Publications by authors named "Gernot Desoye"

153 Publications

FKBPL and SIRT-1 Are Downregulated by Diabetes in Pregnancy Impacting on Angiogenesis and Endothelial Function.

Front Endocrinol (Lausanne) 2021 2;12:650328. Epub 2021 Jun 2.

The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Northern Ireland, United Kingdom.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2021.650328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206806PMC
June 2021

Placental polar lipid composition is associated with placental gene expression and neonatal body composition.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 Sep 23;1866(9):158971. Epub 2021 May 23.

MRC Lifecourse Epidemiology Unit, University of Southampton, UK; NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK. Electronic address:

The polar-lipid composition of the placenta reflects its cellular heterogeneity and metabolism. This study explored relationships between placental polar-lipid composition, gene expression and neonatal body composition. Placental tissue and maternal and offspring data were collected in the Southampton Women's Survey. Lipid and RNA were extracted from placental tissue and polar lipids measured by mass spectrometry, while gene expression was assessed using the nCounter analysis platform. Principal component analysis was used to identify patterns within placental lipid composition and these were correlated with neonatal body composition and placental gene expression. In the analysis of placental lipids, the first three principal components explained 19.1%, 12.7% and 8.0% of variation in placental lipid composition, respectively. Principal component 2 was characterised by high principal component scores for acyl-alkyl-glycerophosphatidylcholines and lipid species containing DHA. Principal component 2 was associated with placental weight and neonatal lean mass; this component was associated with gene expression of APOE, PLIN2, FATP2, FABP4, LEP, G0S2, PNPLA2 and SRB1. Principal components 1 and 3 were not related to birth outcomes but they were associated with the gene expression of lipid related genes. Principal component 1 was associated with expression of LEP, APOE, FATP2 and ACAT2. Principal component 3 was associated with expression of PLIN2, PLIN3 and PNPLA2. This study demonstrates that placentas of different sizes have specific differences in polar-lipid composition and related gene expression. These differences in lipid composition were associated with birth weight and neonatal lean mass, suggesting that placental lipid composition may influence prenatal lean mass accretion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbalip.2021.158971DOI Listing
September 2021

Different regulation of IRE1α and eIF2α pathways by oxygen and insulin in ACH-3P trophoblast model.

Reproduction 2021 May 27;162(1):1-10. Epub 2021 May 27.

Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.

Endoplasmic reticulum (ER)-stress activates the unfolded protein response (UPR), which plays a (patho)physiological role in the placenta. Oxygen and hyperinsulinemia are major regulators of placental development. Thus, we hypothesized that oxygen, insulin and their interplay modulate ER-stress in early pregnancy. Using the human first-trimester trophoblast cell line ACH-3P, we quantified mRNA and protein of several members of UPR by RT-qPCR and Western blotting, respectively. ER-stress induction using tunicamycin and brefeldin A resulted in increased CHOP (4.6-fold change; P ≤ 0.001), XBP1 expression (1.7- and 1.3-fold change, respectively; P ≤ 0.001 and P < 0.05) and XBP1 splicing (7.9- and 12.8-fold change, respectively; P ≤ 0.001). We subsequently analyzed the effect of oxygen (6.5%, 2.5%), insulin (0.1-10 nM) and their interaction using ANCOVA adjusted for cell passage as co-variate. Although GRP78 protein remained unaffected, low oxygen (2.5% O2) increased IRE1α phosphorylation (+52%; P < 0.05) and XBP1 splicing (1.8-fold change; P ≤ 0.001) after 24 h, while eIF2α protein and CHOP expression were downregulated (-28%; P < 0.05 and -24%; P ≤ 0.001; respectively). eIF2α phosphorylation was also reduced after 48 h by low oxygen (-61%; P < 0.05) but increased in the presence of insulin (+46%; P ≤ 0.01). These changes were not PERK-mediated, since PERK phosphorylation and total protein were not altered. Overall, our results suggest that IRE1α and eIF2α UPR-pathways are differentially regulated by oxygen and insulin in early pregnancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/REP-20-0668DOI Listing
May 2021

Mediators of lifestyle intervention effects on neonatal adiposity: are we missing a piece of the puzzle?

Pediatr Res 2021 Mar 22. Epub 2021 Mar 22.

Institute of Sport Science, University of Graz, Graz, Austria.

