Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Molecular Biology of Gestational Diabetes: The Culprit of the Diabetes Pandemic

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

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

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 36746

Share This Special Issue

Special Issue Editors

Prof. Dr. Jens Høiriis Nielsen

E-Mail Website
Guest Editor

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Interests: type 1 diabetes; type 2 diabetes; obesity; beta cell biology
Special Issues, Collections and Topics in MDPI journals

Prof. Susan E. Ozanne

E-Mail Website
Guest Editor

University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Box 289, Addenbrookes Treatment Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
Interests: My research interests are focussed on understanding the mechanisms by which in utero exposures, such as suboptimal nutrition, influence risk of type 2 diabetes, cardiovascular disease, obesity and premature death. The long-term goal is to use this mechanistic insight to design rational intervention strategies to improve health of women and their children

Special Issue Information

Dear Colleagues,

The diabetes pandemic continues to increase worldwide. According to IDF, the number of diabetic patients is estimated to increase from 463 million in 2019 to 700 million in 2045. A major contributor is transgenerational transmission by epigenetic changes occurring during pregnancy. According to IDF, 15.8% of live births are affected by gestational diabetes (GDM). GDM is associated with obesity (maternal and paternal) and diabetes (type 1 and 2). The risk for both offspring and mother to develop type 2 diabetes later in life is increased 7–8-fold. The number and function of the pancreatic beta cells during pregnancy play a central role in the development of diabetes in both mother and offspring. Normally, the beta cell number will increase in the pregnant woman due to hormonal and metabolic changes concomitantly with the fetal development of the pancreas. In GDM, hyperglycemia may result in premature maturation of the fetal beta cells and growth of the child. Malnourishment during pregnancy may result in impaired development of the beta cells in the fetus by fetal programming that may be transmitted to the next generation. Recent studies of gene expression and epigenetic changes during embryonic development of the pancreas have identified a number of non-coding RNAs and histone modifications related to GDM.

The purpose of this Special Issue is to gather the current knowledge in this research area in order to depict novel approaches to prevent or treat GDM and hopefully break the diabetes pandemic.

Prof. Dr. Jens Høiriis Nielsen
Prof. Dr. Susan E. Ozanne
Guest Editors

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
Beta cells
Fetal programming
Epigenetics
Diabetes pandemic
Genetics
Autoimmunity
Microbiota

Published Papers (10 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

16 pages, 5012 KiB

Open AccessArticle

Normal Pregnancy-Induced Islet Beta Cell Proliferation in Mouse Models That Are Deficient in Serotonin-Signaling

by Lotte Goyvaerts, Anica Schraenen, Katleen Lemaire, Peter in’t Veld, Ilse Smolders, Luc Maroteaux and Frans Schuit

Int. J. Mol. Sci. 2022, 23(24), 15816; https://doi.org/10.3390/ijms232415816 - 13 Dec 2022

Cited by 6 | Viewed by 1619

Abstract

During mouse pregnancy placental lactogens stimulate prolactin receptors on pancreatic islet beta cells to induce expression of the tryptophan hydroxylase Tph1, resulting in the synthesis and secretion of serotonin. Presently, the functional relevance of this phenomenon is unclear. One hypothesis is that serotonin-induced activation of 5-HT_2B receptors on beta cells stimulates beta cell proliferation during pregnancy. We tested this hypothesis via three different mouse models: (i) total Tph1KO mice, (ii) 129P2/OlaHsd mice, which are incompetent to upregulate islet Tph1 during pregnancy, whereas Tph1 is normally expressed in the intestine, mammary glands, and placenta, and (iii) Htr2b-deficient mice. We observed normal pregnancy-induced levels of beta cell proliferation in total Tph1KO mice, 129P2/OlaHsd mice, and in Htr2b^−/− mice. The three studied mouse models indicate that islet serotonin production and its signaling via 5-HT_2B receptors are not required for the wave of beta cell proliferation that occurs during normal mouse pregnancy. Full article

(This article belongs to the Special Issue Molecular Biology of Gestational Diabetes: The Culprit of the Diabetes Pandemic)

► Show Figures

Figure 1

21 pages, 3182 KiB

Open AccessArticle

Fetal Programming of the Endocrine Pancreas: Impact of a Maternal Low-Protein Diet on Gene Expression in the Perinatal Rat Pancreas

by Louise Winkel, Morten Rasmussen, Louise Larsen, Louise T. Dalgaard and Jens H. Nielsen

Int. J. Mol. Sci. 2022, 23(19), 11057; https://doi.org/10.3390/ijms231911057 - 21 Sep 2022

