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Risk Factors and Molecular Mechanisms of Gestational Diabetes

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (1 October 2018) | Viewed by 170456

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Dr. Vernon W. Dolinsky

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Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada
Interests: diabetes; obesity; heart disease; fetal programming; mitochondria; epigenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Gestational diabetes mellitus (GDM) is one of the most common pregnancy-related health conditions, affecting 5–10% of pregnant women; however, even-higher incidences are reported among some ethnicities. In addition, GDM is rising in the population. The majority of women who develop GDM have peripheral insulin resistance related to being overweight and obese, although GDM can also occur in the absence of obesity. GDM increases the risk for the development of type 2 diabetes and cardiovascular disease in women. Beyond its effects on maternal health, GDM also has serious health implications for the offspring. GDM is associated with elevated incidence of complications during delivery, fetal postpartum hypoglycemia and congenital defects. In addition, GDM is associated with altered fetal growth as well as an obesity, type 2 diabetes (T2D) and heart disease in the offspring as they age. Considerable interest is focused on finding biomarkers and mechanisms that explain GDM risk, as well as the mechanisms that condition the offspring for an increased risk of disease. This Special Issue of the International Journal of Molecular Sciences, “Risk Factors and Molecular Mechanisms of Gestational Diabetes” will focus on these biomarkers and mechanisms in humans and animal model research. Authors are invited to submit manuscripts that address risk factors, biomarkers and mechanisms of GDM development and their impact on their offspring. In addition, authors may also discuss therapies and interventions for GDM that are focused on improving the health of women and their children exposed to GDM.

Assoc. Prof. Dr. Vernon W. Dolinsky
Guest Editor

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Keywords

Gestational Diabetes
Maternal Obesity
Insulin Resistance
Metabolism
Epigenetics
Lifestyle Interventions and Therapeutics
Placenta
Newborn Complications
Fetal Programming

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Published Papers (11 papers)

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14 pages, 276 KiB

Open AccessArticle

Nesfatin-1 and Vaspin as Potential Novel Biomarkers for the Prediction and Early Diagnosis of Gestational Diabetes Mellitus

by Radzisław Mierzyński, Elżbieta Poniedziałek-Czajkowska, Dominik Dłuski, Jolanta Patro-Małysza, Żaneta Kimber-Trojnar, Maciej Majsterek and Bożena Leszczyńska-Gorzelak

Int. J. Mol. Sci. 2019, 20(1), 159; https://doi.org/10.3390/ijms20010159 - 4 Jan 2019

Cited by 38 | Viewed by 5128

Abstract

Gestational diabetes mellitus (GDM) is considered to be one of the most frequent medical complication observed among pregnant women. The role of adipokines in the pathogenesis of GDM remains strictly unknown. Different adipokines have been studied throughout gestation, and they have been proposed as biomarkers of GDM and other pregnancy-related complications; however, there is no biomarker reported for GDM screening at present. The aim of this study was to evaluate serum nesfatin-1 and vaspin levels in GDM and non-GDM women, to characterize the correlation between these adipokines, and to assess the potential role of circulating adipokines in the prediction of risk of gestational diabetes mellitus. Serum concentrations of nesfatin-1 and vaspin were measured in 153 women with GDM, and in 84 patients with uncomplicated pregnancy by enzyme-linked immunosorbent assay (ELISA) kits, according to the manufacturer’s instructions. Circulating levels of nesfatin-1 and vaspin were significantly lower in the GDM group than in the control group. Nesfatin-1 levels were negatively correlated with vaspin levels. The results of this study point out the possible role of nesfatin-1 and vaspin as potential novel biomarkers for the prediction and early diagnosis of GDM. Further studies are necessary to evaluate the influence of nesfatin-1 and vaspin on glucose metabolism in the early stages of GDM. Full article

(This article belongs to the Special Issue Risk Factors and Molecular Mechanisms of Gestational Diabetes)

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13 pages, 288 KiB

Open AccessArticle

The MTNR1B rs10830963 Variant in Interaction with Pre-Pregnancy BMI is a Pharmacogenetic Marker for the Initiation of Antenatal Insulin Therapy in Gestational Diabetes Mellitus

by Gábor Firneisz, Klara Rosta, Zahra Al-Aissa, Orsolya Hadarits, Jürgen Harreiter, Ákos Nádasdi, Dagmar Bancher-Todesca, László Németh, Péter Igaz, János Rigó, Jr., István Sziller, Alexandra Kautzky-Willer and Anikó Somogyi