We evaluated possible mediators underlying lifestyle intervention effects on neonatal adiposity, assessed with sum of skinfolds and cord blood leptin. This is a secondary analysis of the DALI study, a randomised controlled trial in nine European countries. Pregnant women with a pre-pregnancy body mass index of ≥29 kg/m were randomly assigned to counselling for healthy eating (HE), physical activity (PA), HE&PA combined, or to usual care. We considered five maternal metabolic factors at 24-28 and 35-37 weeks of gestation, and four cord blood factors as possible mediators of the effect of combined HE&PA counselling on neonatal adiposity. From all potential mediators, the intervention only affected cord blood non-esterified fatty acids (NEFA), which was higher in the HE&PA group compared to UC (0.068 (mmol/L), 95% CI: 0.004 to 0.133). Cord blood NEFA did not mediate the HE&PA intervention effects on neonatal sum of skinfolds or cord blood leptin, based on an indirect effect on skinfolds of 0.018 (mm), 95% CI: -0.217 to 0.253 and an indirect effect on leptin of -0.143 (μg/l), 95% CI: -0.560 to 0.273. The Dali study observed reductions in neonatal adiposity in pregnant women with obesity, but we were not able to identify the underlying metabolic pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41390-021-01450-5DOI Listing
March 2021

Pregnancies in Diabetes and Obesity: The Capacity-Load Model of Placental Adaptation.

Diabetes 2021 Apr;70(4):823-830

UCL Great Ormond Street Institute of Child Health, London, U.K.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db20-1111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980199PMC
April 2021

Placental mobilization of free fatty acids contributes to altered materno-fetal transfer in obesity.

Int J Obes (Lond) 2021 May 26;45(5):1114-1123. Epub 2021 Feb 26.

Department of Obstetrics and Gynaecology, Medical University of Graz, Graz, Austria.

Background: Metabolic changes in obese pregnant women, such as changes of plasma lipids beyond physiological levels, may subsequently affect fetal development in utero. These metabolic derangements may remain in the offspring and continue throughout life. The placenta mediates bidirectional exchange of nutrients between mother and fetus. The impact of prepregnancy obesity on placental transfer of lipids is still unknown.

Objective: We aimed to examine materno-to-fetal free fatty acid (FFA) transfer by a combined experimental and modeling approach. Flux of C-labeled FFA was evaluated by ex vivo perfusion of human placentae as a function of prepregnancy obesity. Mathematical modeling complemented ex vivo results by providing FFA kinetic parameters.

Results: Obesity was strongly associated with elevated materno-to-fetal transfer of applied C-FFA. Clearance of polyunsaturated C-docosahexaenoic acid (DHA) was most prominently affected. The use of the mathematical model revealed a lower tissue storage capacity for DHA in obese compared with lean placentae.

Conclusion: Besides direct materno-to-fetal FFA transfer, placental mobilization accounts for the fetal FA supply. Together, with metabolic changes in the mother and an elevated materno-fetal FFA transfer shown in obesity, these changes suggest that they may be transmitted to the fetus, with yet unknown consequences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41366-021-00781-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081658PMC
May 2021

Amino Acid Transporter LAT1 (SLC7A5) Mediates MeHg-Induced Oxidative Stress Defense in the Human Placental Cell Line HTR-8/SVneo.

Int J Mol Sci 2021 Feb 8;22(4). Epub 2021 Feb 8.

Institute of Medical Genetics, Medical University of Vienna, A-1090 Vienna, Austria.

The placental barrier can protect the fetus from contact with harmful substances. The potent neurotoxin methylmercury (MeHg), however, is very efficiently transported across the placenta. Our previous data suggested that L-type amino acid transporter (LAT)1 is involved in placental MeHg uptake, accepting MeHg-L-cysteine conjugates as substrate due to structural similarity to methionine. The aim of the present study was to investigate the antioxidant defense of placental cells to MeHg exposure and the role of LAT1 in this response. When trophoblast-derived HTR-8/SVneo cells were LAT1 depleted by siRNA-mediated knockdown, they accumulated less MeHg. However, they were more susceptible to MeHg-induced toxicity. This was evidenced in decreased cell viability at a usually noncytotoxic concentration of 0.03 µM MeHg (~6 µg/L). Treatment with ≥0.3 µM MeHg increased cytotoxicity, apoptosis rate, and oxidative stress of HTR-8/SVneo cells. These effects were enhanced under LAT1 knockdown. Reduced cell number was seen when MeHg-exposed cells were cultured in medium low in cysteine, a constituent of the tripeptide glutathione (GSH). Because LAT1-deficient HTR-8/SVneo cells have lower GSH levels than control cells (independent of MeHg treatment), we conclude that LAT1 is essential for de novo synthesis of GSH, required to counteract oxidative stress. Genetic predisposition to decreased LAT1 function combined with MeHg exposure could increase the risk of placental damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22041707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915079PMC
February 2021

The Predictive Value of miR-16, -29a and -134 for Early Identification of Gestational Diabetes: A Nested Analysis of the DALI Cohort.

