothers were diagnosed with GDM and 32 had normal glucose tolerance (NGT). All neonates were of normal birth weight and born at term by planned Cesarean section. DNA and RNA were isolated from samples of tissue collected from the fetal side of the placenta immediately after delivery. DNA methylation was quantified at 7 CpG sites within the SLC6A4 distal promoter region using PCR amplification of bisulfite treated DNA and subsequent DNA sequencing. SLC6A4 mRNA levels were measured by reverse transcription—quantitative PCR (RT-qPCR). Functional SLC6A4 polymorphisms (5HTTLPR, STin2, rs25531) were genotyped using standard PCR-based procedures. Average DNA methylation across the 7 analyzed loci was decreased in the GDM as compared to the NGT group (by 27.1%, p = 0.037) and negatively correlated, before and after adjustment for potential confounder/s, with maternal plasma glucose levels at the 24th to 28th week of gestation (p<0.05). Placental SLC6A4 mRNA levels were inversely correlated with average DNA methylation (p = 0.010) while no statistically significant association was found with the SLC6A4 genotypes (p>0.05). The results suggest that DNA methylation of the fetal SLC6A4 gene is sensitive to the maternal metabolic state in pregnancy. They also indicate a predominant role of epigenetic over genetic mechanisms in the regulation of SLC6A4 expression in the human placenta. Longitudinal studies in larger cohorts are needed to verify these results and determine to which degree placental SLC6A4 changes may contribute to long-term outcomes of infants exposed to GDM. [ABSTRACT FROM AUTHOR]

Maternal lipids are strong determinants of fetal fat mass. Here we review the overall lipid metabolism in normal and gestational diabetes mellitus (GDM) pregnancies. During early pregnancy, the increase in maternal fat depots is facilitated by insulin, followed by increased adipose tissue breakdown and subsequent hypertriglyceridemia, mainly as a result of insulin resistance (IR) and estrogen effects. The response to diabetes is variable as a result of greater IR but decreased estrogen levels. The vast majority of fatty acids (FAs) in the maternal circulation are esterified and associated with lipoproteins. These are taken up by the placenta and hydrolyzed by lipases. The released FAs enter various metabolic routes and are released into fetal circulation. Although these determinants are modified in maternal GDM, the fetus does not seem to receive more FAs than in non-GDM pregnancies. Long-chain polyunsaturated FAs are essential for fetal development and are obtained from the mother. Mitochondrial FA oxidation occurs in fetal tissue and in placenta and contributes to energy production. Fetal fat accretion during the last weeks of gestation occurs very rapidly and is sustained not only by FAs crossing the placenta, but also by fetal lipogenesis. Fetal hyperinsulinemia in GDM mothers promotes excess accretion of adipose tissue, which gives rise to altered adipocytokine profiles. Fetal lipoproteins are low at birth, but the GDM effects are unclear. The increase in body fat in neonates of GDM women is a risk factor for obesity in early childhood and later life. [ABSTRACT FROM AUTHOR]

OBJECTIVE Ways to prevent gestational diabetes mellitus (GDM) remain unproven. We compared the impact of three lifestyle interventions (healthy eating [HE], physical activity [PA], and both HE and PA [HE+PA]) on GDM risk in a pilot multicenter randomized trial. RESEARCH DESIGN AND METHODS Pregnant women at risk for GDM (BMI ≥29 kg/m²) from nine European countries were invited to undertake a 75-g oral glucose tolerance test before 20 weeks' gestation. Those without GDM were randomized to HE, PA, or HE+PA. Women received five face-to-face and four optional telephone coaching sessions, based on the principles of motivational interviewing. A gestational weight gain (GWG) <5 kg was targeted. Coaches received standardized training and an intervention toolkit. Primary outcome measures were GWG, fasting glucose, and insulin sensitivity (HOMA) at 35-37 weeks. RESULTS Among the 150 trial participants, 32% developed GDM by 35-37 weeks and 20% achieved GWG <5 kg. HE women had less GWG (-2.6 kg [95% CI -4.9, -0.2]; P = 0.03) and lower fasting glucose (-0.3mmol/L [-0.4,-0.1]; P = 0.01) than those in the PA group at 24-28 weeks. HOMA was comparable. No significant differences between HE+PA and the other groups were observed. CONCLUSIONS An antenatal HE intervention is associated with less GWG and lower fasting glucose comparedwith PA alone. These findings require a larger trial for confirmation but support the use of early HE interventions in obese pregnant women. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to examine the association between mental health status (i.e. depressed mood and pregnancy-related worries) and objectively measured physical activity levels in obese pregnant women from seven European countries. Methods: Baseline data from the vitamin D and lifestyle intervention for the prevention of gestational diabetes mellitus (DALI) study were used. Time spent in moderate-to-vigorous physical activity (MVPA) and sedentary behaviour was measured with accelerometers. Depressed mood was measured with the WHO well-being index (WHO-5) and pregnancy-related worries with the Cambridge Worry Scale (CWS). In addition, socio-demographic characteristics, lifestyle factors, and perceptions and attitude regarding weight management and physical activity were measured. Linear regression analyses were performed to assess the association of mental health status with MVPA and sedentary behaviour. Results: A total of 98 obese pregnant women from Austria, Belgium, Ireland, Italy, Poland, Spain and the Netherlands were included. Women had a mean age of 31.6 ± 5.8 years, a pre-pregnancy BMI of 34.1 ± 4.3 kg/m2, and were on average 15.4 ± 2.8 weeks pregnant. WHO-5 scores indicative of depressed mood (<50) were reported by 27.1 % of the women and most frequently endorsed pregnancy-related worries pertained to own and the baby's health. Women with good well-being spent 85 % more time in MVPA compared to women with a depressed mood (P = 0.03). No differences in MVPA levels were found for women with no, some, or many pregnancy worries. Depressed mood and pregnancy-related worries were not associated with sedentary behaviour. Conclusions: These findings suggest that in pregnant women who are obese, a depressed mood, but not pregnancy-related worries, may be associated with less physical activity. The combined risk of poor mental health and low physical activity levels makes women vulnerable for pregnancy complications. Whether a depressed mood may be a barrier for improving physical activity warrants further study. [ABSTRACT FROM AUTHOR]