Int. J. Mol. Sci. 2018, 19(12), 3734; https://doi.org/10.3390/ijms19123734 - 23 Nov 2018

Cited by 19 | Viewed by 3945

Abstract

The rs10830963 variant of the Melatonin Receptor 1B (MTNR1B) gene is associated with the development of gestational diabetes mellitus (GDM). We hypothesized that carrying the rs10830963/G risk allele had effect on antenatal insulin therapy (AIT) initiation in GDM in a body mass index (BMI)-dependent manner. Design: In this post hoc analysis the MTNR1B rs10830963 genotype and the clinical data of 211 Caucasian GDM patients were assessed. As a first step, a pre-pregnancy BMI threshold was determined where the effect of MTNR1B rs10830963/G allele carrying on AIT initiation was the most significant using logistic regression. Maternal age adjusted real-life odds ratios (OR) values were calculated. The chi-square test was also used to calculate the p value and 10.000 bootstrap simulations were performed in each case to re-assess the statistical power and the OR. Carrying the MTNR1B rs10830963/G allele increased the odds of AIT initiation (OR = 5.2, p = 0.02 [χ² test], statistical power = 0.53) in GDM patients with pre-pregnancy BMI ≥ 29 kg/m². The statistical power reached 0.77, when the pre-pregnancy BMI cutoff of 27 kg/m² was used and the genetic effect on AIT initiation was still significant, but only using the logistic regression model. Carrying the MTNR1B rs10830963/G risk allele—in interaction with pre-pregnancy BMI—is likely be considered as a candidate pharmacogenetic marker of antenatal insulin therapy initiation and should be further assessed in precision medicine trials in GDM. Full article

(This article belongs to the Special Issue Risk Factors and Molecular Mechanisms of Gestational Diabetes)

11 pages, 483 KiB

Open AccessArticle

Most Women with Previous Gestational Diabetes Mellitus Have Impaired Glucose Metabolism after a Decade

by Wahlberg Jeanette, Ekman Bertil and Arnqvist J. Hans

Int. J. Mol. Sci. 2018, 19(12), 3724; https://doi.org/10.3390/ijms19123724 - 23 Nov 2018

Cited by 2 | Viewed by 4739

Abstract

Of 1324 women diagnosed with gestational diabetes mellitus (GDM) in Sweden, 25% reported >10 years after the delivery that they had developed diabetes mellitus. We assessed the long-term risk of all glucose metabolic abnormalities in a subgroup of these women. Women (n = 51) previously diagnosed with GDM by capillary blood glucose ≥9.0 mmol/L (≈plasma glucose ≥10.0 mmol/L) after a 2 h 75 g oral glucose tolerance test (OGTT) were included. All underwent a clinical and biochemical evaluation, including a second 2 h 75 g OGTT. Individuals with known type 1 diabetes were excluded. At the follow-up, 12/51 (24%) reported previously diagnosed type 2 diabetes. Another four cases were diagnosed after the second OGTT, increasing the prevalence to 16/51 cases (31%). Impaired fasting plasma glucose (IFG) was diagnosed in 13/51 women and impaired glucose tolerance (IGT) in 10/51 women, leaving only 12 women (24%) with normal glucose tolerance. In addition, 2/51 women had high levels of glutamic acid decarboxylase (GAD) antibodies; of these, one woman classified as type 2 diabetes was reclassified as type 1 diabetes, and the second GAD-positive woman was diagnosed with IGT. Of the women diagnosed with GDM by a 2 h 75 g OGTT, a large proportion had impaired glucose metabolism a decade later, including type 1 and type 2 diabetes. Full article

(This article belongs to the Special Issue Risk Factors and Molecular Mechanisms of Gestational Diabetes)

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13 pages, 462 KiB

Open AccessArticle

Uric Acid and Xanthine Levels in Pregnancy Complicated by Gestational Diabetes Mellitus—The Effect on Adverse Pregnancy Outcomes

by Anna Pleskacova, Vendula Bartakova, Katarina Chalasova, Lukas Pacal, Katerina Kankova and Josef Tomandl

Int. J. Mol. Sci. 2018, 19(11), 3696; https://doi.org/10.3390/ijms19113696 - 21 Nov 2018

