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Biomedicines
Special Issues
Metabolic Disorders in Pregnancy: From (Epi)genetics to Functional Consequences
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Metabolic Disorders in Pregnancy: From (Epi)genetics to Functional Consequences

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (15 August 2022) | Viewed by 20615

Special Issue Editors

Dr. Jasminka Štefulj

E-Mail Website1 Website2
Guest Editor
Department of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
Interests: (epi)genetics of complex diseases; obesity; diabetes; mental disorders; serotonin
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Gernot Desoye

E-Mail Website
Co-Guest Editor
Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria
Interests: placenta; fetal growth; diabetes; obesity; insulin
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Metabolic disorders in pregnancy are a growing health problem worldwide. The global epidemic of obesity is increasing the number of women who enter pregnancy with excessive body fat, predisposing them to develop pregnancy-related metabolic conditions such as gestational diabetes mellitus (GDM). Both maternal obesity and GDM are associated with serious short-term and long-term adverse consequences for mother and child. The aim of this Special Issue is to gather the latest studies that deepen our current understanding of the pathophysiological mechanisms involved in metabolic disorders in pregnancy, with a focus on maternal obesity and GDM. We are particularly interested in studies of genetic and epigenetic factors, their interactions, functional consequences at the molecular, cellular, and whole organism levels, and potential utility as diagnostic or prognostic biomarkers. Studies on the influence of fetal sex and the role of the placenta are also appreciated. Both original research articles and reviews are of interest.


Dr. Jasminka Štefulj
Guest Editor

Prof. Dr. Gernot Desoye
Co-Guest Editor

 

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Keywords

  • pregnancy
  • obesity
  • gestational diabetes mellitus
  • genetic variants
  • epigenetics
  • DNA methylation
  • histone modification
  • microRNA
  • sex differences
  • placenta

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Published Papers (8 papers)

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Research

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15 pages, 3114 KiB  
Article
DNA Methylation and Gene Expression in Blood and Adipose Tissue of Adult Offspring of Women with Diabetes in Pregnancy—A Validation Study of DNA Methylation Changes Identified in Adolescent Offspring
by Eleonora Manitta, Irene Carolina Fontes Marques, Sandra Stokholm Bredgaard, Louise Kelstrup, Azadeh Houshmand-Oeregaard, Tine Dalsgaard Clausen, Louise Groth Grunnet, Elisabeth Reinhardt Mathiesen, Louise Torp Dalgaard, Romain Barrès, Allan Arthur Vaag, Peter Damm and Line Hjort
Biomedicines 2022, 10(6), 1244; https://doi.org/10.3390/biomedicines10061244 - 26 May 2022
Cited by 3 | Viewed by 2352
Abstract
Maternal gestational diabetes and obesity are associated with adverse outcomes in offspring, including increased risk of diabetes and cardiovascular diseases. Previously, we identified a lower DNA methylation degree at genomic sites near the genes ESM1, MS4A3, and TSPAN14 in the blood [...] Read more.
Maternal gestational diabetes and obesity are associated with adverse outcomes in offspring, including increased risk of diabetes and cardiovascular diseases. Previously, we identified a lower DNA methylation degree at genomic sites near the genes ESM1, MS4A3, and TSPAN14 in the blood cells of adolescent offspring exposed to gestational diabetes and/or maternal obesity in utero. In the present study, we aimed to investigate if altered methylation and expression of these genes were detectable in blood, as well in the metabolically relevant subcutaneous adipose tissue, in a separate cohort of adult offspring exposed to gestational diabetes and obesity (O-GDM) or type 1 diabetes (O-T1D) in utero, compared with the offspring of women from the background population (O-BP). We did not replicate the findings of lower methylation of ESM1, MS4A3, and TSPAN14 in blood from adults, either in O-GDM or O-T1D. In contrast, in adipose tissue of O-T1D, we found higher MS4A3 DNA methylation, which will require further validation. The adipose tissue ESM1 expression was lower in O-GDM compared to O-BP, which in turn was not associated with maternal pre-pregnancy BMI nor the offspring’s own adiposity. Adipose tissue TSPAN14 expression was slightly lower in O-GDM compared with O-BP, but also positively associated with maternal pre-pregnancy BMI, as well as offspring’s own adiposity and HbA1c levels. In conclusion, the lower DNA methylation in blood from adolescent offspring exposed to GDM could not be confirmed in the present cohort of adult offspring, potentially due to methylation remodeling with increased aging. In offspring adipose tissue, ESM1 expression was associated with maternal GDM, and TSPAN14 expression was associated with both maternal GDM, as well as pre-pregnancy BMI. These altered expression patterns are potentially relevant to the concept of developmental programming of cardiometabolic diseases and require further studies. Full article
(This article belongs to the Special Issue Metabolic Disorders in Pregnancy: From (Epi)genetics to Functional Consequences)
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13 pages, 1312 KiB  
Article
Physical Activity and Sedentary Time in Pregnancy: An Exploratory Study on Oxidative Stress Markers in the Placenta of Women with Obesity
by Saghi Zafaranieh, Anna M. Dieberger, Barbara Leopold-Posch, Berthold Huppertz, Sebastian Granitzer, Markus Hengstschläger, Claudia Gundacker, Gernot Desoye, Mireille N. M. van Poppel and DALI Core Investigator Group
Biomedicines 2022, 10(5), 1069; https://doi.org/10.3390/biomedicines10051069 - 5 May 2022
Cited by 5 | Viewed by 2480
Abstract
Regular moderate-to-vigorous physical activity (MVPA) and reduced sedentary time (ST) improve maternal glucose metabolism in pregnancy. More MVPA and less ST outside pregnancy increase antioxidant capacity, hence, are beneficial in preventing oxidative stress. The placenta is the first line of defense for the [...] Read more.
Regular moderate-to-vigorous physical activity (MVPA) and reduced sedentary time (ST) improve maternal glucose metabolism in pregnancy. More MVPA and less ST outside pregnancy increase antioxidant capacity, hence, are beneficial in preventing oxidative stress. The placenta is the first line of defense for the fetus from an adverse maternal environment, including oxidative stress. However, effects of MVPA and ST on oxidative stress markers in the placenta are unknown. The purpose of this study was to assess the association of MVPA and ST in pregnancy with oxidative stress markers in placentas of overweight/obese women (BMI ≥ 29 kg/m2). MVPA and ST were objectively measured with accelerometers at <20 weeks, 24–27 and 35–37 weeks of gestation. Using linear Bayesian multilevel models, the associations of MVPA and ST (mean and changes) with mRNA expression of a panel of 11 oxidative stress related markers were assessed in 96 women. MVPA was negatively correlated with HSP70 mRNA expression in a sex-independent manner and with GCLM expression only in placentas of female fetuses. ST was positively associated with HO-1 mRNA expression in placentas of male neonates. None of the other markers were associated with MVPA or ST. We speculate that increasing MVPA and reducing ST attenuates the oxidative stress state in placentas of obese pregnant women. Full article
(This article belongs to the Special Issue Metabolic Disorders in Pregnancy: From (Epi)genetics to Functional Consequences)
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14 pages, 1287 KiB  
Article
Cord Blood Advanced Lipoprotein Testing Reveals an Interaction between Gestational Diabetes and Birth-Weight and Suggests a New Early Biomarker of Infant Obesity
by Francisco Algaba-Chueca, Elsa Maymó-Masip, Mónica Ballesteros, Albert Guarque, Alejandro Majali-Martínez, Olga Freixes, Núria Amigó, Sonia Fernández-Veledo, Joan Vendrell and Ana Megía
Biomedicines 2022, 10(5), 1033; https://doi.org/10.3390/biomedicines10051033 - 29 Apr 2022
Cited by 2 | Viewed by 1964
Abstract
Abnormal lipid metabolism is associated with gestational diabetes mellitus (GDM) and is observed in neonates with abnormal fetal growth. However, the underlying specific changes in the lipoprotein profile remain poorly understood. Thus, in the present study we used a novel nuclear magnetic resonance [...] Read more.
Abnormal lipid metabolism is associated with gestational diabetes mellitus (GDM) and is observed in neonates with abnormal fetal growth. However, the underlying specific changes in the lipoprotein profile remain poorly understood. Thus, in the present study we used a novel nuclear magnetic resonance (NMR)-based approach to profile the umbilical cord serum lipoproteins. Two-dimensional diffusion-ordered 1H-NMR spectroscopy showed that size, lipid content, number and concentration of particles within their subclasses were similar between offspring born to control (n = 74) and GDM (n = 62) mothers. Subsequent data stratification according to newborn birth-weight categories, i.e., small (n = 39), appropriate (n = 50) or large (n = 49) for gestational age (SGA, AGA and LGA, respectively), showed an interaction between GDM and birth-weight categories for intermediate-density lipoproteins (IDL)-cholesterol content and IDL- and low-density lipoproteins (LDL)-triglyceride content, and the number of medium very low-density lipoproteins (VLDL) and LDL particles specifically in AGA neonates. Moreover, in a 2-year follow-up study, we observed that small LDL particles were independently associated with offspring obesity at 2 years (n = 103). Collectively, our data demonstrate that GDM disturbs triglyceride and cholesterol lipoprotein content across birth-weight categories, with AGA neonates born to GDM mothers displaying a profile more similar to that of adults with dyslipidemia. Furthermore, an altered fetal lipoprotein pattern was associated with the development of obesity at 2 years. Full article
(This article belongs to the Special Issue Metabolic Disorders in Pregnancy: From (Epi)genetics to Functional Consequences)
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18 pages, 1780 KiB  
Article
The Temporal Profile of Circulating miRNAs during Gestation in Overweight and Obese Women with or without Gestational Diabetes Mellitus
by Anja Elaine Sørensen, Mireille N. M. van Poppel, Gernot Desoye, David Simmons, Peter Damm, Dorte Møller Jensen, Louise Torp Dalgaard and The DALI Core Investigator Group
Biomedicines 2022, 10(2), 482; https://doi.org/10.3390/biomedicines10020482 - 18 Feb 2022
Cited by 9 | Viewed by 2487
Abstract
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, [...] Read more.
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. Full article
(This article belongs to the Special Issue Metabolic Disorders in Pregnancy: From (Epi)genetics to Functional Consequences)
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19 pages, 2076 KiB  
Article
Maternal Metabolic State and Fetal Sex and Genotype Modulate Methylation of the Serotonin Receptor Type 2A Gene (HTR2A) in the Human Placenta
by Marina Horvatiček, Maja Perić, Ivona Bečeheli, Marija Klasić, Maja Žutić, Maja Kesić, Gernot Desoye, Sandra Nakić Radoš, Marina Ivanišević, Dubravka Hranilovic and Jasminka Štefulj
Biomedicines 2022, 10(2), 467; https://doi.org/10.3390/biomedicines10020467 - 17 Feb 2022
Cited by 9 | Viewed by 2589
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Metabolic Disorders in Pregnancy: From (Epi)genetics to Functional Consequences)
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Review

