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Molecular Advances in Gestational Diabetes Mellitus

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 July 2025 | Viewed by 10834

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Special Issue Editor

Dr. Natasha Singh

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Guest Editor

Department of Metabolism, Digestion and Reproduction, Imperial College London, Chelsea and Westminster Hospital, London SW10 9NH, UK
Interests: diabetes in pregnancy; gestational diabetes; preterm birth

Special Issue Information

Dear Colleagues,

Gestational diabetes mellitus (GDM) is increasing in prevalence globally, and it is substantially related to an increased risk of type 2 diabetes (T2DM) after pregnancy in both pregnant women and their offspring. Little is known about how modifiable risk factors act on a mechanistic level to lower the longer-term risk of T2DM in women and their offspring.

In this Special Issue, entitled “Molecular Advances in Gestational Diabetes Mellitus”, we aim to present papers which deal with the newest research in the field of the molecular mechanisms that underpin the transgenerational impact of GDM. We welcome reviews and original research papers from fundamental and clinical research addressing how the maternal metabolome, placental signaling pathways, umbilical cord DNA methylation, and stem cell differentiation in GDM pregnancies compare to non-GDM pregnancies, as well as the impact of lifestyle, metformin, and insulin on treatment pathways.

Dr. Natasha Singh
Guest Editor

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Keywords

metabolome
placental insulin signaling
DNA methylation
mitochondrial oxidation
MTOR
amino acids lipidomics
proteomics
gluconeogenesis
GDM

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Published Papers (6 papers)

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Research

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14 pages, 1161 KiB

Open AccessArticle

Effects of Endocrine Disrupting Chemicals on Fetal Weight: Exposure Monitoring Among Mothers with Gestational Diabetes Mellitus and Their Fetuses

by Subeen Hong, Sae Kyung Choi, Jeong Ha Wie, Jae Eun Shin, Yun Sung Jo, Yeon Hee Kim, Byung Soo Kang, Oyoung Kim, Sangeun Won, Hee Ju Yoon, Hyeon Soo Kim, In Yang Park, Mihi Yang and Hyun Sun Ko

Int. J. Mol. Sci. 2025, 26(9), 4226; https://doi.org/10.3390/ijms26094226 - 29 Apr 2025

Abstract

Gestational diabetes mellitus (GDM) requires lifestyle changes that may alter exposure to endocrine-disrupting chemicals (EDCs). This study aimed to assess maternal and fetal exposure to EDCs—including bisphenol-A (BPA), monoethyl phthalate (MEP), and perfluorooctanoic acid (PFOA)—during the COVID-19 pandemic and to evaluate their association with fetal birthweight. Maternal urine (second and third trimester) and paired cord blood samples were analyzed from 58 GDM and 118 non-GDM pregnancies using UPLC-MS/MS. Significant correlations were found between maternal urine and cord blood levels of BPA and MEP. Cord blood BPA levels were significantly lower in GDM mothers (0.35 vs. 0.72 μg/L, p < 0.05), suggesting reduced exposure due to dietary interventions. However, maternal urinary BPA levels in GDM pregnancies were positively associated with fetal birthweight (β = 2.69, p < 0.05), indicating increased susceptibility to obesogenic effects. PFOA was present in all cord blood but only 41% of maternal urine samples. These findings underscore the dual impact of GDM-related lifestyle changes: reduced EDC transfer to the fetus, yet persistent metabolic vulnerability. Full article

(This article belongs to the Special Issue Molecular Advances in Gestational Diabetes Mellitus)

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19 pages, 8150 KiB

Open AccessArticle

Early Prediction of Fetal Macrosomia Through Maternal Lipid Profiles

by Vitaliy Chagovets, Natalia Frankevich, Natalia Starodubtseva, Alisa Tokareva, Elena Derbentseva, Sergey Yuryev, Anastasia Kutzenko, Gennady Sukhikh and Vladimir Frankevich

Int. J. Mol. Sci. 2025, 26(3), 1149; https://doi.org/10.3390/ijms26031149 - 28 Jan 2025

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Abstract

The prevalence of fetal macrosomia is steadily increasing worldwide, reaching up to 20%. Fetal macrosomia complicates pregnancy and delivery. Current prediction strategies are inaccurate, and most patients with fetal macrosomia go into labor with an “unknown status”. The aim of this study was to develop a system for predicting fetal macrosomia based on the lipid profiles of pregnant women’s blood serum. In total, 110 patients were included in this study: 30 patients had gestational diabetes mellitus (GDM) and 80 did not. During the observation, blood samples were collected at three time points: in the first trimester (11–13 weeks of pregnancy), in the second trimester (24–26 weeks), and in the third trimester (30–32 weeks). Lipids were detected by flow injection analysis with mass spectrometry. Lipid profiles of pregnant women were discriminated by orthogonal projection on latent structure discriminant analysis (OPLS-DA) in all three trimesters. The developed OPLS-DA models allowed for the prediction of the occurrence of fetal macrosomia during pregnancy. Three sets of models were developed: models independent of GDM status with a sensitivity of 0.85 and specificity of 0.91, models for patients with positive GDM status with a sensitivity of 0.91 and specificity of 0.96, and models for patients with negative GDM status with a sensitivity of 0.93 and specificity of 0.92. Phosphatidylcholines and sphingomyelins were the most important discriminative features. These lipid groups probably play an important role in the pathogenesis of fetal macrosomia and may serve as laboratory markers of this pregnancy complication. Full article