Viewed by 2148

Abstract

In rats, the time of birth is characterized by a transient rise in beta cell replication, as well as beta cell neogenesis and the functional maturation of the endocrine pancreas. However, the knowledge of the gene expression during this period of beta cell expansion is incomplete. The aim was to characterize the perinatal rat pancreas transcriptome and to identify regulatory pathways differentially regulated at the whole organ level in the offspring of mothers fed a regular control diet (CO) and of mothers fed a low-protein diet (LP). We performed mRNA expression profiling via the microarray analysis of total rat pancreas samples at embryonic day (E) 20 and postnatal days (P) 0 and 2. In the CO group, pancreas metabolic pathways related to sterol and lipid metabolism were highly enriched, whereas the LP diet induced changes in transcripts involved in RNA transcription and gene regulation, as well as cell migration and apoptosis. Moreover, a number of individual transcripts were markedly upregulated at P0 in the CO pancreas: growth arrest specific 6 (Gas6), legumain (Lgmn), Ets variant gene 5 (Etv5), alpha-fetoprotein (Afp), dual-specificity phosphatase 6 (Dusp6), and angiopoietin-like 4 (Angptl4). The LP diet induced the downregulation of a large number of transcripts, including neurogenin 3 (Neurog3), Etv5, Gas6, Dusp6, signaling transducer and activator of transcription 3 (Stat3), growth hormone receptor (Ghr), prolactin receptor (Prlr), and Gas6 receptor (AXL receptor tyrosine kinase; Axl), whereas upregulated transcripts were related to inflammatory responses and cell motility. We identified differentially regulated genes and transcriptional networks in the perinatal pancreas. These data revealed marked adaptations of exocrine and endocrine in the pancreas to the low-protein diet, and the data can contribute to identifying novel regulators of beta cell mass expansion and functional maturation and may provide a valuable tool in the generation of fully functional beta cells from stem cells to be used in replacement therapy. Full article

(This article belongs to the Special Issue Molecular Biology of Gestational Diabetes: The Culprit of the Diabetes Pandemic)

► Show Figures

Figure 1

15 pages, 2982 KiB

Open AccessArticle

Acetone Ingestion Mimics a Fasting State to Improve Glucose Tolerance in a Mouse Model of Gestational Hyperglycemia

by Sandra Szlapinski, Brenda Strutt, Madeline Deane, Edith Arany, Jamie Bennett and David J. Hill

Int. J. Mol. Sci. 2021, 22(23), 12914; https://doi.org/10.3390/ijms222312914 - 29 Nov 2021

Cited by 1 | Viewed by 2103

Abstract

Gestational diabetes mellitus results, in part, from a sub-optimal β-cell mass (BCM) during pregnancy. Artemisinins were reported to increase BCM in models of diabetes by α- to β-cell conversion leading to enhanced glucose tolerance. We used a mouse model of gestational glucose intolerance to compare the effects of an artemisinin (artesunate) on glycemia of pregnant mice with vehicle treatment (acetone) or no treatment. Animals were treated daily from gestational days (GD) 0.5 to 6.5. An intraperitoneal glucose tolerance test was performed prior to euthanasia at GD18.5 or post-partum. Glucose tolerance was significantly improved in both pregnant and non-pregnant mice with both artesunate and vehicle-alone treatment, suggesting the outcome was primarily due to the acetone vehicle. In non-pregnant, acetone-treated animals, improved glucose tolerance was associated with a higher BCM and a significant increase in bihormonal insulin and glucagon-containing pancreatic islet cells, suggesting α- to β-cell conversion. BCM did not differ with treatment during pregnancy or post-partum. However, placental weight was higher in acetone-treated animals and was associated with an upregulation of apelinergic genes. Acetone-treated animals had reduced weight gain during treatment despite comparable food consumption to non-treated mice, suggesting transient effects on nutrient uptake. The mean duodenal and ileum villus height was reduced following exposure to acetone. We conclude that acetone treatment may mimic transient fasting, resulting in a subsequent improvement in glucose tolerance during pregnancy. Full article

(This article belongs to the Special Issue Molecular Biology of Gestational Diabetes: The Culprit of the Diabetes Pandemic)

► Show Figures

Figure 1

14 pages, 1575 KiB

Open AccessArticle

Maternal Metformin Intervention during Obese Glucose-Intolerant Pregnancy Affects Adiposity in Young Adult Mouse Offspring in a Sex-Specific Manner

by Josca M. Schoonejans, Heather L. Blackmore, Thomas J. Ashmore, Catherine E. Aiken, Denise S. Fernandez-Twinn and Susan E. Ozanne

