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Risk Factors and Molecular Mechanisms of Gestational Diabetes III

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

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 16334

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Special Issue Editor

Dr. Vernon W. Dolinsky

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Guest Editor

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 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 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.

Dr. Vernon W. Dolinsky
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Gestational diabetes
Maternal obesity
Insulin resistance
Metabolism
Epigenetics
Lifestyle
interventions and therapeutics
Placenta
Newborn complications
Fetal programming

Published Papers (5 papers)

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Research

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17 pages, 1593 KiB

Open AccessArticle

Estradiol (E2) Improves Glucose-Stimulated Insulin Secretion and Stabilizes GDM Progression in a Prediabetic Mouse Model

by Moritz Liebmann, Melissa Asuaje Pfeifer, Katharina Grupe and Stephan Scherneck

Int. J. Mol. Sci. 2022, 23(12), 6693; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126693 - 15 Jun 2022

Cited by 7 | Viewed by 2308

Abstract

Female New Zealand obese (NZO) mice are an established model of preconceptional (pc.) prediabetes that progresses as gestational diabetes mellitus (GDM) during gestation. It is known that NZO mice show improvement in insulin sensitivity and glucose-stimulated insulin secretion (GSIS) during gestation in vivo. The latter is no longer detectable in ex vivo perifusion experiments in isolated islets of Langerhans, suggesting a modulation by extrapancreatic factors. Here, we demonstrated that plasma 17β-estradiol (E2) levels increased markedly in NZO mice during gestation. The aim of this work was to determine whether these increased E2 levels are responsible for the improvement in metabolism during gestation. To achieve this goal, we examined its effects in isolated islets and primary hepatocytes of both NZO and metabolically healthy NMRI mice. E2 increased GSIS in the islets of both strains significantly. Hepatic glucose production (HGP) failed to be decreased by insulin in NZO hepatocytes but was reduced by E2 in both strains. Hepatocytes of pregnant NZO mice showed significantly lower glucose uptake (HGU) compared with NMRI controls, whereby E2 stimulation diminished this difference. Hepatocytes of pregnant NZO showed reduced glycogen content, increased cyclic adenosine monophosphate (cAMP) levels, and reduced AKT activation. These differences were abolished after E2 stimulation. In conclusion, our data indicate that E2 stabilizes and prevents deterioration of the metabolic state of the prediabetic NZO mice. E2 particularly increases GSIS and improves hepatic glucose utilization to a lower extent. Full article

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

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22 pages, 3115 KiB

Open AccessArticle

Role of Serotonin (5-HT) in GDM Prediction Considering Islet and Liver Interplay in Prediabetic Mice during Gestation

by Melissa Asuaje Pfeifer, Moritz Liebmann, Till Beuerle, Katharina Grupe and Stephan Scherneck

Int. J. Mol. Sci. 2022, 23(12), 6434; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126434 - 09 Jun 2022

Cited by 6 | Viewed by 2389

Abstract

Gestational diabetes (GDM) is characterized by a glucose tolerance disorder. This may first appear during pregnancy or pre-exist before conception as a form of prediabetes, but there are few data on the pathogenesis of the latter subtype. Female New Zealand obese (NZO) mice serve as a model for this subpopulation of GDM. It was recently shown that GDM is associated with elevated urinary serotonin (5-hydroxytryptamine, 5-HT) levels, but the role of the biogenic amine in subpopulations with prediabetes remains unclear. 5-HT is synthesized in different tissues, including the islets of Langerhans during pregnancy. Furthermore, 5-HT receptors (HTRs) are expressed in tissues important for the regulation of glucose homeostasis, such as liver and pancreas. Interestingly, NZO mice showed elevated plasma and islet 5-HT concentrations as well as impaired glucose-stimulated 5-HT secretion. Incubation of isolated primary NZO islets with 5-HT revealed an inhibitory effect on insulin and glucagon secretion. In primary NZO hepatocytes, 5-HT aggravated hepatic glucose production (HGP), decreased glucose uptake (HGU), glycogen content, and modulated AKT activation as well as cyclic adenosine monophosphate (cAMP) increase, indicating 5-HT downstream modulation. Treatment with an HTR2B antagonist reduced this 5-HT-mediated deterioration of the metabolic state. With its strong effect on glucose metabolism, these data indicate that 5-HT is already a potential indicator of GDM before conception in mice. Full article