Cells 2021 01 15;10(1). Epub 2021 Jan 15.

Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark.

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/m) 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, = 0.001, compared with fasting plasma glucose (AUC 0.687, = 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10010170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830355PMC
January 2021

Maternal Obesity Affects the Glucose-Insulin Axis During the First Trimester of Human Pregnancy.

Front Endocrinol (Lausanne) 2020 9;11:566673. Epub 2020 Oct 9.

Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.

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. In this cross-sectional study, maternal blood samples ( = 323) were collected during voluntary pregnancy termination (gestational age 4-11 weeks) after overnight fasting. Smokers ( = 198) were identified by self-report and serum cotinine levels (ELISA). Maternal BMI (kg/m) 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/m), overweight (BMI 25.0-29.9 kg/m) and obese (BMI ≥ 30.0 kg/m), 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). IS 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 IS between gestational age periods, BMI and leptin groups. C-peptide and IS were log-transformed before analyses. At weeks 7-9, fasting glucose and C-peptide levels were lower ( < 0.01 and < 0.001, respectively) and insulin sensitivity higher ( < 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% ( < 0.01) between the normal weight and the overweight group and by 39% ( < 0.001) between the overweight and obese group. In the leptin groups, C-peptide increased by 25% ( < 0.001) between the 1st and 2nd leptin tertile and by 15% ( < 0.05) between the 2nd and 3rd leptin tertile. IS decreased with higher BMI and fat mass. IS decreased by 18% ( < 0.01) between the normal weight and the overweight group and by 30% ( < 0.01) between the overweight and the obese group. In the leptin groups, IS decreased by 22% ( < 0.001) between the 1st and 2nd leptin tertile and by 14% ( < 0.05) between the 2nd and 3rd leptin tertile. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2020.566673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586307PMC
May 2021

In vitro function and in situ localization of Multidrug Resistance-associated Protein (MRP)1 (ABCC1) suggest a protective role against methyl mercury-induced oxidative stress in the human placenta.

Arch Toxicol 2020 11 11;94(11):3799-3817. Epub 2020 Sep 11.

Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.

Methyl mercury (MeHg) is an organic highly toxic compound that is transported efficiently via the human placenta. Our previous data suggest that MeHg is taken up into placental cells by amino acid transporters while mercury export from placental cells mainly involves ATP binding cassette (ABC) transporters. We hypothesized that the ABC transporter multidrug resistance-associated protein (MRP)1 (ABCC1) plays an essential role in mercury export from the human placenta. Transwell transport studies with MRP1-overexpressing Madin-Darby Canine Kidney (MDCK)II cells confirmed the function of MRP1 in polarized mercury efflux. Consistent with this, siRNA-mediated MRP1 gene knockdown in the human placental cell line HTR-8/SVneo resulted in intracellular mercury accumulation, which was associated with reduced cell viability, accompanied by increased cytotoxicity, apoptosis, and oxidative stress as determined via the glutathione (GSH) status. In addition, the many sources claiming different localization of MRP1 in the placenta required a re-evaluation of its localization in placental tissue sections by immunofluorescence microscopy using an MRP1-specific antibody that was validated in-house. Taken together, our results show that (1) MRP1 preferentially mediates apical-to-basolateral mercury transport in epithelial cells, (2) MRP1 regulates the GSH status of placental cells, (3) MRP1 function has a decisive influence on the viability of placental cells exposed to low MeHg concentrations, and (4) the in situ localization of MRP1 corresponds to mercury transport from maternal circulation to the placenta and fetus. We conclude that MRP1 protects placental cells from MeHg-induced oxidative stress by exporting the toxic metal and by maintaining the placental cells' GSH status in equilibrium.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00204-020-02900-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603445PMC
November 2020

Performance of early pregnancy HbA for predicting gestational diabetes mellitus and adverse pregnancy outcomes in obese European women.

Diabetes Res Clin Pract 2020 Oct 21;168:108378. Epub 2020 Aug 21.

Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Public and Occupational Health, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands; Institute of Sport Science, University of Graz, Graz, Austria.

Aims: To investigate the performance of early pregnancy HbA 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/m) underwent a baseline HbA 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 HbA at the two time points were 0.55 (0.50-0.59) and 0.54 (0.47-0.61), respectively. An early HbA ≥ 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 HbA is of limited use for predicting either GDM or adverse outcomes in overweight/obese European women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.diabres.2020.108378DOI Listing
October 2020

Sex matters: XIST and DDX3Y gene expression as a tool to determine fetal sex in human first trimester placenta.

Placenta 2020 08 26;97:68-70. Epub 2020 Jun 26.