(This article belongs to the Special Issue Molecular Advances in Gestational Diabetes Mellitus)

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26 pages, 1014 KiB

Open AccessArticle

Evaluation of Selected Pro- and Anti-Inflammatory Adipokines in Colostrum from Mothers with Gestational Diabetes Mellitus

by Jolanta Lis-Kuberka, Marta Berghausen-Mazur and Magdalena Orczyk-Pawiłowicz

Int. J. Mol. Sci. 2025, 26(1), 40; https://doi.org/10.3390/ijms26010040 - 24 Dec 2024

Viewed by 1003

Abstract

Adipokines related to gestational diabetes mellitus (GDM) are an emerging area of interest. The aim of this study was to evaluate the associations between GDM and adipokine levels in human milk. This was an observational cohort study targeting mothers with gestational diabetes, which evaluated the association of maternal hyperglycemia severity, classified as GDM-G1 (diet treatment) and GDM-G2 (insulin treatment), with colostral adipokines involved in pro- and anti-inflammatory processes. Colostrum was collected from hyperglycemic (N = 34) and normoglycemic (N = 26) mothers, and adipokine levels were determined by immunoenzymatic assay. Among anti-inflammatory adipokines, only for irisin and vaspin, but not for obestatin and adropin, were significantly different levels noted between the GDM-G1, GDM-G2 and non-GDM cohorts. Colostrum of the GDM-G2 subgroup contained more vaspin (4.77 ng/mL) than that of normoglycemic mothers (3.12 ng/mL) and more irisin (26.95 μg/mL) than in the GDM-G1 subgroup (17.59 μg/mL). The levels of pro-inflammatory adipokines, namely, dermcidin, chemerin and visfatin, were at similar levels irrespective of maternal glycemia. Moreover, irisin showed a negative correlation with dermcidin in GDM-G2 and non-GDM cohorts. Associations were observed between colostral irisin and maternal preconception BMI, dermcidin and gestational age, and vaspin and maternal age. This study provides evidence that the way of restoring glucose homeostasis in pregnant women has an impact on the anti-inflammatory adipokines irisin and vaspin, but not on obestatin and adropin. GDM, regardless of severity, did not influence the colostral pro-inflammatory adipokines visfatin, chemerin and dermcidin. Full article

(This article belongs to the Special Issue Molecular Advances in Gestational Diabetes Mellitus)

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14 pages, 1942 KiB

Open AccessArticle

Association Between Zinc Status and Insulin Resistance/Sensitivity Check Indexes in Gestational Diabetes Mellitus

by Mariana P. Genova, Irena Ivanova, Emilia Naseva and Bisera Atanasova

Int. J. Mol. Sci. 2024, 25(22), 12193; https://doi.org/10.3390/ijms252212193 - 13 Nov 2024

Viewed by 1116

Abstract

Gestational diabetes mellitus (GDM) is considered the most common metabolic disorder of the pregnancy period. It is characterized by pancreatic beta-cell dysfunction in the setting of chronic insulin resistance. Zinc is a nutrient involved in numerous metabolic processes and shows a relationship with glycometabolic disorders and GDM. The latest data have demonstrated the association of zinc with insulin sensitivity and resistance. The exact role of zinc in the connection with indexes of insulin resistance and insulin sensitivity is still not fully clarified. The aim of the study is to analyze the newly calculated indexes Glu/Zn, Ins/Zn, and HOMA-IR/Zn as surrogate markers to explore the correlation between serum zinc status and some indexes of insulin sensitivity and insulin resistance. The possible role of these indexes as markers of insulin resistance in pregnant women was analyzed too. An ROC analysis demonstrated that HOMA-IR/Zn with AUC 0.989, p < 0.001 (95% CI 0.967–1.000) and Ins/Zn with AUC 0.947, p < 0.001 (95% CI 0.889–1.000) in the GDM group, and only HOMA-IR/Zn index with AUC 0.953, p < 0.001 (95% CI 0.877–1.000) in healthy pregnant women, have good power as markers of insulin resistance in both groups. We speculate that these new ratios could be suitable for the assessment of pregnant women at high risk of insulin resistance development and, probably, for the evaluation of the specific pathophysiologic characteristics of women with GDM. Full article

(This article belongs to the Special Issue Molecular Advances in Gestational Diabetes Mellitus)

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13 pages, 861 KiB

Open AccessArticle

Dietary Regulation of Lipid Metabolism in Gestational Diabetes Mellitus: Implications for Fetal Macrosomia

by Natalia Frankevich, Vitaliy Chagovets, Alisa Tokareva, Natalia Starodubtseva, Elizaveta Limonova, Gennady Sukhikh and Vladimir Frankevich