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

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15 pages, 2232 KiB

Open AccessArticle

Extracellular Vesicles as an Index for Endothelial Injury and Cardiac Dysfunction in a Rodent Model of GDM

by Stephanie M. Kereliuk, Fengxia Xiao, Dylan Burger and Vernon W. Dolinsky

Int. J. Mol. Sci. 2022, 23(9), 4970; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094970 - 29 Apr 2022

Cited by 3 | Viewed by 2059

Abstract

Gestational diabetes mellitus (GDM) increases risk of adverse pregnancy outcomes and maternal cardiovascular complications. It is widely believed that maternal endothelial dysfunction is a critical determinant of these risks, however, connections to maternal cardiac dysfunction and mechanisms of pathogenesis are unclear. Circulating extracellular vesicles (EVs) are emerging biomarkers that may provide insights into the pathogenesis of GDM. We examined the impact of GDM on maternal cardiac and vascular health in a rat model of diet-induced obesity-associated GDM. We observed a >3-fold increase in circulating levels of endothelial EVs (p < 0.01) and von Willebrand factor (p < 0.001) in GDM rats. A significant increase in mitochondrial DNA (mtDNA) within circulating extracellular vesicles was also observed suggesting possible mitochondrial dysfunction in the vasculature. This was supported by nicotinamide adenine dinucleotide deficiency in aortas of GDM mice. GDM was also associated with cardiac remodeling (increased LV mass) and a marked impairment in maternal diastolic function (increased isovolumetric relaxation time [IVRT], p < 0.01). Finally, we observed a strong positive correlation between endothelial EV levels and IVRT (r = 0.57, p < 0.05). In summary, we observed maternal vascular and cardiac dysfunction in rodent GDM accompanied by increased circulating endothelial EVs and EV-associated mitochondrial DNA. Our study highlights a novel method for assessment of vascular injury in GDM and highlights vascular mitochondrial injury as a possible therapeutic target. Full article

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

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Review

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23 pages, 1809 KiB

Open AccessReview

New Insights into Adipokines in Gestational Diabetes Mellitus

by Jorge Valencia-Ortega, Rebeca González-Reynoso, Edgar G. Ramos-Martínez, Aldo Ferreira-Hermosillo, María I. Peña-Cano, Enrique Morales-Ávila and Renata Saucedo

Int. J. Mol. Sci. 2022, 23(11), 6279; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23116279 - 03 Jun 2022

Cited by 15 | Viewed by 2403

Abstract

Gestational diabetes mellitus (GDM) is the most common metabolic disorder of pregnancy and has considerable short- and long-term consequences for the health of both the mother and the newborn. Within its pathophysiology, genetic, nutritional, epigenetic, immunological, and hormonal components have been described. Within the last two items, it is known that different hormones and cytokines secreted by adipose tissue, known collectively as adipokines, are involved in the metabolic alterations underlying GDM. Although the maternal circulating profile of adipokines in GDM has been extensively studied, and there are excellent reviews on the subject, it is in recent years that more progress has been made in the study of their expression in visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), placenta, and their concentrations in the umbilical circulation. Thus, this review compiles and organizes the most recent findings on the maternal and umbilical circulating profile and the levels of expression of adipokines in VAT, SAT, and placenta in GDM. Full article

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

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17 pages, 793 KiB

Open AccessReview

Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease

by Stephanie M. Kereliuk and Vernon W. Dolinsky

Int. J. Mol. Sci. 2022, 23(8), 4467; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084467 - 18 Apr 2022

Cited by 16 | Viewed by 6366

Abstract

Globally, cardiovascular disease remains the leading cause of death. Most concerning is the rise in cardiovascular risk factors including obesity, diabetes and hypertension among youth, which increases the likelihood of the development of earlier and more severe cardiovascular disease. While lifestyle factors are involved in these trends, an increasing body of evidence implicates environmental exposures in early life on health outcomes in adulthood. Maternal obesity and diabetes during pregnancy, which have increased dramatically in recent years, also have profound effects on fetal growth and development. Mounting evidence is emerging that maternal obesity and diabetes during pregnancy have lifelong effects on cardiovascular risk factors and heart disease development. However, the mechanisms responsible for these observations are unknown. In this review, we summarize the findings of recent experimental studies, showing that maternal obesity and diabetes during pregnancy affect energy metabolism and heart disease development in the offspring, with a focus on the mechanisms involved. We also evaluate early proof-of-concept studies for interventions that could mitigate maternal obesity and gestational diabetes-induced cardiovascular disease risk in the offspring. Full article

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

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