Department of Obstetrics and Gynecology, Medical University of Graz, Graz, 8036, Austria. Electronic address:

Fetal sex influences placental function as well as maternal and fetal health, being an important factor to consider in pregnancy studies. However, fetal sex determination in the first trimester of pregnancy still faces some technical limitations. Here we describe an RT-qPCR technique to determine fetal sex based on X-inactive specific transcript (XIST) and DEAD-Box helicase 3 Y-linked (DDX3Y) gene expression. This method is straightforward, reliable, fast and applicable on both, placental tissue and primary cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.placenta.2020.06.016DOI Listing
August 2020

Less sedentary time is associated with a more favourable glucose-insulin axis in obese pregnant women-a secondary analysis of the DALI study.

Int J Obes (Lond) 2021 02 13;45(2):296-307. Epub 2020 Jul 13.

Institute of Sport Science, University of Graz, Graz, Austria.

Background/objectives: Obese pregnant women are at high risk of developing gestational diabetes mellitus (GDM), which might be reduced by sufficient physical activity (PA) and reduced sedentary time (ST). We assessed whether PA and ST are longitudinally associated with the glucose-insulin axis in obese pregnant women.

Subjects/methods: In this secondary analysis of the DALI (vitamin D And Lifestyle Intervention for gestational diabetes mellitus prevention) study, pregnant women, <20 weeks gestation, with a pre-pregnancy body mass index (BMI) ≥ 29 kg/m, without GDM on entry were included. Time spent in moderate-to-vigorous PA (MVPA) and ST were measured objectively with accelerometers at <20 weeks, 24-28 weeks and 35-37 weeks of gestation. Fasting glucose (mmol/l) and insulin (mU/l), insulin resistance (HOMA-IR) and first-phase and second-phase insulin release (Stumvoll first and second phase) were assessed at the same time. Linear mixed regression models were used to calculate between-participant differences and within-participant changes over time. Analyses were adjusted for gestational age, randomisation, pre-pregnancy BMI, education and age. MVPA, Insulin, HOMA-IR and Stumvoll first and second phase were log-transformed for analyses due to skewness.

Results: 232 women were included in the analysis. Concerning differences between participants, more ST was associated with higher fasting glucose (Estimate: 0.008; 95% CI: 0.002, 0.014), fasting insulin (0.011; 0.002, 0.019), HOMA-IR (0.012; 0.004, 0.021) and Stumvoll first and second phase (0.008; 0.001, 0.014 and 0.007; 0.001, 0.014). Participants with more MVPA had lower Stumvoll first and second phase (-0.137; -0.210, -0.064 and -0.133; -0.202, -0.063). Concerning changes over time, an increase in ST during gestation was associated with elevated Stumvoll first and second phase (0.006; 0.000, 0.011).

Conclusions: As the glucose-insulin axis is more strongly associated with ST than MVPA in our obese population, pregnant women could be advised to reduce ST in addition to increasing MVPA. Moreover, our findings suggest that behaviour change interventions aiming at GDM risk reduction should start in early or pre-pregnancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41366-020-0639-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840500PMC
February 2021

Role of A Novel Angiogenesis FKBPL-CD44 Pathway in Preeclampsia Risk Stratification and Mesenchymal Stem Cell Treatment.

J Clin Endocrinol Metab 2021 Jan;106(1):26-41

The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Northern Ireland, UK.

Context: Preeclampsia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies.

Objective: To investigate the diagnostic and therapeutic target potential of the angiogenesis proteins, FK506-binding protein like (FKBPL) and CD44.

Design And Intervention: FKBPL and CD44 plasma concentration or placental expression were determined in women pre- or postdiagnosis of preeclampsia. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signaling.

Settings And Participants: Human samples prediagnosis (15 and 20 weeks of gestation; n ≥ 57), or postdiagnosis (n = 18 for plasma; n = 4 for placenta) of preeclampsia were used to determine FKBPL and CD44 levels, compared to healthy controls. Trophoblast or endothelial cells were exposed to low/high oxygen, and treated with MSC-conditioned media (MSC-CM) or a FKBPL overexpression plasmid.

Main Outcome Measures: Preeclampsia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signaling in trophoblast and endothelial cells were assessed.

Results: The CD44/FKBPL ratio was reduced in placenta and plasma following clinical diagnosis of preeclampsia. At 20 weeks of gestation, a high plasma CD44/FKBPL ratio was independently associated with the 2.3-fold increased risk of preeclampsia (odds ratio = 2.3, 95% confidence interval [CI] 1.03-5.23, P = 0.04). In combination with high mean arterial blood pressure (>82.5 mmHg), the risk further increased to 3.9-fold (95% CI 1.30-11.84, P = 0.016). Both hypoxia and MSC-based therapy inhibited FKBPL-CD44 signaling, enhancing cell angiogenesis.