Int. J. Mol. Sci. 2021, 22(15), 8104; https://doi.org/10.3390/ijms22158104 - 28 Jul 2021

Cited by 20 | Viewed by 4180

Abstract

Background: Metformin is commonly used to treat gestational diabetes mellitus. This study investigated the effect of maternal metformin intervention during obese glucose-intolerant pregnancy on the gonadal white adipose tissue (WAT) of 8-week-old male and female mouse offspring. Methods: C57BL/6J female mice were provided with a control (Con) or obesogenic diet (Ob) to induce pre-conception obesity. Half the obese dams were treated orally with 300 mg/kg/d of metformin (Ob-Met) during pregnancy. Gonadal WAT depots from 8-week-old offspring were investigated for adipocyte size, macrophage infiltration and mRNA expression of pro-inflammatory genes using RT-PCR. Results: Gestational metformin attenuated the adiposity in obese dams and increased the gestation length without correcting the offspring in utero growth restriction and catch-up growth caused by maternal obesity. Despite similar body weight, the Ob and Ob-Met offspring of both sexes showed adipocyte hypertrophy in young adulthood. Male Ob-Met offspring had increased WAT depot weight (p < 0.05), exaggerated adipocyte hyperplasia (p < 0.05 vs. Con and Ob offspring), increased macrophage infiltration measured via histology (p < 0.05) and the mRNA expression of F4/80 (p < 0.05). These changes were not observed in female Ob-Met offspring. Conclusions: Maternal metformin intervention during obese pregnancy causes excessive adiposity, adipocyte hyperplasia and WAT inflammation in male offspring, highlighting sex-specific effects of prenatal metformin exposure on offspring WAT. Full article

(This article belongs to the Special Issue Molecular Biology of Gestational Diabetes: The Culprit of the Diabetes Pandemic)

► Show Figures

Figure 1

16 pages, 3113 KiB

Open AccessArticle

Lipid Metabolism Is Dysregulated before, during and after Pregnancy in a Mouse Model of Gestational Diabetes

by Samuel Furse, Denise S. Fernandez-Twinn, Davide Chiarugi, Albert Koulman and Susan E. Ozanne

Int. J. Mol. Sci. 2021, 22(14), 7452; https://doi.org/10.3390/ijms22147452 - 12 Jul 2021

Cited by 17 | Viewed by 4470

Abstract

The aim of the current study was to test the hypothesis that maternal lipid metabolism was modulated during normal pregnancy and that these modulations are altered in gestational diabetes mellitus (GDM). We tested this hypothesis using an established mouse model of diet-induced obesity with pregnancy-associated loss of glucose tolerance and a novel lipid analysis tool, Lipid Traffic Analysis, that uses the temporal distribution of lipids to identify differences in the control of lipid metabolism through a time course. Our results suggest that the start of pregnancy is associated with several changes in lipid metabolism, including fewer variables associated with de novo lipogenesis and fewer PUFA-containing lipids in the circulation. Several of the changes in lipid metabolism in healthy pregnancies were less apparent or occurred later in dams who developed GDM. Some changes in maternal lipid metabolism in the obese-GDM group were so late as to only occur as the control dams’ systems began to switch back towards the non-pregnant state. These results demonstrate that lipid metabolism is modulated in healthy pregnancy and the timing of these changes is altered in GDM pregnancies. These findings raise important questions about how lipid metabolism contributes to changes in metabolism during healthy pregnancies. Furthermore, as alterations in the lipidome are present before the loss of glucose tolerance, they could contribute to the development of GDM mechanistically. Full article

(This article belongs to the Special Issue Molecular Biology of Gestational Diabetes: The Culprit of the Diabetes Pandemic)

► Show Figures

Figure 1

Review

Jump to: Research

21 pages, 3647 KiB

Open AccessReview

Circulating microRNA as Biomarkers for Gestational Diabetes Mellitus—A Systematic Review and Meta-Analysis

by Sofie Dinesen, Alisar El-Faitarouni, Nanna Lond Skov Frisk, Anja Elaine Sørensen and Louise Torp Dalgaard

Int. J. Mol. Sci. 2023, 24(7), 6186; https://doi.org/10.3390/ijms24076186 - 24 Mar 2023