Cited by 16 | Viewed by 4506

Abstract

Uric acid (UA) levels are associated with many diseases including those related to lifestyle. The aim of this study was to evaluate the influence of clinical and anthropometric parameters on UA and xanthine (X) levels during pregnancy and postpartum in women with physiological pregnancy and pregnancy complicated by gestational diabetes mellitus (GDM), and to evaluate their impact on adverse perinatal outcomes. A total of 143 participants were included. Analyte levels were determined by HPLC with ultraviolet detection (HPLC-UV). Several single-nucleotide polymorphisms (SNPs) in UA transporters were genotyped using commercial assays. UA levels were higher within GDM women with pre-gestational obesity, those in high-risk groups, and those who required insulin during pregnancy. X levels were higher in the GDM group during pregnancy and also postpartum. Positive correlations between UA and X levels with body mass index (BMI) and glycemia levels were found. Gestational age at delivery was negatively correlated with UA and X levels postpartum. Postpartum X levels were significantly higher in women who underwent caesarean sections. Our data support a possible link between increased UA levels and a high-risk GDM subtype. UA levels were higher among women whose glucose tolerance was severely disturbed. Mid-gestational UA and X levels were not linked to adverse perinatal outcomes. Full article

(This article belongs to the Special Issue Risk Factors and Molecular Mechanisms of Gestational Diabetes)

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11 pages, 265 KiB

Open AccessArticle

Ghrelin in Serum and Urine of Post-Partum Women with Gestational Diabetes Mellitus

by Żaneta Kimber-Trojnar, Jolanta Patro-Małysza, Katarzyna E. Skórzyńska-Dziduszko, Jan Oleszczuk, Marcin Trojnar, Radzisław Mierzyński and Bożena Leszczyńska-Gorzelak

Int. J. Mol. Sci. 2018, 19(10), 3001; https://doi.org/10.3390/ijms19103001 - 1 Oct 2018

Cited by 13 | Viewed by 6067

Abstract

Women with a previous history of gestational diabetes mellitus (GDM) have a significantly increased risk of developing type 2 diabetes, obesity, and cardiovascular diseases in the future. The aim of the study was to evaluate ghrelin concentrations in serum and urine in the GDM group in the early post-partum period, with reference to laboratory results, body composition, and hydration status. The study subjects were divided into two groups, that is, 28 healthy controls and 26 patients with diagnosed GDM. The maternal body composition and hydration status were evaluated by the bioelectrical impedance analysis (BIA) method. The concentrations of ghrelin in the maternal serum and urine were determined via enzyme-linked immunosorbent assay (ELISA). The laboratory and BIA results of the mothers with GDM were different from those without GDM. Urine ghrelin positively correlated with serum ghrelin and high-density lipoprotein cholesterol (HDL) levels in healthy mothers. There were direct correlations between urine ghrelin and HDL as well as triglycerides levels in the GDM group. Neither the lean tissue index nor body cell mass index were related to the serum ghrelin concentrations in this group. Only the urine ghrelin of healthy mothers correlated with the fat tissue index. Our results draw attention to urine as an easily available and appropriable biological material for further studies. Full article

(This article belongs to the Special Issue Risk Factors and Molecular Mechanisms of Gestational Diabetes)

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17 pages, 865 KiB

Open AccessArticle

Gestational Diabetes Alters the Metabolomic Profile in 2nd Trimester Amniotic Fluid in a Sex-Specific Manner

by Kathleen O’Neill, Jacqueline Alexander, Rikka Azuma, Rui Xiao, Nathaniel W. Snyder, Clementina A. Mesaros, Ian A. Blair and Sara E. Pinney

Int. J. Mol. Sci. 2018, 19(9), 2696; https://doi.org/10.3390/ijms19092696 - 10 Sep 2018

Cited by 39 | Viewed by 6144

Abstract

Maternal diabetes and obesity induce marked abnormalities in glucose homeostasis and insulin secretion in the fetus, and are linked to obesity, diabetes, and metabolic disease in the offspring, with specific metabolic characterization based on offspring sex. Gestational diabetes (GDM) has profound effects on the intrauterine milieu, which may reflect and/or modulate the function of the maternal–fetal unit. In order to characterize metabolic factors that affect offspring development, we profiled the metabolome of second trimester amniotic fluid (AF) from women who were subsequently diagnosed with gestational diabetes (GDM) using a targeted metabolomics approach, profiling 459 known biochemicals through gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) assays. Using a nested case-control study design, we identified 69 total biochemicals altered by GDM exposure, while sex-specific analysis identified 44 and 58 metabolites in male and female offspring, respectively. The most significant changes were in glucose, amino acid, glutathione, fatty acid, sphingolipid, and bile acid metabolism with specific changes identified based on the offspring sex. Targeted isotope dilution LC/MS confirmatory assays measured significant changes in docosahexaenoic acid and arachidonic acid. We conclude that the sex-specific alterations in GDM maternal–fetal metabolism may begin to explain the sex-specific metabolic outcomes seen in offspring exposed to GDM in utero. Full article

(This article belongs to the Special Issue Risk Factors and Molecular Mechanisms of Gestational Diabetes)

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Review

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16 pages, 716 KiB

Open AccessReview

Maternal Cognitive Impairment Associated with Gestational Diabetes Mellitus—A Review of Potential Contributing Mechanisms

by Cini Mathew John, Nur Intan Saidaah Mohamed Yusof, Siti Hajar Abdul Aziz and Fazlin Mohd Fauzi

Int. J. Mol. Sci. 2018, 19(12), 3894; https://doi.org/10.3390/ijms19123894 - 5 Dec 2018

Cited by 28 | Viewed by 5769

Abstract

Gestational diabetes mellitus (GDM) carries many risks, where high blood pressure, preeclampsia and future type II diabetes are widely acknowledged, but less focus has been placed on its effect on cognitive function. Although the multifactorial pathogenesis of maternal cognitive impairment is not completely understood, it shares several features with type 2 diabetes mellitus (T2DM). In this review, we discuss some key pathophysiologies of GDM that may lead to cognitive impairment, specifically hyperglycemia, insulin resistance, oxidative stress, and neuroinflammation. We explain how these incidents: (i) impair the insulin-signaling pathway and/or (ii) lead to cognitive impairment through hyperphosphorylation of τ protein, overexpression of amyloid-β and/or activation of microglia. The aforementioned pathologies impair the insulin-signaling pathway primarily through serine phosphorylation of insulin receptor substances (IRS). This then leads to the inactivation of the phosphatidylinositol 3-kinase/Protein kinase B (PI3K/AKT) signaling cascade, which is responsible for maintaining brain homeostasis and normal cognitive functioning. PI3K/AKT is crucial in maintaining normal cognitive function through the inactivation of glycogen synthase kinase 3β (GSκ3β), which hyperphosphorylates τ protein and releases pro-inflammatory cytokines that are neurotoxic. Several biomarkers were also highlighted as potential biomarkers of GDM-related cognitive impairment such as AGEs, serine-phosphorylated IRS-1 and inflammatory markers such as tumor necrosis factor α (TNF-α), high-sensitivity C-reactive protein (hs-CRP), leptin, interleukin 1β (IL-1β), and IL-6. Although GDM is a transient disease, its complications may be long-term, and hence increased mechanistic knowledge of the molecular changes contributing to cognitive impairment may provide important clues for interventional strategies. Full article

(This article belongs to the Special Issue Risk Factors and Molecular Mechanisms of Gestational Diabetes)

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14 pages, 474 KiB

Open AccessReview

Programming of Vascular Dysfunction in the Intrauterine Milieu of Diabetic Pregnancies

by Nada A. Sallam, Victoria A. C. Palmgren, Radha D. Singh, Cini M. John and Jennifer A. Thompson

Int. J. Mol. Sci. 2018, 19(11), 3665; https://doi.org/10.3390/ijms19113665 - 20 Nov 2018

Cited by 24 | Viewed by 5306

Abstract

With the rising global tide of obesity, gestational diabetes mellitus (GDM) burgeoned into one of the most common antenatal disorders worldwide. Macrosomic babies born to diabetic mothers are more likely to develop risk factors for cardiovascular disease (CVD) before they reach adulthood. Rodent studies in offspring born to hyperglycemic pregnancies show vascular dysfunction characterized by impaired nitric oxide (NO)-mediated vasodilation and increased production of contractile prostanoids by cyclooxygenase 2 (COX-2). Vascular dysfunction is a key pathogenic event in the progression of diabetes-related vascular disease, primarily attributable to glucotoxicity. Therefore, glucose-induced vascular injury may stem directly from the hyperglycemic intrauterine environment of GDM pregnancy, as evinced by studies showing endothelial activation and inflammation at birth or in childhood in offspring born to GDM mothers. This review discusses potential mechanisms by which intrauterine hyperglycemia programs dysfunction in the developing vasculature. Full article

(This article belongs to the Special Issue Risk Factors and Molecular Mechanisms of Gestational Diabetes)

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14 pages, 1443 KiB

Open AccessReview

Maternal β-Cell Adaptations in Pregnancy and Placental Signalling: Implications for Gestational Diabetes

by Brittany L. Moyce and Vernon W. Dolinsky

Int. J. Mol. Sci. 2018, 19(11), 3467; https://doi.org/10.3390/ijms19113467 - 5 Nov 2018

Cited by 81 | Viewed by 9727

Abstract

Rates of gestational diabetes mellitus (GDM) are on the rise worldwide, and the number of pregnancies impacted by GDM and resulting complications are also increasing. Pregnancy is a period of unique metabolic plasticity, during which mild insulin resistance is a physiological adaptation to prioritize fetal growth. To compensate for this, the pancreatic β-cell utilizes a variety of adaptive mechanisms, including increasing mass, number and insulin-secretory capacity to maintain glucose homeostasis. When insufficient insulin production does not overcome insulin resistance, hyperglycemia can occur. Changes in the maternal system that occur in GDM such as lipotoxicity, inflammation and oxidative stress, as well as impairments in adipokine and placental signalling, are associated with impaired β-cell adaptation. Understanding these pathways, as well as mechanisms of β-cell dysfunction in pregnancy, can identify novel therapeutic targets beyond diet and lifestyle interventions, insulin and antihyperglycemic agents currently used for treating GDM. Full article

(This article belongs to the Special Issue Risk Factors and Molecular Mechanisms of Gestational Diabetes)

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21 pages, 1407 KiB

Open AccessReview

The Pathophysiology of Gestational Diabetes Mellitus

by Jasmine F Plows, Joanna L Stanley, Philip N Baker, Clare M Reynolds and Mark H Vickers

Int. J. Mol. Sci. 2018, 19(11), 3342; https://doi.org/10.3390/ijms19113342 - 26 Oct 2018

Cited by 1010 | Viewed by 108871

Abstract

Gestational diabetes mellitus (GDM) is a serious pregnancy complication, in which women without previously diagnosed diabetes develop chronic hyperglycemia during gestation. In most cases, this hyperglycemia is the result of impaired glucose tolerance due to pancreatic β-cell dysfunction on a background of chronic insulin resistance. Risk factors for GDM include overweight and obesity, advanced maternal age, and a family history or any form of diabetes. Consequences of GDM include increased risk of maternal cardiovascular disease and type 2 diabetes and macrosomia and birth complications in the infant. There is also a longer-term risk of obesity, type 2 diabetes, and cardiovascular disease in the child. GDM affects approximately 16.5% of pregnancies worldwide, and this number is set to increase with the escalating obesity epidemic. While several management strategies exist—including insulin and lifestyle interventions—there is not yet a cure or an efficacious prevention strategy. One reason for this is that the molecular mechanisms underlying GDM are poorly defined. This review discusses what is known about the pathophysiology of GDM, and where there are gaps in the literature that warrant further exploration. Full article

(This article belongs to the Special Issue Risk Factors and Molecular Mechanisms of Gestational Diabetes)

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27 pages, 303 KiB

Open AccessReview

Molecular Biomarkers for Gestational Diabetes Mellitus

by Stephanie Dias, Carmen Pheiffer, Yoonus Abrahams, Paul Rheeder and Sumaiya Adam

Int. J. Mol. Sci. 2018, 19(10), 2926; https://doi.org/10.3390/ijms19102926 - 26 Sep 2018

Cited by 76 | Viewed by 8644

Abstract

Gestational diabetes mellitus (GDM) is a growing public health problem worldwide. The condition is associated with perinatal complications and an increased risk for future metabolic disease in both mothers and their offspring. In recent years, molecular biomarkers received considerable interest as screening tools for GDM. The purpose of this review is to provide an overview of the current status of single-nucleotide polymorphisms (SNPs), DNA methylation, and microRNAs as biomarkers for GDM. PubMed, Scopus, and Web of Science were searched for articles published between January 1990 and August 2018. The search terms included “gestational diabetes mellitus”, “blood”, “single-nucleotide polymorphism (SNP)”, “DNA methylation”, and “microRNAs”, including corresponding synonyms and associated terms for each word. This review updates current knowledge of the candidacy of these molecular biomarkers for GDM with recommendations for future research avenues. Full article

(This article belongs to the Special Issue Risk Factors and Molecular Mechanisms of Gestational Diabetes)

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