Conclusions: The FKBPL-CD44 pathway appears to have a central role in the pathogenesis of preeclampsia, showing promising utilities for early diagnostic and therapeutic purposes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765643PMC
January 2021

Matrix metalloproteinase 15 plays a pivotal role in human first trimester cytotrophoblast invasion and is not altered by maternal obesity.

FASEB J 2020 08 2;34(8):10720-10730. Epub 2020 Jul 2.

Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.

Adequate anchoring of the placenta in the uterus through invasion of first trimester cytotrophoblasts (CTB) is required for a successful pregnancy. This process is mediated by matrix metalloproteinases (MMPs) and regulated by the maternal environment. Obesity is known to alter the intrauterine milieu and has been related to impaired invasion. We hypothesized that placental MMP15, a novel membrane-type MMP, is involved in CTB invasion and regulated by maternal obesity in early pregnancy. Thus, in this study MMP15 was immunolocalized to invasive extravillous and interstitial CTB. MMP15 silencing in chorionic villous explants using two different siRNAs reduced trophoblast outgrowth length (-35%, P ≤ .001 and -26%, P < .05) and area (-43%, P ≤ .001 and -36%, P ≤ .01) without altering trophoblast proliferation or apoptosis. Short-term treatment of primary first trimester trophoblasts with IL-6 (10 ng/mL), interleukin 10 (IL-10) (50 ng/mL), and tumor necrosis factor α (TNF-α) (10 ng/mL) did not affect MMP15 protein levels. Likewise, MMP15 mRNA and protein levels were unaltered between human first trimester placentas from control pregnancies vs those complicated with maternal obesity. Overall, our results suggest that the role of MMP15 in placental development and function in early pregnancy is limited to CTB invasion without being affected by short- and long-term inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.202000773RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496590PMC
August 2020

Cell Type- and Sex-Specific Dysregulation of Thyroid Hormone Receptors in Placentas in Gestational Diabetes Mellitus.

Int J Mol Sci 2020 Jun 5;21(11). Epub 2020 Jun 5.

Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Maistrasse 11, 80337 Munich, Germany.

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 ( < 0.05). The SCT difference of GDM vs. control was strongest ( < 0.01) in female placentas. THRα2 was only weakly present and immunolabelling was weaker ( < 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 ( < 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21114056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313460PMC
June 2020

The importance of maternal insulin resistance throughout pregnancy on neonatal adiposity.

Paediatr Perinat Epidemiol 2021 01 30;35(1):83-91. Epub 2020 Apr 30.

Institution of Sport Science, University of Graz, Graz, Austria.

Background: Although previous studies evaluated the association of maternal health parameters with neonatal adiposity, little is known regarding the complexity of the relationships among different maternal health parameters throughout pregnancy and its impact on neonatal adiposity.

Objectives: To evaluate the direct and indirect associations between maternal insulin resistance during pregnancy, in women with obesity, and neonatal adiposity. In addition, associations between maternal fasting glucose, triglycerides (TG), non-esterified fatty acids (NEFA), and neonatal adiposity were also assessed.

Methods: This is a longitudinal, secondary analysis of the DALI study, an international project conducted in nine European countries with pregnant women with obesity. Maternal insulin resistance (HOMA-IR), fasting glucose, TG, and NEFA were measured three times during pregnancy (<20, 24-28, and 35-37 weeks of gestation). Offspring neonatal adiposity was estimated by the sum of four skinfolds. Structural equation modelling was conducted to evaluate the direct and indirect relationships among the variables of interest.

Results: Data on 657 mother-infant pairs (50.7% boys) were analysed. Neonatal boys exhibited lower mean sum of skinfolds compared to girls (20.3 mm, 95% CI 19.7, 21.0 vs 21.5 mm, 95% CI 20.8, 22.2). In boys, maternal HOMA-IR at <20 weeks was directly associated with neonatal adiposity (β = 0.35 mm, 95% CI 0.01, 0.70). In girls, maternal HOMA-IR at 24-28 weeks was only indirectly associated with neonatal adiposity, which implies that this association was mediated via maternal HOMA-IR, glucose, triglycerides, and NEFA during pregnancy (β = 0.26 mm, 95% CI 0.08, 0.44).

Conclusions: The timing of the role of maternal insulin resistance on neonatal adiposity depends on fetal sex. Although the association was time-dependent, maternal insulin resistance was associated with neonatal adiposity in both sexes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ppe.12682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891448PMC
January 2021

Temporal relationships between maternal metabolic parameters with neonatal adiposity in women with obesity differ by neonatal sex: Secondary analysis of the DALI study.

Pediatr Obes 2020 07 6;15(7):e12628. Epub 2020 Mar 6.

Institute of Sport Science, University of Graz, Graz, Austria.

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/m 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ijpo.12628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317347PMC
July 2020

Growing fat in utero: timing is everything.

Lancet Diabetes Endocrinol 2020 04 2;8(4):259-260. Epub 2020 Mar 2.

Department of Obstetrics and Gynaecology, Medical University Graz, Graz, Austria.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-8587(20)30064-4DOI Listing
April 2020

Plasma Glycated CD59 Predicts Early Gestational Diabetes and Large for Gestational Age Newborns.

J Clin Endocrinol Metab 2020 04;105(4)

Divisions of Hematology, Brigham & Women's Hospital, Boston, Massachusetts.

Context: Gestational diabetes mellitus (GDM) diagnosed in early pregnancy is a health care challenge because it increases the risk of adverse outcomes. Plasma-glycated CD59 (pGCD59) is an emerging biomarker for diabetes and GDM. The aim of this study was to assess the performance of pGCD59 as a biomarker of early GDM and its association with delivering a large for gestational age (LGA) infant.

Objectives: To assess the performance of pGCD59 to identify women with GDM in early pregnancy (GDM < 20) and assess the association of pGCD59 with LGA and potentially others adverse neonatal outcomes linked to GDM.

Methods: Blood levels of pGCD59 were measured in samples from 693 obese women (body mass index > 29) undergoing a 75-g, 2-hour oral glucose tolerance test (OGTT) at <20 weeks' gestation in the Vitamin D and Lifestyle Intervention study: the main analyses included 486 subjects who had normal glucose tolerance throughout the pregnancy, 207 who met criteria for GDM at <20 weeks, and 77 diagnosed with GDM at pregnancy weeks 24 through 28. Reference tests were 75-g, 2-hour OGTT adjudicated based on International Association of Diabetes and Pregnancy Study Group criteria. The index test was a pGCD59 ELISA.

Results: Mean pGCD59 levels were significantly higher (P < 0.001) in women with GDM < 20 (3.9 ± 1.1 standard peptide units [SPU]) than in those without (2.7 ± 0.7 SPU). pGCD59 accurately identified GDM in early pregnancy with an area under the curve receiver operating characteristic curves of 0.86 (95% confidence interval [CI], 0.83-0.90). One-unit increase in maternal pGCD59 level was associated with 36% increased odds of delivering an LGA infant (odds ratio for LGA vs non-LGA infant: 1.4; 95% CI, 1.1-1.8; P = 0.016).

Conclusion: Our results indicate that pGCD59 is a simple and accurate biomarker for detection of GDM in early pregnancy and risk assessment of LGA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082084PMC
April 2020

Both glycaemic control and insulin dose during pregnancy in women with type 1 diabetes are associated with neonatal anthropometric measures and placental weight.

Diabetes Metab Res Rev 2020 07 3;36(5):e3300. Epub 2020 Mar 3.

Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

Background: To investigate longitudinal associations of maternal glucose/HbA 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), HbA (%, 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 HbA .

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/dmrr.3300DOI Listing
July 2020

Diabetes Mellitus, Obesity, and the Placenta.

Obstet Gynecol Clin North Am 2020 Mar 18;47(1):65-79. Epub 2019 Dec 18.

Department of Obstetrics and Gynaecology, Medical University of Graz, Auenbruggerplatz 14, Graz 8036, Austria.

The placenta is exposed to metabolic derangements in the maternal and fetal circulation. The effects of the early placental "exposome" determine further trajectories. Overstimulation of the fetal pancreas in early gestation results in fetal hyperinsulinemia, augmenting glucose transfer with adverse effects on the fetus. The manifold placental changes at the end of pregnancy can be regarded as adaptive responses to protect the fetus from diabetes and obesity. The causal role of the placenta, if any, in mediating long-term effects on offspring development is an important area of current and future research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ogc.2019.11.001DOI Listing
March 2020

Hyperglycemia-induced endothelial dysfunction is alleviated by thioredoxin mimetic peptides through the restoration of VEGFR-2-induced responses and improved cell survival.

Int J Cardiol 2020 06 30;308:73-81. Epub 2019 Dec 30.

Experimental and Molecular Cardiology, Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany; Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands; Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Münster, Germany; Department of Internal Medicine I, SRH Central Hospial, Suhl, Germany. Electronic address:

Background: 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.

Methods And Results: 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.