Int. J. Mol. Sci. 2024, 25(20), 11248; https://doi.org/10.3390/ijms252011248 - 19 Oct 2024

Cited by 1 | Viewed by 1264

Abstract

The primary therapeutic approach for managing hyperglycemia today is diet therapy. Lipids are not only a source of nutrients but also play a role in initiating adipocyte differentiation in the fetus, which may explain the development of fetal macrosomia and future metabolic disorders in children born to mothers with gestational diabetes mellitus (GDM). Alterations in the maternal blood lipid profile, influenced by adherence to a healthy diet in mothers with GDM and the occurrence of fetal macrosomia, represent a complex and not fully understood process. The aim of this study was to examine the characteristics of the blood plasma lipid profile in pregnant women with GDM across all trimesters based on adherence to diet therapy. The clinical part of the study followed a case-control design, including 110 women: 80 in the control group, 20 in a GDM group adhering to the diet, and 10 in a GDM group not adhering to the diet. The laboratory part was conducted as a longitudinal dynamic study, with venous blood samples collected at three time points: 11–13, 24–26, and 30–32 weeks of pregnancy. A significant impact of diet therapy on the composition of blood lipids throughout pregnancy was demonstrated, starting as early as the first trimester. ROC analysis indicated high effectiveness of the models developed, with an AUC of 0.98 for the 30- to 32-week model and sensitivity and specificity values of 1 and 0.9, respectively. An association was found between dietary habits, maternal blood lipid composition at 32 weeks, and newborn weight. The changes in lipid profiles during macrosomia development and under diet therapy were found to be diametrically opposed, confirming at the molecular level that diet therapy can normalize not only carbohydrate metabolism but also lipid metabolism in both the mother and fetus. Based on the data obtained, it is suggested that after further validation, the developed models could be used to improve the prognosis of macrosomia by analyzing blood plasma lipid profiles at various stages of pregnancy. Full article

(This article belongs to the Special Issue Molecular Advances in Gestational Diabetes Mellitus)

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Review

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25 pages, 4545 KiB

Open AccessReview

Cellular and Molecular Pathophysiology of Gestational Diabetes

by Johnatan Torres-Torres, Irma Eloisa Monroy-Muñoz, Javier Perez-Duran, Juan Mario Solis-Paredes, Zaira Alexi Camacho-Martinez, Deyanira Baca, Salvador Espino-y-Sosa, Raigam Martinez-Portilla, Lourdes Rojas-Zepeda, Hector Borboa-Olivares and Enrique Reyes-Muñoz

Int. J. Mol. Sci. 2024, 25(21), 11641; https://doi.org/10.3390/ijms252111641 - 30 Oct 2024

Cited by 5 | Viewed by 6106

Abstract

Gestational diabetes (GD) is a metabolic disorder characterized by glucose intolerance during pregnancy, significantly impacting maternal and fetal health. Its global prevalence is approximately 14%, with risk factors including obesity, family history of diabetes, advanced maternal age, and ethnicity, which are linked to cellular and molecular disruptions in glucose regulation and insulin resistance. GD is associated with short- and long-term complications for both the mother and the newborn. For mothers, GD increases the risk of developing type 2 diabetes, cardiovascular diseases, and metabolic syndrome. In the offspring, exposure to GD in utero predisposes them to obesity, glucose intolerance, and metabolic disorders later in life. This review aims to elucidate the complex cellular and molecular mechanisms underlying GD to inform the development of effective therapeutic strategies. A systematic review was conducted using medical subject headings (MeSH) terms related to GD’s cellular and molecular pathophysiology. Inclusion criteria encompassed original studies, systematic reviews, and meta-analyses focusing on GD’s impact on maternal and fetal health, adhering to PRISMA guidelines. Data extraction captured study characteristics, maternal and fetal outcomes, key findings, and conclusions. GD disrupts insulin signaling pathways, leading to impaired glucose uptake and insulin resistance. Mitochondrial dysfunction reduces ATP production and increases reactive oxygen species, exacerbating oxidative stress. Hormonal influences, chronic inflammation, and dysregulation of the mammalian target of rapamycin (mTOR) pathway further impair insulin signaling. Gut microbiota alterations, gene expression, and epigenetic modifications play significant roles in GD. Ferroptosis and placental dysfunction primarily contribute to intrauterine growth restriction. Conversely, fetal macrosomia arises from maternal hyperglycemia and subsequent fetal hyperinsulinemia, resulting in excessive fetal growth. The chronic inflammatory state and oxidative stress associated with GD exacerbate these complications, creating a hostile intrauterine environment. GD’s complex pathophysiology involves multiple disruptions in insulin signaling, mitochondrial function, inflammation, and oxidative stress. Effective management requires early detection, preventive strategies, and international collaboration to standardize care and improve outcomes for mothers and babies. Full article

(This article belongs to the Special Issue Molecular Advances in Gestational Diabetes Mellitus)

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