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11 pages, 599 KiB  
Review
Proteomic Approaches in the Study of Placenta of Pregnancy Complicated by Gestational Diabetes Mellitus
by Annunziata Lapolla and Pietro Traldi
Biomedicines 2022, 10(9), 2272; https://doi.org/10.3390/biomedicines10092272 - 14 Sep 2022
Cited by 3 | Viewed by 2052
Abstract
Gestational diabetes mellitus (GDM), a glucose intolerance developing or first recognized during pregnancy, leads to a series of short- and long-term maternal and fetal complications, somehow related to placenta structural and functional changes. The focus and the objective of the present review are [...] Read more.
Gestational diabetes mellitus (GDM), a glucose intolerance developing or first recognized during pregnancy, leads to a series of short- and long-term maternal and fetal complications, somehow related to placenta structural and functional changes. The focus and the objective of the present review are to discuss the results which can be obtained by different mass spectrometric approaches in the study of placenta protein profile. Thus, matrix-assisted laser desorption/ionization mass spectrometry (MALDI) has been applied on placenta omogenates before and after one-dimensional electrophoretic separation, followed by tryptic digestion. MALDI imaging was used for direct investigation on the placenta tissue (both maternal and fetal sides). The results showed that some differences among the absolute abundances of some proteins are present for placenta samples from GDM patients. The majority of investigations were carried out by two-dimensional electrophoresis (2DE) followed by LC-MS/MS or, directly by the label-free LC-MSE approach. It should be emphasized that all these techniques were showed differences in the protein expression between the placenta samples from healthy or GDM subjects. 2DE was also employed to separate and compare placental protein levels from GDM and the control groups: differentially expressed proteins between the two groups were identified by MALDI-TOF/TOF mass spectrometry and were further confirmed by Western blotting. The physiopathological significance of the obtained results are reported and discussed in this narrative review. The experimental data obtained until now show that the newest, mass spectrometric approaches can be considered a valid tool to investigate the possible changes of placenta in the presence of GDM. Full article
(This article belongs to the Special Issue Metabolic Disorders in Pregnancy: From (Epi)genetics to Functional Consequences)
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15 pages, 1164 KiB  
Review
Extracellular Vesicles—New Players in Cell-to-Cell Communication in Gestational Diabetes Mellitus
by Carlos Palma, H. David McIntyre and Carlos Salomon
Biomedicines 2022, 10(2), 462; https://doi.org/10.3390/biomedicines10020462 - 16 Feb 2022
Cited by 9 | Viewed by 3161
Abstract
Research in extracellular vesicles (EVs) has contributed to a better understanding of physiological and pathophysiological conditions. Biologically active cargo, such as miRNAs and proteins, is critical in many different biological processes. In this context, pregnancy is one of the most complex physiological states, [...] Read more.
Research in extracellular vesicles (EVs) has contributed to a better understanding of physiological and pathophysiological conditions. Biologically active cargo, such as miRNAs and proteins, is critical in many different biological processes. In this context, pregnancy is one of the most complex physiological states, which needs a highly regulated system to ensure the correct nourishment and development of the baby. However, pre-existent maternal conditions and habits can modify the EV-cargo and dysregulate the system leading to pregnancy complications, with gestational diabetes mellitus (GDM) being one of the most reported and influential. Calcification and aging of muscle cells, protein modification in vascular control or variations in the levels of specific miRNAs are some of the changes observed or led by EV populations as adaptation to GDM. Interestingly, insulin sensitivity and glucose tolerance changes are not fully understood to date. Nevertheless, the increasing evidence generated has opened new possibilities in the biomarker discovery field but also in the understanding of cellular mechanisms modified and involved in GDM. This brief review aims to discuss some of the findings in GDM and models used for that purpose and their potential roles in the metabolic alterations during pregnancy, with a focus on insulin sensitivity and glucose tolerance. Full article
(This article belongs to the Special Issue Metabolic Disorders in Pregnancy: From (Epi)genetics to Functional Consequences)
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Other

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15 pages, 911 KiB  
Systematic Review
The Maternal and Fetal Outcomes of Pregnancy in Wilson’s Disease: A Systematic Literature Review and Meta-Analysis
by Tomasz Litwin, Jan Bembenek, Agnieszka Antos, Iwona Kurkowska-Jastrzębska, Adam Przybyłkowski, Marta Skowrońska, Łukasz Smoliński and Anna Członkowska
Biomedicines 2022, 10(9), 2072; https://doi.org/10.3390/biomedicines10092072 - 24 Aug 2022
Cited by 4 | Viewed by 2228
Abstract
Wilson’s disease (WD) is a rare, treatable genetic disorder with multi-organ symptoms related mainly to copper accumulation. Most patients become aware of the disease as young adults, thus knowledge on fertility, pregnancy course and outcome is very important both for patients and physicians. [...] Read more.
Wilson’s disease (WD) is a rare, treatable genetic disorder with multi-organ symptoms related mainly to copper accumulation. Most patients become aware of the disease as young adults, thus knowledge on fertility, pregnancy course and outcome is very important both for patients and physicians. The aim of this study was to perform a systematic review and meta-analysis of pregnancy outcomes in women with WD. This systematic literature review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were identified by searching the PubMed database (up to 12 January 2022) and by screening reference lists. We found 49 publications, including 13 retrospective studies and 36 series and case reports on pregnancy outcomes in WD patients. In total, descriptions of 449 pregnant women with 822 pregnancies were retrieved. Successful deliveries were achieved in 78.3% (644/822) of all pregnancies. Spontaneous abortions were observed in 21.7% (178/822) of pregnancies, more frequently in patients who were untreated 68.6% (96/140). Analyzing maternal outcome, 2.2% (18/822) of pregnancies were associated with the aggravation of neurological symptoms. Symptoms of hepatic deterioration were observed in 4.6% (38/822) of cases. These were usually transient and recovered after pregnancy; however, death due to liver failure was observed in 0.2% (2/822) of cases. Birth defects occurred in 4.7% (39/822) of pregnancies. The available meta-analysis showed statistically significant positive associations between anti-copper treatment and pregnancy outcome. Our results document the significance of anti-copper treatment as the main factor leading to successful pregnancy, as well as positive outcomes for women with WD. Full article
(This article belongs to the Special Issue Metabolic Disorders in Pregnancy: From (Epi)genetics to Functional Consequences)
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