Conclusions: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2019.12.065DOI Listing
June 2020

Maternal Obesity Alters Placental Cell Cycle Regulators in the First Trimester of Human Pregnancy: New Insights for BRCA1.

Int J Mol Sci 2020 Jan 11;21(2). Epub 2020 Jan 11.

Department of Obstetrics and Gynecology, Medical University of Graz, 8036 Graz, Austria.

In the first trimester of pregnancy, placental development involves a wide range of cellular processes. These include trophoblast proliferation, fusion, and differentiation, which are dependent on tight cell cycle control. The intrauterine environment affects placental development, which also includes the trophoblast cell cycle. In this work, we focus on maternal obesity to assess whether an altered intrauterine milieu modulates expression and protein levels of placental cell cycle regulators in early human pregnancy. For this purpose, we use first trimester placental tissue from lean and obese women (gestational week 5-11, = 58). Using a PCR panel, a cell cycle protein array, and STRING database analysis, we identify a network of cell cycle regulators increased by maternal obesity in which breast cancer 1 (BRCA1) is a central player. Immunostaining localizes BRCA1 predominantly to the villous and the extravillous cytotrophoblast. Obesity-driven BRCA1 upregulation is not able to be explained by DNA methylation (EPIC array) or by short-term treatment of chorionic villous explants at 2.5% oxygen with tumor necrosis factor α (TNF-α) (50 mg/mL), leptin (100 mg/mL), interleukin 6 (IL-6) (100 mg/mL), or high glucose (25 nM). Oxygen tension rises during the first trimester, but this change in vitro has no effect on BRCA1 (2.5% and 6.5% O). We conclude that maternal obesity affects placental cell cycle regulation and speculate this may alter placental development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21020468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014057PMC
January 2020

The Effects of Lifestyle and/or Vitamin D Supplementation Interventions on Pregnancy Outcomes: What Have We Learned from the DALI Studies?

Curr Diab Rep 2019 12 16;19(12):162. Epub 2019 Dec 16.

Institute of Metabolic Science, Addenbrookes Hospital, Cambridge, England.

Purpose Of Review: The DALI (vitamin D and lifestyle intervention in the prevention of gestational diabetes mellitus (GDM)) study aimed to prevent GDM with lifestyle interventions or Vitamin D supplementation (1600 IU/day). This review summarizes the learnings from the DALI studies among pregnant women with a BMI ≥ 29 kg/m.

Recent Findings: Women diagnosed with GDM earlier in pregnancy had a worse metabolic profile than those diagnosed later. A combined physical activity (PA) and healthy eating (HE) lifestyle intervention improved both behaviours, limited gestational weight gain (GWG) and was cost-effective. Although GDM risk was unchanged, neonatal adiposity was reduced due to less sedentary time. Neither PA nor HE alone limited GWG or GDM risk. Fasting glucose was higher with HE only intervention, and lower with Vitamin D supplementation. Our combined intervention did not prevent GDM, but was cost-effective, limited GWG and reduced neonatal adiposity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11892-019-1282-7DOI Listing
December 2019

Evidence of Human Milk Oligosaccharides in Cord Blood and Maternal-to-Fetal Transport across the Placenta.

Nutrients 2019 Nov 4;11(11). Epub 2019 Nov 4.

Department of Obstetrics and Gynecology, Medical University of Graz, 8036 Graz, Austria.

Human milk oligosaccharides (HMOs) are present in maternal serum in early gestation, raising the question of whether HMOs can cross the placental barrier and reach fetal circulation. Here, we aimed to detect HMOs in cord blood, and assess HMO composition and concentration in relation to maternal HMOs. In an ex-vivo placental perfusion model, we asked whether HMOs can pass over the placenta. Using HPLC, we measured HMOs in maternal serum and matching venous cord blood samples collected at delivery from normal pregnancies ( = 22). To investigate maternal-to-fetal transport, we perfused isolated placental cotyledons from term pregnancies ( = 3) with 2'-fucosyllactose (2'FL) in a double closed setting. We found up to 18 oligosaccharides typically present in maternal serum in all cord serum samples investigated. Median total cord blood HMO concentration did not differ from the concentration in maternal serum. HMO composition resembled the composition in maternal serum, with the strongest correlations for 2'FL and LDFT. After 180 min perfusion, we found 22% of maternally offered 2'FL in the fetal circuit without reaching equilibrium. Our results provide direct evidence of HMOs in cord blood, and suggest that the placenta transfers HMOs from the maternal to fetal circuit. Future studies will investigate potential differences in the transfer of specific HMOs, or in pregnancy disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu11112640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893815PMC
November 2019

Gestational diabetes mellitus.