Cited by 6 | Viewed by 2502

Abstract

Gestational diabetes mellitus (GDM) is a severe pregnancy complication for both the woman and the child. Women who suffer from GDM have a greater risk of developing Type 2 diabetes mellitus (T2DM) later in life. Identification of any potential biomarkers for the early prediction of gestational diabetes can help prevent the disease in women with a high risk. Studies show microRNA (miRNA) as a potential biomarker for the early discovery of GDM, but there is a lack of clarity as to which miRNAs are consistently altered in GDM. This study aimed to perform a systematic review and meta-analysis to investigate miRNAs associated with GDM by comparing GDM cases with normoglycemic controls. The systematic review was performed according to PRISMA guidelines with searches in PubMed, Web of Science, and ScienceDirect. The primary search resulted in a total of 849 articles, which were screened according to the prior established inclusion and exclusion criteria. Following the screening of articles, the review was based on the inclusion of 35 full-text articles, which were evaluated for risk of bias and estimates of quality, after which data were extracted and relative values for miRNAs were calculated. A meta-analysis was performed for the miRNA species investigated in three or more studies: MiR-29a, miR-330, miR-134, miR-132, miR-16, miR-223, miR-155, miR-122, miR-17, miR-103, miR-125, miR-210, and miR-222. While some miRNAs showed considerable between-study variability, miR-29a, miR-330, miR-134, miR-16, miR-223, and miR-17 showed significant overall upregulation in GDM, while circulating levels of miR-132 and miR-155 were decreased among GDM patients, suggesting further studies of these as biomarkers for early GDM discovery. Full article

(This article belongs to the Special Issue Molecular Biology of Gestational Diabetes: The Culprit of the Diabetes Pandemic)

► Show Figures

Figure 1

12 pages, 619 KiB

Open AccessReview

Incretins as a Potential Treatment Option for Gestational Diabetes Mellitus

by Aleksandra Pilszyk, Magdalena Niebrzydowska, Zuzanna Pilszyk, Magdalena Wierzchowska-Opoka and Żaneta Kimber-Trojnar

Int. J. Mol. Sci. 2022, 23(17), 10101; https://doi.org/10.3390/ijms231710101 - 3 Sep 2022

Cited by 5 | Viewed by 4476

Abstract

Gestational diabetes mellitus (GDM) is a metabolic disease affecting an increasing number of pregnant women around the world. It is not only associated with numerous perinatal complications but also has long-term consequences impacting maternal health and fetal development. To prevent them, it is important to keep glucose levels under control. As much as 15–30% of GDM patients will require treatment with insulin, metformin, or glyburide. With that in mind, it is crucial to keep searching for novel and improved pharmacotherapies. Nowadays, there are ongoing studies investigating the use of other groups of drugs that have proven successful in the treatment of T2DM. Glucagon-like peptide-1 (GLP-1) receptor agonist and dipeptidyl peptidase-4 (DPP-4) inhibitor are among the drugs targeting the incretin system and are currently receiving significant attention. The aim of our review is to demonstrate the potential of these medications in treating GDM and preventing its later complications. It seems that both groups may be successful in the GDM management used alone or as an addition to better-known drugs, including metformin and glyburide. However, more clinical trials are needed to confirm their importance in GDM treatment and to demonstrate effective therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Biology of Gestational Diabetes: The Culprit of the Diabetes Pandemic)

► Show Figures

Figure 1

20 pages, 715 KiB

Open AccessReview

Novel Biomolecules in the Pathogenesis of Gestational Diabetes Mellitus 2.0

by Monika Ruszała, Aleksandra Pilszyk, Magdalena Niebrzydowska, Żaneta Kimber-Trojnar, Marcin Trojnar and Bożena Leszczyńska-Gorzelak

Int. J. Mol. Sci. 2022, 23(8), 4364; https://doi.org/10.3390/ijms23084364 - 14 Apr 2022

Cited by 16 | Viewed by 4328

Abstract

Gestational diabetes mellitus (GDM) has become a major public health problem and one of the most discussed issues in modern obstetrics. GDM is associated with serious adverse perinatal outcomes and long-term health consequences for both the mother and child. Currently, the importance and purposefulness of finding a biopredictor that will enable the identification of women with an increased risk of developing GDM as early as the beginning of pregnancy are highly emphasized. Both “older” molecules, such as adiponectin and leptin, and “newer” adipokines, including fatty acid-binding protein 4 (FABP4), have proven to be of pathophysiological importance in GDM. Therefore, in our previous review, we presented 13 novel biomolecules, i.e., galectins, growth differentiation factor-15, chemerin, omentin-1, osteocalcin, resistin, visfatin, vaspin, irisin, apelin, FABP4, fibroblast growth factor 21, and lipocalin-2. The purpose of this review is to present the potential and importance of another nine lesser known molecules in the pathogenesis of GDM, i.e., 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), angiopoietin-like protein-8 (ANGPTL-8), nesfatin-1, afamin, adropin, fetuin-A, zonulin, secreted frizzled-related proteins (SFRPs), and amylin. It seems that two of them, fetuin-A and zonulin in high serum levels, may be applied as biopredictors of GDM. Full article