The article presents the study on placental vitamin D receptor in gestational diabetes mellitus and normal pregnancy. It discusses how the study was conducted which involved staining of placental tissue for vitamin D receptor and human leukocyte antigen G to identify extravillous trophoblasts. The results reportedly revealed that vitamin D receptor is upregulated in fetoplacental endothelial cells and extravillous trophoblasts.

Objective Chemerin is a novel adipokine implicated in inflammation and obesity. We hypothesized that foetal chemerin would be elevated in gestational diabetes mellitus ( GDM) and correlate with foetal and maternal adiposity. Design Observational, longitudinal study. Subjects and measurements Foetal chemerin was measured separately in arterial and venous cord blood of 30 infants born to mothers with ( n = 15) and without GDM ( n = 15), in their mothers in early third trimester and at delivery and in amniotic fluid (week 32) of women with GDM. Expression of chemerin and its receptor in human foetal tissues commercially available and in placental cells was measured by quantitative PCR. Associations between foetal and maternal anthropometric and metabolic variables were assessed in multivariate regression models. Results In GDM, foetal arterial but not venous cord blood chemerin levels were elevated by about 60% ( P < 0·05). Venous cord blood chemerin was higher in infants of obese women ( P < 0·01). In multivariate analyses, neither amniotic fluid nor cord blood chemerin levels correlated with birth weight or ponderal index. Both arterial and venous chemerin levels were related to maternal chemerin at birth, and arterial chemerin was associated with GDM status in addition. Maternal levels were unaltered in GDM, but higher in maternal obesity. Foetal liver produces fourfold more chemerin mRNA than other foetal tissues, whereas its receptor prevails in spleen. Conclusions Based on multivariate analyses, foetal growth appears unrelated to foetal chemerin. Maternal obesity and GDM have differential effects on foetal chemerin levels. Site of major production (liver) and action (spleen) differ in human foetal tissues. [ABSTRACT FROM AUTHOR]

Circulating non-coding microRNAs (miRNAs) are important for placentation, but their expression profiles across gestation in pregnancies, which are complicated by gestational diabetes mellitus (GDM), have not been fully established. Investigating a single time point is insufficient, as pregnancy is dynamic, involving several processes, including placenta development, trophoblast proliferation and differentiation and oxygen sensing. Thus, the aim of this study was to compare the temporal expression of serum miRNAs in pregnant women with and without GDM. This is a nested case-control study of longitudinal data obtained from a multicentric European study (the 'DALI' study). All women (n = 82) were overweight/obese (BMI ≥ 29 kg/m2) and were normal glucose tolerant (NGT) at baseline (before 20 weeks of gestation). We selected women (n = 41) who were diagnosed with GDM at 24–28 weeks, according to the IADPSG/WHO2013 criteria. They were matched with 41 women who remained NGT in their pregnancy. miRNA (miR-16-5p, -29a-3p, -103-3p, -134-5p, -122-5p, -223-3p, -330-3p and miR-433-3p) were selected based on their suggested importance for placentation, and measurements were performed at baseline and at 24–28 and 35–37 weeks of gestation. Women with GDM presented with overall miRNA levels above those observed for women remaining NGT. In both groups, levels of miR-29a-3p and miR-134-5p increased consistently with progressing gestation. The change over time only differed for miR-29a-3p when comparing women with GDM with those remaining NGT (p = 0.044). Our findings indicate that among overweight/obese women who later develop GDM, miRNA levels are already elevated early in pregnancy and remain above those of women who remain NGT during their pregnancy. Maternal circulating miRNAs may provide further insight into placentation and the cross talk between the maternal and fetal compartments. [ABSTRACT FROM AUTHOR]

The serotonin receptor 2A gene (HTR2A) is a strong candidate for the fetal programming of future behavior and metabolism. Maternal obesity and gestational diabetes mellitus (GDM) have been associated with an increased risk of metabolic and psychological problems in offspring. We tested the hypothesis that maternal metabolic status affects methylation of HTR2A in the placenta. The prospective study included 199 pairs of mothers and healthy full-term newborns. Genomic DNA was extracted from feto-placental samples and analyzed for genotypes of two polymorphisms (rs6311, rs6306) and methylation of four cytosine residues (−1665, −1439, −1421, −1224) in the HTR2A promoter region. Placental HTR2A promoter methylation was higher in male than female placentas and depended on both rs6311 and rs6306 genotypes. A higher maternal pre-gestational body mass index (pBMI) and, to a lesser extent, diagnosis of GDM were associated with reduced HTR2A promoter methylation in female but not male placentas. Higher pBMI was associated with reduced methylation both directly and indirectly through increased GDM incidence. Tobacco use during pregnancy was associated with reduced HTR2A promoter methylation in male but not female placentas. The obtained results suggest that HTR2A is a sexually dimorphic epigenetic target of intrauterine exposures. The findings may contribute to a better understanding of the early developmental origins of neurobehavioral and metabolic disorders associated with altered HTR2A function. [ABSTRACT FROM AUTHOR]

The placenta is positioned between the maternal and fetal circulation and hence plays a key role in transporting maternal nutrients to the developing fetus. Fetal growth changes in the 2 most frequent pregnancy pathologies, gestational diabetes mellitus and fetal growth restriction, are predominantly characterized by an exaggerated and restricted fat accretion, respectively. Glucose, by its regulating effect on fetal insulin concentrations, and lipids have been strongly implicated in fetal fat deposition. Transplacental glucose flux is highly efficient and limited only by nutrient availability (flow-limited)-ie, driven by the maternal-fetal glucose concentration gradient and blood flow, with little, if any, effect of placental morphology, glucose consumption, and transporter expression. This explains why, despite changes in these determinants in both pathologies, transplacental glucose flux is unaltered. [ABSTRACT FROM AUTHOR]

The article focuses on the determination of obese women having marked insulin resistance in early pregnancy through the gestational diabetes mellitus (GDM) recommendations of the 2013 World Health Organization and the International Association of Diabetes and Pregnancy Study Groups (IADPSG). Topics discussed include an overview of GDM, its diagnosis, its prevalence, and its treatment.

Fragestellung: Eine Analyse des geburtshilflichen und neonatalen Outcomes bei Gestationsdiabetikerinnen, die sich zur Therapieentscheidung einer Amniozentese zur Fruchtwasserinsulinbestimmung unterzogen oder Blutzuckertagesprofile mit Ermittlung der mittleren Blutglukose oder beide Methoden wählten. Material und Methodik: 408 Schwangerschaften mit Gestationsdiabetes wurden retrospektiv untersucht. 307 Schwangere wurden mit Diät behandelt (Klasse A) und 101 mit Diät und Insulin (Klasse AB). Geburtshilfliche und anthropometrische Daten wurden in Abhängigkeit der verwendeten Untersuchungsmethode innerhalb der Klassen mit Pearsons χ2 oder dem exakten Fisher-Test verglichen. Ergebnisse:Klasse A - Ältere Schwangere entschieden sich signifikant häufiger für die nichtinvasive Methode (p = 0,007). Das Gestationsalter bei der Geburt (p = 0,396) sowie der Geburtsmodus (p = 0,79) zeigten keine signifikanten Unterschiede. Dasselbe galt für das mittlere Geburtsgewicht (p = 0,348) und ein Geburtsgewicht >75. Perzentile (p = 0,473). Ein Geburtsgewicht >90. Perzentile trat signifikant häufiger bei Schwangerschaften auf, die mit beiden Methoden getestet wurden (p = 0,005). Der mittlere Ponderal-Index (PI; p = 0,434), die Nabelarterien- (p = 0,065) und Nabelvenen-pH-Werte (p = 0,052) sowie die Apgar-Werte nach 1 (p = 0,56) und 5 min (p = 0,072) erbrachten keinen Unterschied. Allerdings war ein Apgar <7 nach 1 min signifikant häufiger bei Kindern von Schwangeren, mit beiden Testmethoden. Keine Unterschiede fanden sich für die Nabelschnurglukose (p = 0,325) und Nabelschnurinsulin (p = 0,535). Klasse AB - In dieser Klasse fanden sich keine signifikanten Unterschiede für die untersuchten Parameter: Alter der Mutter (p = 0,062), Gestationsalter bei der Geburt (p = 0,219), Geburtsmodus (p = 0,386), mittleres Geburtsgewicht (p = 0,59), Geburtsgewicht >75. und >90. Perzentile (p = 0,701 und p = 0,487), mittlerer PI (p = 0,156), Nabelarterien- und -venen-pH (p = 0,197 und p = 0,056), Apgar-Werte nach 1 und 5 min (p = 0,58 und p = 0,52), Nabelschnurinsulin und -glukose (p = 0,67 und p = 0,11). Schlussfolgerungen: Diese retrospektive Analyse zeigte keinen Vorteil für das geburtshilfliche und neonatale Outcome bei Gestationsdiabetikerinnen, deren Therapie aufgrund der Höhe des Fruchtwasserinsulins festgelegt wurde, weshalb diese Methode als eine von mehreren Optionen angesehen werden muss. Purpose: To compare the obstetric and neonatal outcome in pregnancies complicated by gestational diabetes mellitus after amniocentesis for amniotic fluid insulin measurement or maternal blood glucose monitoring or both as selection criterion for therapy. Material and Methods: In a retrospective study, 408 diabetic pregnancies were analyzed; 307 were treated with diet alone (group 1) and 101 with diet and insulin (group 2). Pearson's χ2 or Fisher's exact test was used to assess obstetric and anthropometric data within these groups, and p values <0.05 were considered statistically significant. Results:Group 1 - According to the method used, no significant differences were found for gestational age at birth (p = 0.396), mode of delivery (p = 0.79) and neonatal outcome parameters determined as mean birth weight (p = 0.348), birth weight above the 75th percentile (p = 0.473), mean ponderal index (PI; p = 0.434), pH of umbilical-artery (p = 0.065) and of umbilical-vein blood (p = 0.052), mean Apgar scores at 1 (p = 0.56) and 5 min (p = 0.072), insulin (p = 0.25) and glucose (p = 0.535) in cord blood. Significant differences were found for birth weight above the 90th percentile (p = 0.005) and Apgar score <7 at 1 min (p = 0.019). Group 2 - Again, no significant differences were observed in terms of gestational age at birth (p = 0.219), mode of delivery (p = 0.386), mean birth weight (p = 0.59), birth weight above the 75th (p = 0.701) and 90th percentiles (p = 0.487), mean PI (p = 0.156), pH of umbilical-artery (p = 0.197) and umbilical-vein blood (p = 0.056), Apgar scores at 1 (p = 0.58) and 5 min (p = 0.52), insulin (p = 0.67) and glucose (p = 0.11) in cord blood. Conclusion: In retrospective analysis there was no significant difference in outcome parameters in pregnancies complicated by gestational diabetes dependent on the method used as selection criterion for therapy. Copyright © 2010 S. Karger AG, Basel Objectif: Une analyse des résultats obstétriques et néonatals lors du diabète gestationnel chez des patientes qui se sont soumises à une amniocentèse pour évaluer le taux d'insuline du liquide amniotique, à une détermination du glucose sanguin moyen maternel ou aux deux méthodes. Matériel et méthode: 408 grossesses compliquées par un diabète gestationnel ont été étudiées rétrospectivement; 307 patientes ont été traitées par régime alimentaire (groupe A) et 101 par régime et insuline (groupe AB). Les données obstétriques et anthropométriques de ces deux groupes ont été comparées en fonction des méthodes utilisées par le test χ2 de Pearson et le test exact de Fisher. Résultats:Groupe A - Les femmes enceintes plus âgées ont choisi la méthode non invasive plus fréquemment de manière significative (p = 0,007). L'âge gestationnel à la naissance (p = 0,396) et le mode d'accouchement (p = 0,79) ne présentaient pas de différence significative, ainsi que le poids moyen à la naissance (p = 0,348) et le poids >75e percentile (p = 0,473). Un poids de naissance >90e percentile était significativement plus fréquent lors des grossesses analysées par les deux méthodes (p = 0,005). L'indexe pondéral moyen (PI; p = 0,434), les valeurs pH de l'artère (p = 0,065) et de la veine ombilicales (p = 0,052) ainsi que les valeurs Apgar après 1 (p = 0,56) et 5 min (p = 0,072) ne démontraient pas de différence. Toutefois, une valeur Apgar <7 après 1 min était plus fréquente chez les enfants de patientes examinées par les deux méthodes. Il n'y avait pas de différences quant au glucose (p = 0,325) et à l'insuline (p = 0,535) du cordon ombilical. Groupe AB - Il n'y avait pas de différences significatives pour les paramètres analysés: âge de la mère (p = 0,062), âge gestationnel à la naissance (p = 0,219), mode d'accouchement (p = 0,386), poids moyen à la naissance (p = 0,59), poids >75e et >90e percentile (p = 0,701 et p = 0,487), PI moyen (p = 0,156), valeurs pH de l'artère (p = 0,197) et de la veine ombilicales (p = 0,056), valeurs Apgar après 1 et 5 min (p = 0,58 et p = 0,52), insuline et glucose du cordon ombilical (p = 0,67 et p = 0,11). Conclusions: Cette analyse rétrospective n'a pas montré de bénéfice quant aux résultats obstétriques et néonatals pour les patientes souffrant d'un diabète gestationnel dont le traitement avait été choisi selon le taux d'insuline du liquide amniotique, et c'est pourquoi cette méthode doit être considérée comme une option parmi d'autres seulement. [ABSTRACT FROM AUTHOR]

The insulin/insulin-like growth factor (IGF) system regulates fetal and placental growth and development. In maternal diabetes, components of this system including insulin, IGF1, IGF2 and various IGF-binding proteins are deregulated in the maternal or fetal circulation, or in the placenta. The placenta expresses considerable amounts of insulin and IGF1 receptors at distinct locations on both placental surfaces. This makes the insulin and the IGF1 receptor accessible to fetal and/or maternal insulin, IGF1 and IGF2. Unlike the receptor for IGF1, the insulin receptor undergoes a gestational change in expression site from the trophoblast at the beginning of pregnancy to the endothelium at term. Insulin and IGFs are implicated in the receptor-mediated regulation of placental growth and transport, trophoblast invasion and placental angiogenesis. The dysregulation of the growth factors and their receptors may be involved in placental and fetal changes observed in diabetes, i.e. enhanced placental and fetal growth, placental hypervascularization and higher levels of fetal plasma amino acids. [ABSTRACT FROM AUTHOR]

The article focuses on human placenta in gestational diabetes mellitus (GDM). It states that the adaptive responses of the placenta to the diabetic environment may help limit fetal growth within a normal range. It mentions that insulin and cytokines are potential regulators of placental function in GDM.

Early identification of gestational diabetes mellitus (GDM) aims to reduce the risk of adverse maternal and perinatal outcomes. Currently, no circulating biomarker has proven clinically useful for accurate prediction of GDM. In this study, we tested if a panel of small non-coding circulating RNAs could improve early prediction of GDM. We performed a nested case-control study of participants from the European multicenter 'Vitamin D and lifestyle intervention for GDM prevention (DALI)' trial using serum samples from obese pregnant women (BMI ≥ 29 kg/m2) entailing 82 GDM cases (early- and late- GDM), and 41 age- and BMI-matched women with normal glucose tolerance (NGT) throughout pregnancy (controls). Anthropometric, clinical and biochemical characteristics were obtained at baseline (<20 weeks of gestation) and throughout gestation. Baseline serum microRNAs (miRNAs) were measured using quantitative real time PCR (qPCR). Elevated miR-16-5p, -29a-3p, and -134-5p levels were observed in women, who were NGT at baseline and later developed GDM, compared with controls who remained NGT. A combination of the three miRNAs could distinguish later GDM from NGT cases (AUC 0.717, p = 0.001, compared with fasting plasma glucose (AUC 0.687, p = 0.004)) as evaluated by area under the curves (AUCs) using Receiver Operator Characteristics (ROC) analysis. Elevated levels of individual miRNAs or a combination hereof were associated with higher odds ratios of GDM. Conclusively, circulating miRNAs early in pregnancy could serve as valuable predictive biomarkers of GDM. [ABSTRACT FROM AUTHOR]

Thyroid hormones are essential for development of trophoblasts and the fetus. They also regulate a wide range of metabolic processes. We investigated the influence of maternal gestational diabetes mellitus (GDM) on thyroid hormone receptor (THR) isoforms THRα1, THRα2, THRβ1 and THRβ2 of the human placenta in a sex- and cell-type specific manner. Term placental tissue was obtained from women with (n = 40) or without GDM (control; n = 40). THRs levels were measured by semi-quantitative immunohistochemistry and real-time qRT-PCR. We localized THR immunostaining in syncytiotrophoblast (SCT), which was the tissue with the strongest signal. Double immunofluorescence identified THR in decidual cells in the stroma and in extravillous cytotrophoblasts. GDM did not change THRα1 immunolabelling intensity in decidua, but was associated with a stronger immunolabelling in SCT compared to GDM (p < 0.05). The SCT difference of GDM vs. control was strongest (p < 0.01) in female placentas. THRα2 was only weakly present and immunolabelling was weaker (p < 0.05) in SCT of only male GDM placentas in comparison to male controls. THRβ1/β2 immunostaining was weak in all cell types without changes in GDM. However, more THRβ1/2 protein was present (p < 0.001) in male than female placentas. All these protein changes were paralleled by changes of THR transcript levels. The data show that THR are expressed in term trophoblast in relation to fetal sex. Maternal GDM influences predominantly THRα1 in SCT, with the strongest GDM effect in SCT of female placentas. [ABSTRACT FROM AUTHOR]

Gestational diabetes is the most common medical complication in pregnancy. Historically, gestational diabetes was considered a pregnancy complication involving treatment of rising glycaemia late in the second trimester. However, recent evidence challenges this view. Pre-pregnancy and pregnancy-specific factors influence gestational glycaemia, with open questions regarding roles of non-glycaemic factors in the aetiology and consequences of gestational diabetes. Varying patterns of insulin secretion and resistance in early and late pregnancy underlie a heterogeneity of gestational diabetes in the timing and pathophysiological subtypes with clinical implications: early gestational diabetes and insulin resistant gestational diabetes subtypes are associated with a higher risk of pregnancy complications. Metabolic perturbations of early gestational diabetes can affect early placental development, affecting maternal metabolism and fetal development. Fetal hyperinsulinaemia can affect the development of multiple fetal tissues, with short-term and long-term consequences. Pregnancy complications are prevented by managing glycaemia in early and late pregnancy in some, but not all women with gestational diabetes. A better understanding of the pathophysiology and heterogeneity of gestational diabetes will help to develop novel management approaches with focus on improved prevention of maternal and offspring short-term and long-term complications, from pre-conception, throughout pregnancy, and beyond. [ABSTRACT FROM AUTHOR]

Key points In utero exposure to gestational diabetes mellitus (GDM) programs the fetus, increasing offspring risk for endothelial dysfunction and cardiovascular disease later in life. Hyperglycaemia is widely recognized as the driving force of diabetes‐induced programming. We have previously shown that GDM exposure alters DNA methylation and gene expression associated with actin remodelling in primary feto‐placental arterial endothelial cells (fpEC). Thus, we hypothesized that hyperglycaemic insults underlie programmed changes in fpEC morphology and actin organization by GDM. Therefore, arterial fpECs isolated after normal and GDM pregnancy, as well as normal fpECs that were exposed to hyperglycaemia in vitro, were analysed for the effect of GDM and hyperglycaemia on actin organization and network formation. Integration of gene expression and DNA methylation data identified the RhoA activator active BCR‐related (ABR) as programmed by GDM and altered by in vitro hyperglycaemia. ABR silencing in GDM‐exposed cells reduced RhoA activity by 34 ± 26% (P = 0.033) and restored normal fpEC phenotype. In fact, in vitro hyperglycaemia induced a similar fpEC phenotype as intrauterine exposure to GDM, i.e. round morphology and increased network formation on Matrigel by 34 ± 33% (P = 0.022) vs. 22 ± 20% for GDM (P = 0.004). Thus, we identified ABR as a novel glucose sensitive regulator of actin organization and cell shape, programmed by GDM and upregulated by hyperglycaemia. Identification of mechanisms induced by hyperglycaemia and affecting endothelial function in the long term will contribute to understanding GDM‐induced programming of offspring endothelial dysfunction and cardiovascular disease. Future studies could focus on investigating the prevention or reversal of such malprogramming. In utero exposure to gestational diabetes mellitus (GDM) affects future health of the offspring, with an increased risk for endothelial dysfunction and cardiovascular disease in later life. GDM alters DNA methylation and expression of ABR in feto‐placental arterial endothelial cells (fpEC), a model for endothelial cells exposed to the intrauterine environment of the fetus. GDM phenotype of fpECs is also induced by hyperglycaemia in vitro, and is characterized by altered actin organization and cell shape, which can be restored by ABR silencing. Revealing the cellular mechanisms induced by GDM and hyperglycaemia is important for understanding the mechanisms of how these conditions disturb endothelial function in the offspring. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Preeclampsia (PE), fetal growth restriction (FGR) and gestational diabetes mellitus (GDM) are major pregnancy complications affecting maternal and fetal health. The placenta and the vasoconstrictor endothelin-1 (ET-1) have a controlling and mediating role in these conditions. This study tested the hypothesis that the expression of ET-1 and its receptors (ETA and ETB) is altered in these pathologies and differs between early (gestational week [GW]≤34) and late (GW>34) third trimester pregnancies. Main methods: The study included 88 women (GW 28-41) with PE (blood pressure >140/90mmHg, protein >300mg/24hrs; n=14), FGR (<10th birthweight centile and pathological umbilical blood flow; n=13), PE+FGR (n=5) and GDM (n=21), and gestational age-matched controls (n=35). ET-1, ETA and ETB mRNA and ETA and ETB protein were quantified in placental tissues by real-time PCR and immunoblotting. Key findings: The ET/ETR mRNA system is altered in PE and PE+FGR and GDM. Expression of ET-1, ETA and ETB is upregulated in early onset PE and PE+FGR with stronger effect in PE+FGR. GDM down regulated ET/ETR mRNA in the placentas in late third trimester of pregnancy. ET/ETR protein is virtually unchanged. Significance: Early onset PE (≤GW34) with or without FGR is associated with increased mRNA expression of the ET/ETR system, while in late onset PE and GDM the opposite effect was observed. This study supports the emerging concept that early and late onset PE are different diseases. [Copyright &y& Elsevier]

Aims: To investigate the performance of early pregnancy HbA1c for predicting gestational diabetes mellitus (GDM) and adverse pregnancy outcomes in obese women.Methods: Post hoc analysis using data from the Vitamin D And Lifestyle Intervention for GDM prevention trials conducted across 9 European countries (2012-2014). Pregnant women (BMI ≥ 29 kg/m2) underwent a baseline HbA1c and oral glucose tolerance tests at < 20 weeks, 24-28 weeks, and 35-37 weeks. Women with GDM were referred for treatment.Results: Among the 869 women tested, the prevalence of GDM was 25.9% before 20 weeks, with a further 8.6% at 24-28 weeks. The areas under the curves for HbA1c at the two time points were 0.55 (0.50-0.59) and 0.54 (0.47-0.61), respectively. An early HbA1c ≥ 5.7% (39 mmol/mol) (N = 111) showed low sensitivity (18.2%) with 89.1% specificity for GDM before 20 weeks, at 24-28 weeks (sensitivity of 8.0% and specificity of 88.6% after excluding early GDM), and throughout gestation (sensitivity of 15.9% and specificity of 89.4%). The ≥ 5.7% (39 mmol/mol) threshold was significantly associated with concurrent GDM before 20 weeks (adjusted OR (aOR) 2.77(1.39-5.51)) and throughout gestation (aOR 1.72 (1.02-2.89)), but not adverse pregnancy outcomes.Conclusions: Early pregnancy HbA1c is of limited use for predicting either GDM or adverse outcomes in overweight/obese European women. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is an important cardiovascular risk factor characterized by elevated plasma glucose levels. High glucose (HG) negatively influences endothelial cell (EC) function, which is characterized by the inability of ECs to respond to vascular endothelial growth factor (VEGF-A) stimulation. We aimed to identify potential strategies to improve EC function in diabetes. Human umbilical cord endothelial cells (HUVECs) were subjected to hyperglycemic milieu by exposing cells to HG together with glucose metabolite, methylglyoxal (MG) in vitro. Hyperglycemic cells showed reduced chemotactic responses towards VEGF-A as revealed by Boyden chamber migration assays, indicating the development of "VEGF resistance" phenotype. Furthermore, HG/MG-exposed cells were defective in their general migratory and proliferative responses and were in a pro-apoptotic state. Mechanistically, the exposure to HG/MG resulted in reactive oxygen species (ROS) accumulation which is secondary to the impairment of thioredoxin (Trx) activity in these cells. Pharmacological and genetic targeting of Trx recapitulated VEGF resistance. Functional supplementation of Trx using thioredoxin mimetic peptides (TMP) reversed the HG/MG-induced ROS generation, improved the migration, proliferation, survival and restored VEGF-A-induced chemotaxis and sprouting angiogenesis of hyperglycemic ECs. Importantly, TMP treatment reduced ROS accumulation and improved VEGF-A responses of placental arterial endothelial cells isolated from gestational diabetes mellitus patients. Our findings suggest a putative role for Trx in modulating EC function and its functional impairment in HG conditions contribute to EC dysfunction. Supplementation of TMP could be used as a novel strategy to improve endothelial cell function in diabetes. • Impaired Trx activity related to hyperglycemia contributes to endothelial dysfunction through induction of oxidative stress. • Dysfunctional endothelial cells exhibit a "VEGF resistance" phenotype and show reduced cell surface expression of VEGFR-2. • Dysfunctional endothelial cells show reduced migration, proliferation and survival. • Thioredoxin mimetic peptides (TMP) reverse DM-induced endothelial dysfunction by alleviating oxidative stress. • Use of TMPs could be a novel strategy to improve endothelial function in diabetes. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is associated with excessive oxidative stress which may affect placental vascular function. Cholesterol homeostasis is crucial for maintaining fetoplacental endothelial function. We aimed to investigate whether and how GDM affects cholesterol metabolism in human fetoplacental endothelial cells (HPEC). HPEC were isolated from fetal term placental arterial vessels of GDM or control subjects. Cellular reactive oxygen species (ROS) were detected by H 2 DCFDA fluorescent dye. Oxysterols were quantified by gas chromatography–mass spectrometry analysis. Genes and proteins involved in cholesterol homeostasis were detected by real-time PCR and immunoblotting, respectively. Cholesterol efflux was determined from [ 3 H]-cholesterol labeled HPEC and [ 14 C]-acetate was used as cholesterol precursor to measure cholesterol biosynthesis and esterification. We detected enhanced formation of ROS and of specific, ROS-derived oxysterols in HPEC isolated from GDM versus control pregnancies. ROS-generated oxysterols were simultaneously elevated in cord blood of GDM neonates. Liver-X receptor activation in control HPEC by synthetic agonist TO901319, 7-ketocholesterol, or 7β-hydroxycholesterol upregulated ATP-binding cassette transporters (ABC)A1 and ABCG1 expression, accompanied by increased cellular cholesterol efflux. Upregulation of ABCA1 and ABCG1 and increased cholesterol release to apoA-I and HDL 3 (78 ± 17%, 40 ± 9%, respectively) were also observed in GDM versus control HPEC. The LXR antagonist GGPP reversed ABCA1 and ABCG1 upregulation and reduced the increased cholesterol efflux in GDM HPEC. Similar total cellular cholesterol levels were detected in control and GDM HPEC, while GDM enhanced cholesterol biosynthesis along with upregulated 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and sterol O-acyltransferase 1 (SOAT1) mRNA and protein levels. Our results suggest that in GDM cellular cholesterol homeostasis in the fetoplacental endothelium is modulated via LXR activation and helps to maintain its proper functionality. [ABSTRACT FROM AUTHOR]

Introduction. We explored beliefs, perceived barriers, and preferences regarding lifestyle changes among overweight European pregnant women to help inform the development of future lifestyle interventions in the prevention of gestational diabetes mellitus. Methods. An explorative mixed methods, two-staged study was conducted to gather information from pregnant European women (BMI ≥ 25 kg/m2). In three European countries 21 interviews were conducted, followed by 71 questionnaires in six other European countries. Content analysis and descriptive and chi-square statistics were applied (p<0.05). Results. Women preferred to obtain detailed information about their personal risk. The health of their baby was a major motivating factor. Perceived barriers for physical activity included pregnancy-specific issues such as tiredness and experiencing physical complaints. Insufficient time was a barrier more frequently reported by women with children. Abstaining from snacking was identified as a challenge for the majority of women, especially for those without children. Women preferred to obtain support from their partner, as well as health professionals and valued flexible lifestyle programs. Conclusions. Healthcare professionals need to inform overweight pregnant women about their personal risk, discuss lifestyle modification, and assist in weight management. Lifestyle programs should be tailored to the individual, taking into account barriers experienced by overweight first-time mothers and multipara women. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is related to neonatal macrosomia and an increased risk of vascular events. We hypothesized that GDM exerts qualitative effects on neonatal high-density lipoprotein (HDL). HDL was isolated from control (n = 11) and GDM maternal/neonatal donors (n = 9) and subjected to shotgun proteomics. Differences in HDL mobility were assessed by FPLC and native gel-electrophoresis. Paraoxonase (PON1) activity, cholesterol ester-transfer protein (CETP) mass and activity, phospholipid, triglyceride and cholesterol concentrations were quantified with commercial kits. Total anti-oxidative capacity and cholesterol efflux capability of HDLs were measured. Four proteins involved in lipid metabolism, inflammation and innate immunity were differentially expressed between controls and GDM neonates. ApoM (decreased, p < 0.05) and SAA1 (increased, p < 0.05) showed the same differences on both, maternal and neonatal GDM HDL. Lower PON1 protein expression was corroborated by lower activity ( p < 0.05) which in turn was associated with attenuated anti-oxidant capacity of GDM HDL. Protein changes were accompanied by increased levels of triglycerides and decreased levels of cholesterol esters, respectively. The observed differences in GDM HDL lipid moiety may be related to CETP mass and activity alterations. The rate of cholesterol efflux from term trophoblasts to maternal and from placental endothelial cells to neonatal GDM HDL was impaired ( p < 0.05). In conclusion, GDM causes changes in HDL composition and is intimately associated with impaired cholesterol efflux capability as well as diminished anti-oxidative particle properties. Remodeling of neonatal GDM HDL in utero supports the hypothesis that maternal conditions in pregnancy impact neonatal lipoprotein metabolism. [ABSTRACT FROM AUTHOR]