Nat Rev Dis Primers 2019 07 11;5(1):47. Epub 2019 Jul 11.

Department of Obstetrics, Center for Pregnant Women with Diabetes, Rigshospitalet and The Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Hyperglycaemia that develops during pregnancy and resolves after birth has been recognized for over 50 years, but uniform worldwide consensus is lacking about threshold hyperglycaemic levels that merit a diagnosis of 'gestational diabetes mellitus' (GDM) and thus treatment during pregnancy. GDM is currently the most common medical complication of pregnancy, and prevalence of undiagnosed hyperglycaemia and even overt diabetes in young women is increasing. Maternal overweight and obesity, later age at childbearing, previous history of GDM, family history of type 2 diabetes mellitus and ethnicity are major GDM risk factors. Diagnosis is usually performed using an oral glucose tolerance test (OGTT), although a non-fasting, glucose challenge test (GCT) is used in some parts of the world to screen women for those requiring a full OGTT. Dietary modification and increased physical activity are the primary treatments for GDM, but pharmacotherapy, usually insulin, is used when normoglycaemia is not achieved. Oral hypoglycaemic agents, principally metformin and glibenclamide (glyburide), are also used in some countries. Treatment improves immediate pregnancy outcomes, reducing excess fetal growth and adiposity and pregnancy-related hypertensive disorders. GDM increases the risk of long-term complications, including obesity, impaired glucose metabolism and cardiovascular disease, in both the mother and infant. Optimal management of mother and infant during long-term follow-up remains challenging, with very limited implementation of preventive strategies in most parts of the world.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41572-019-0098-8DOI Listing
July 2019

Nutritional Lifestyle Intervention in Obese Pregnant Women, Including Lower Carbohydrate Intake, Is Associated With Increased Maternal Free Fatty Acids, 3-β-Hydroxybutyrate, and Fasting Glucose Concentrations: A Secondary Factorial Analysis of the European Multicenter, Randomized Controlled DALI Lifestyle Intervention Trial.

Diabetes Care 2019 08 10;42(8):1380-1389. Epub 2019 Jun 10.

Gender Medicine Unit, Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria

Objective: In our randomized controlled trial, we investigated the impact of healthy eating (HE) aiming for restricted gestational weight gain (GWG) and physical activity (PA) interventions on maternal and neonatal lipid metabolism.

Research Design And Methods: Obese pregnant women ( = 436) were included before 20 weeks' gestation and underwent glucose testing (oral glucose tolerance test) and lipid profiling at baseline and 24-28 and 35-37 gestational weeks after an at least 10-h overnight fast. This secondary analysis had a factorial design with comparison of HE ( = 221) versus no HE ( = 215) and PA ( = 218) versus no PA ( = 218). Maternal changes in triglycerides (TG), LDL cholesterol, HDL cholesterol, free fatty acids (FFAs), and leptin from baseline to end of pregnancy and neonatal outcomes were analyzed using general linear models with adjustment for relevant parameters.

Results: At 24-28 weeks' gestation, FFAs (mean ± SD, 0.60 ± 0.19 vs. 0.55 ± 0.17 mmol/L, < 0.01) were increased after adjustment for FFA at baseline, maternal age, BMI at time of examination, gestational week, insulin resistance, self-reported food intake, self-reported physical activity, and maternal smoking, and GWG was lower (3.3 ± 2.6 vs. 4.3 ± 2.8 kg, < 0.001, adjusted mean differences -1.0 [95% CI -1.5; -0.5]) in HE versus no HE. Fasting glucose levels (4.7 ± 0.4 vs. 4.6 ± 0.4 mmol/L, < 0.05) and 3-β-hydroxybutyrate (3BHB) (0.082 ± 0.065 vs. 0.068 ± 0.067 mmol/L, < 0.05) were higher in HE. Significant negative associations between carbohydrate intake and FFA, 3BHB, and fasting glucose at 24-28 weeks' gestation were observed. No differences between groups were found in oral glucose tolerance test or leptin or TG levels at any time. Furthermore, in PA versus no PA, no similar changes were found. In cord blood, elevated FFA levels were found in HE after full adjustment (0.34 ± 0.22 vs. 0.29 ± 0.16 mmol/L, = 0.01).

Conclusions: HE intervention was associated with reduced GWG, higher FFAs, higher 3BHB, and higher fasting glucose at 24-28 weeks of gestation, suggesting induction of lipolysis. Increased FFA was negatively associated with carbohydrate intake and was also observed in cord blood. These findings support the hypothesis that maternal antenatal dietary restriction including carbohydrates is associated with increased FFA mobilization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc19-0418DOI Listing
August 2019
-->