(This article belongs to the Special Issue Molecular Biology of Gestational Diabetes: The Culprit of the Diabetes Pandemic)

► Show Figures

Graphical abstract

27 pages, 4316 KiB

Open AccessReview

Genomics and Epigenomics of Gestational Diabetes Mellitus: Understanding the Molecular Pathways of the Disease Pathogenesis

by Nadia Abu Samra, Herbert F. Jelinek, Habiba Alsafar, Farah Asghar, Muhieddine Seoud, Shahad M. Hussein, Hisham M. Mubarak, Siddiq Anwar, Mashal Memon, Nariman Afify, Ridda Manzoor, Zahrah Al-Homedi and Wael Osman

Int. J. Mol. Sci. 2022, 23(7), 3514; https://doi.org/10.3390/ijms23073514 - 23 Mar 2022

Cited by 9 | Viewed by 5879

Abstract

One of the most common complications during pregnancy is gestational diabetes mellitus (GDM), hyperglycemia that occurs for the first time during pregnancy. The condition is multifactorial, caused by an interaction between genetic, epigenetic, and environmental factors. However, the underlying mechanisms responsible for its pathogenesis remain elusive. Moreover, in contrast to several common metabolic disorders, molecular research in GDM is lagging. It is important to recognize that GDM is still commonly diagnosed during the second trimester of pregnancy using the oral glucose tolerance test (OGGT), at a time when both a fetal and maternal pathophysiology is already present, demonstrating the increased blood glucose levels associated with exacerbated insulin resistance. Therefore, early detection of metabolic changes and associated epigenetic and genetic factors that can lead to an improved prediction of adverse pregnancy outcomes and future cardio-metabolic pathologies in GDM women and their children is imperative. Several genomic and epigenetic approaches have been used to identify the genes, genetic variants, metabolic pathways, and epigenetic modifications involved in GDM to determine its etiology. In this article, we explore these factors as well as how their functional effects may contribute to immediate and future pathologies in women with GDM and their offspring from birth to adulthood. We also discuss how these approaches contribute to the changes in different molecular pathways that contribute to the GDM pathogenesis, with a special focus on the development of insulin resistance. Full article

(This article belongs to the Special Issue Molecular Biology of Gestational Diabetes: The Culprit of the Diabetes Pandemic)

► Show Figures

Figure 1

18 pages, 870 KiB

Open AccessReview

A Glimpse at the Size of the Fetal Liver—Is It Connected with the Evolution of Gestational Diabetes?

by Matei-Alexandru Cozma, Mihnea-Alexandru Găman, Elena-Codruța Dobrică, Steluța Constanța Boroghină, Mihaela Adela Iancu, Sanda Maria Crețoiu and Anca Angela Simionescu

Int. J. Mol. Sci. 2021, 22(15), 7866; https://doi.org/10.3390/ijms22157866 - 23 Jul 2021

Cited by 8 | Viewed by 3533

Abstract

Gestational diabetes mellitus (GDM) is defined as an impairment of glucose tolerance, manifested by hyperglycemia, which occurs at any stage of pregnancy. GDM is more common in the third trimester of pregnancy and usually disappears after birth. It was hypothesized that the glycemic status of the mother can modulate liver development and growth early during the pregnancy. The simplest modality to monitor the evolution of GDM employs noninvasive techniques. In this category, routinely obstetrical ultrasound (OUS) examinations (simple or 2D/3D) can be employed for specific fetal measurements, such as fetal liver length (FLL) or volume (FLV). FLL and FLV may emerge as possible predictors of GDM as they positively relate to the maternal glycated hemoglobin (HbA1c) levels and to the results of the oral glucose tolerance test. The aim of this review is to offer insight into the relationship between GDM and fetal nutritional status. Risk factors for GDM and the short- and long-term outcomes of GDM pregnancies are also discussed, as well as the significance of different dietary patterns. Moreover, the review aims to fill one gap in the literature, investigating whether fetal liver growth can be used as a predictor of GDM evolution. To conclude, although studies pointed out a connection between fetal indices and GDM as useful tools in the early detection of GDM (before 23 weeks of gestation), additional research is needed to properly manage GDM and offspring health. Full article

(This article belongs to the Special Issue Molecular Biology of Gestational Diabetes: The Culprit of the Diabetes Pandemic)

► Show Figures

Journal Menu

Journal Browser

Molecular Biology of Gestational Diabetes: The Culprit of the Diabetes Pandemic

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (10 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI