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Aims: Gestational diabetes mellitus (GDM) provides offspring with a hyper-metabolic intrauterine microenvironment. In this study, we aimed to identify key differential microRNAs in GDM-derived exosomes and explore the potential mechanisms of abnormal embryonic development of islets in offspring., Main Methods: Exosomes were extracted from umbilical vein blood of GDM and non-GDM (NGDM) parturients for microRNA sequencing. Offspring islets were collected on E18.5 and P0 to detect the expression and location of key proteins by immunofluorescence. Target binding of miR-7-19488 and PIK3R2 mRNA was verified using a dual-luciferase reporter assay. The miR-7-19488-mimic, PI3K/mTOR inhibitors were used to treat primarily islet cells to explore the relationship among miR-7-19488, PI3K, and Akt-FoxO1/mTORC1 signaling. The miR-7-19488 agomir was synthesized for further in vivo validation., Key Findings: GDM-derived exosomes caused the overdevelopment of offspring-islets at E18.5 with an increased production of insulin and glucagon co-staining cells, increased number of α cells synthesizing GLP-1, and stimulation of mTORC1 singling, which were more serious at birth. The up-regulated miR-7-19488 in GDM-exosomes targeted PIK3R2 mRNA, leading to translation stagnation of p85β and activation of PI3K-Akt singling in fetal islets. Importantly, the activated PI3K-Akt-FoxO1 singling promoted development and differentiation of α and β cells and enhanced the GLP-1/GLP-1R axis, which cooperates with miR-7-19488 to activate PI3K-Akt-FoxO1/mTORC1 signaling, leading to the early initiation of the functional maturation of overdeveloped β cells., Significance: miR-7-19488 loaded in GDM-derived exosomes induce the abnormal overdevelopment and functional maturation of fetal islets, which is one of the contributors of high incidence of diabetes in adulthood., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2025. Published by Elsevier Inc.)

Background: Gestational diabetes mellitus (GDM) is diabetes with reduced glucose tolerance that is found or diagnosed during pregnancy, which seriously affects the health of mothers and infants, and its incidence is increasing year by year. The necroptotic apoptosis regulator RIP3 has been proposed to be active in managing pancreatic islet cell survival and inflammatory response. Still, its role and mechanism in GDM have not yet been clarified., Method: The effect of high glucose induction and RIP3 on the viability of Pancreatic β-cells and insulin secretion was observed in vitro experiments. C57BL/6J mice were used to establish the GDM model. Weight, serum glucose levels, and insulin levels were measured to evaluate the improvement of diabetes symptoms in GDM mice by sh-RIP3. The levels of IL-1β, IL-6, and TNF-α were determined by ELISA and qRT-PCR assays. Hematoxylin and Eosin (HE) staining assay was applied to detect islet cell morphology and inflammatory damage in pancreatic tissue. Progeny weight and litter size were also recorded to evaluate reproductive function in GDM mice. Western blot was performed to express TLR4/MyD88/NF-κB signal-related proteins., Results: Knockdown of RIP3 ameliorated GDM symptoms, improved glucose tolerance and insulin sensitivity, suppressed inflammation, and enhanced fetal outcomes, possibly by TLR4/MyD88/NF-κB signaling pathway activation in GDM mice., Conclusion: The present study provided evidence that the downregulation of RIP3 alleviates insulin resistance and inflammation in GDM mice by mediating the TLR4/MyD88/NF-κB signaling pathway, which made RIP3 a new potential therapeutic target for GDM treatment in the future., Competing Interests: Declarations. Ethics approval and consent to participate: Ethical approval was obtained from the Ethics Committee of The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital and the study is reported following ARRIVE guidelines. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Many physiological changes accompany pregnancy, most of them involving metabolic perturbations. Alterations in microbiota composition occur both before and during pregnancy and have recently been correlated with an important role in the development of metabolic complications, such as insulin resistance and gestational diabetes mellitus (GDM). These changes may be influenced by physiological adaptations to pregnancy itself, as well as by dietary modifications during gestation. Medical nutritional therapy (MNT) applied to pregnant women at risk stands out as one of the most important factors in increasing the microbiota's diversity at both the species and genus levels. In this review, we discuss the physiological changes during pregnancy and their impact on the composition of the intestinal microbiota, which may contribute to GDM. We also discuss findings from previous studies regarding the effectiveness of MNT in reducing insulin resistance. In the future, additional studies should aim to identify specific gut microbial profiles that serve as early indicators of insulin resistance during gestation. Early diagnosis, achievable through stool analysis or metabolite profiling, may facilitate the timely implementation of dietary or pharmaceutical modifications, thereby mitigating the development of insulin resistance and its associated sequelae.

Gestational Diabetes Mellitus (GDM) is an emerging maternal health problem with increasing incidences. The lack of complete understanding of its pathophysiological mechanisms and novel regulatory biomarkers makes early diagnosis difficult. High-throughput RNA sequencing and computational bioinformatics analyses were conducted to identify novel hub genes, and their regulatory mechanisms were validated through qRT-PCR, western blot, and siRNA-mediated knockdown studies. Intermediate metabolites and circulatory levels of amino acids in the serum of GDM patients and healthy controls were measured. Transcriptomic studies identified SNW1 as the most sensitive and specific biomarker, significantly up-regulated in GDM (fold change = 1.09; p < 0.001). Metabolomic studies indicated significantly elevated gluconeogenesis in GDM, evidenced by decreased levels of alanine and increased levels of pyruvate and glucose compared to controls. siRNA-mediated knockdown of SNW1 in PANC1 cells resulted in significant down-regulation of alanine aminotransferase (ALT/GPT) and insulin receptor substrate (IRS1), while glucose transporters (GLUT2/GLUT4) and insulin (INS) were significantly up-regulated at both mRNA and protein levels. This study identified SNW1 as a novel insulin-resistant gene that induces hyperglycemia by elevating gluconeogenesis and decreasing glucose uptake. SNW1 may be considered a potential therapeutic target with clinical utility for the management of GDM., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics statement consent to participate: This study was carried out following the required local ethical recommendations (Banaras Hindu University). All procedures followed were following the ethical standards of the responsible committee on human experimentation. Informed consent was obtained from all patients for being included in the study., (© 2025. The Author(s).)

Objective: We here investigated whether lactation during puerperium could help to reverse the diabetogenic effect of gestation and further explored the lipid profiling changes upon breastfeeding., Methods: Thirty-five women diagnosed with GDM were recruited, and fasting plasma samples were collected at ~6 weeks postpartum. Maternal metabolic parameters were determined, and an untargeted lipidomic analysis was performed. The relationship between underlying lipidomic responses and lactation was explored., Results: Improved glucose homeostasis and insulin sensitivity were observed in GDM women who adopted breastfeeding during the puerperium. Further lipidomics analysis revealed prominent correlations between lipid constitution changes and breastfeeding in women with GDM. A total of 766 lipid species were identified, 33 of which were found to be significantly altered in response to lactation. Significant associations between dysregulated lipids and maternal metabolic parameters were also shown. Subsequently, we identified a panel of three lipids that were strongly associated with breastfeeding, from which we constructed a predictive model with higher discriminating power., Conclusions: We generally revealed that lactation during puerperium appears to have favorable effects on diabetogenic risk factors for GDM women. We also discovered that lipidomic changes related to lactation could elucidate the mother's recovery from GDM pregnancy., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims: Gestational diabetes mellitus (GDM) is the most common complication of pregnancy and is known to be associated with an increased risk of postpartum metabolic disease. Based on the important role that the intestinal microbiota plays in blood glucose regulation and insulin sensitivity, supplementation of probiotic and postbiotic strains could improve glucose metabolism and tolerance in GDM., Main Methods: 56 4-week-old female C57BL/6J-mice were divided into 4 groups (n = 14 animals/group): control (CNT), high-fat/high-sucrose (HFS), pA1c® alive (pA1c®) and heat-inactivated pA1c® (pA1c®HI). Serum biochemical parameters were analyzed, gene expression analyses were conducted, and fecal microbiota composition was evaluated by shot-gun sequencing., Key Findings: pA1c®- and pA1c® HI-supplemented groups presented reduced fasting blood glucose levels and reduced insulin resistance during gestation and exhibited lower visceral adiposity and increased muscle tissue, together with an improvement in intrahepatic TGs content and ALT levels. Liver gene expression analyses demonstrated that pA1c® and pA1c® HI activities were mediated by modulation of the insulin receptor, but also by an overexpression of beta-oxidation genes, and downregulation of fatty acid biosynthesis genes. Shot-gun metagenomics demonstrated that Pediococcus acidilactici was detected in the feces of all the pA1c® and pA1c® HI-group after the supplementation period (75 % of the microbial profile was Pediococcus acidilactici) in only nine weeks of supplementation, and modulated gut microbiota composition., Significance: These results may be considered as future perspectives for the development of preventive, even therapeutic options for GDM based on hyperglycemia reduction, blood glucose regulation, hepatic steatosis attenuation and insulin resistance alleviation., Competing Interests: Declaration of competing interest All the authors listed have contributed significantly to the work. J.A. is shareholder of the company Genbioma Aplicaciones S.L. J.A. and M.O. are co-authors of the patent cited in the manuscript [PCT/EP2020/087284]. The rest of the authors declare no conflict of interest. The data presented in this manuscript have not been published and are not under consideration for publication elsewhere., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: Gestational diabetes mellitus (GDM) affects 14% of all pregnancies worldwide and is associated with cardiometabolic risk. We aimed to exploit high-resolution wearable device time-series data to create a fine-grained physiological characterisation of the postpartum GDM state in free-living conditions, including clinical variables, daily glucose dynamics, food and drink consumption, physical activity, sleep patterns and heart rate., Methods: In a prospective observational study, we employed continuous glucose monitors (CGMs), a smartphone food diary, triaxial accelerometers and heart rate and heart rate variability monitors over a 2 week period to compare women who had GDM in the previous pregnancy (GDM group) and women who had a pregnancy with normal glucose metabolism (non-GDM group) at 1-2 months after delivery (baseline) and 6 months later (follow-up). We integrated CGM data with ingestion events recorded with the smartphone app MyFoodRepo to quantify the rapidity of returning to preprandial glucose levels after meal consumption. We inferred the properties of the underlying 24 h rhythm in the baseline glucose. Aggregating the baseline and follow-up data in a linear mixed model, we quantified the relationships between glycaemic variables and wearable device-derived markers of circadian timing., Results: Compared with the non-GDM group (n=15), the GDM group (n=22, including five with prediabetes defined based on fasting plasma glucose [5.6-6.9 mmol/l (100-125 mg/dl)] and/or HbA 1c [39-47 mmol/mol (5.7-6.4%)]) had a higher BMI, HbA 1c and mean amplitude of glycaemic excursion at baseline (all p≤0.05). Integrating CGM data and ingestion events showed that the GDM group had a slower postprandial glucose decrease (p=0.01) despite having a lower proportion of carbohydrate intake, similar mean glucose levels and a reduced amplitude of the underlying glucose 24 h rhythm (p=0.005). Differences in CGM-derived variables persisted when the five women with prediabetes were removed from the comparison. Longitudinal analysis from baseline to follow-up showed a significant increase in fasting plasma glucose across both groups. The CGM-derived metrics showed no differences from baseline to follow-up. Late circadian timing (i.e. sleep midpoint, eating midpoint and peak time of heart rate) was correlated with higher fasting plasma glucose and reduced amplitudes of the underlying glucose 24 h rhythm (all p≤0.05)., Conclusions/interpretation: We reveal GDM-related postpartum differences in glucose variability and 24 h rhythms, even among women clinically considered to be normoglycaemic. Our results provide a rationale for future interventions aimed at improving glucose variability and encouraging earlier daily behavioural patterns to mitigate the long-term cardiometabolic risk of GDM., Trial Registration: ClinicalTrials.gov no. NCT04642534., Competing Interests: Acknowledgements: The authors wish to thank all participants and their families, the clinical team at the Maternity ward and Gestational Diabetes clinic, CHUV, the laboratory team at the Serum Biobank, CHUV, Y. Dibner at EPFL for the RedCap development, the Clinical Trial Unit at CHUV, the team at Digital Epidemiology laboratory, EPFL and the annotators of all recorded collected food and drink pictures via the MyFoodRepo app. Data availability: The data are available upon reasonable request to the corresponding authors. Funding: Open access funding provided by University of Geneva. This project was supported by the Leenaards Foundation (THC, JJP, CD), the Vontobel Foundation (THC, CD), the Swiss Life Jubiläumsstiftung Foundation (THC, FS), the Swiss Society of Endocrinology and Diabetes (THC, FS, NEP) and the Hjelt Foundation (NEP). THC’s research is supported by grants from the Swiss National Science Foundation (SNSF, PZ00P3-167826, 32003B-212559), the Nutrition 2000plus Foundation and the Medical Board of the Geneva University Hospitals. CD’s research is supported by SNSF grants 310030-184708 and 310030-219187, the Vontobel Foundation, the Olga Mayenfisch Foundation, Ligue Pulmonaire Genevoise, Swiss Cancer League (KFS-5266-02-2021-R), the Velux Foundation, the ISREC Foundation and the Gertrude von Meissner Foundation. JJP’s research is supported by SNSF grant 32003B-176119, the Gottfried und Julia Bangerter-Rhyner Foundation, an unrestricted educational grant from Novo Nordisk and a grant from the Dreyfus Foundation. Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: NEP, CD, JJP and THC conceptualised the study. NEP, CD, JJP and THC acquired funding. NEP, JM, ADB, FS, SU, FN, CD, JJP and THC developed and implemented the methodology. JM, SU, AH, JJP and THC collected the data. NEP, ADB, SB, FN, MS and THC analysed the data. NEP, MS and THC developed/worked on the software. NEP and THC created the visualisation. NEP and THC wrote the original draft manuscript. CD, JJP and THC performed supervision and project administration. All authors have read, edited and agreed to the published version of the manuscript. NEP, CD, JJP and THC are responsible for the integrity of the work as a whole., (© 2024. The Author(s).)

Aim: To characterize the gingival crevicular fluid (GCF) and plasma extracellular vesicles (EVs) and explore their proteomic cargo in healthy pregnant women compared to those with gestational diabetes mellitus (GDM) and periodontitis., Methods: One-hundred and four pregnant women were recruited at 24-30 gestation weeks. GDM was diagnosed by an oral glucose tolerance test. GCF and plasma samples were obtained to isolate EVs and characterized by nanoparticle tracking, immunoassays, electron microscopy and mass spectrometry., Results: Of the recruits,17.3% women were healthy, 50% had periodontitis and 32.7% had both GDM and periodontitis. Probing depth, clinical attachment loss and bleeding on probing were more severe in GDM and periodontitis pregnancies (p < 0.0001). Additionally, this group showed an increase concentration of total, small and large GCF-EVs (p = 0.0015, p = 0.0011 and p = 0.0008, respectively), with decreased expression of CD9, CD81 and CD81/CD63 ratio (p = 0.0461, p = 0.0164 and p = 0.0005, respectively). No differences were observed in plasmatic EVs concentration or markers expression. Proteomic analysis of GCF-EVs showed peptides of both host and bacterial origin. Gene ontology analysis revealed that proteins of GCF-EVs participate in immune inflammatory responses, glucose metabolism and insulin response mechanisms., Conclusion: GCF-EVs were increased in both GDM and periodontitis, and their proteomic cargo suggest their involvement in immune inflammatory response, glucose metabolism and insulin pathways during pregnancy., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Gestational diabetes is marked impaired glucose tolerance, poses various adverse outcomes including increased BMI and obesity. These outcomes results from excess lipid accumulation which is marked by elevated triglycerides. In GDM, placenta exhibits altered lipid metabolism, including reduced fatty acid oxidation and increased triglyceride accumulation. These elevated triglycerides can also contribute to oxidative stress in GDM. SIRT7 plays an important role in regulating lipid metabolism and triglycerides levels. This study aimed to investigate the potential of miRNA to regulate the placental SIRT7 in GDM. PCR analysis reveals that SIRT7 expression along with oxidative stress markers elevated in GDM placenta. These elevated SIRT7 levels were positively correlated with BMI and triglycerides levels in GDM subjects. miR-125b-5p was identified to regulate SIRT7 mRNA using in-silico approaches. Expression levels of miR-125b-5p were found to be downregulated in GDM placenta and found to be negatively correlated with SIRT7 mRNA expression. To confirm the hypothesis BeWo cells were transfected with anti-miR-125b and miR-125b-mimic. Anti-miR overexpressed the SIRT7 expression where mimic dysregulated it. Additionally, overexpressing miR-125b-5p controlled the elevated SIRT7 caused by the exposure of high glucose in BeWo cells. Collectively this study indicated that miR-125b-5p may regulate lipid metabolism via SIRT7 contributing to GDM. These findings highlights the warrant of further research to develop the therapeutic approaches that target miR-125b-5p to reduce lipid accumulation and obesity in GDM., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Ramkumar KM reports was provided by SRM Institute of Science and Technology., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Offspring of women with gestational diabetes mellitus (GDM) face an increased risk of long-term neurodevelopmental abnormalities. This study explores the altered expression of key placental fatty acid transport proteins-FATP2, FATP4, FATP6, FABP4, and FAT/CD36-in GDM patients, and the potential of docosahexaenoic acid (DHA) to mitigate neurodevelopmental risks in offspring by enhancing their expression through activation of peroxisome proliferator-activated receptor γ (PPAR-γ). Our findings demonstrate that placental FATP4 expression is reduced in GDM patients. In HTR8/SVneo cells, PPAR-γ activation upregulated the expression of FATP4, FAT/CD36, and FABP4, while PPAR-γ inhibition only reduced FAT/CD36 expression. DHA treatment led to increased expression of FATP4, FATP/CD36 and FABP4, which was partially reversed by PPAR-γ inhibition. Consistent results were observed in an insulin-resistant cell model. Supplementing GDM mice with exogenous DHA restored placental FATP4 expression and improved offspring social behavior and cognitive function. These results suggest that DHA supplementation during pregnancy could reduce the adverse effects of GDM on placental FATP4 expression and support better neurodevelopmental outcomes in offspring by promoting essential fatty acid transport through the PPAR-γ/FATP4 pathway. This study highlights the therapeutic potential of DHA in improving fetal outcomes in GDM pregnancies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Gestational Diabetes Mellitus (GDM) is the most frequent complication during pregnancy. Pharmacological interventions, such as peptide drugs that focused on improving the insulin sensitivity might be promising in the prevention and treatment of GDM. In this study, we aimed to investigate the role and mechanism of a novel peptide, named AGDMP1 (Anti-GDM peptide 1), which we previously identified lower in the serum of GDM patients using mass spectrometry, on the adipose insulin resistance in GDM. We found that AGDMP1 had a high affinity for adipose tissues in vivo. AGDMP1 markedly improved glucose homeostasis and insulin resistance in GDM mice. This was associated with reduced inflammation and upregulated AKT/GLUT4 signaling pathway in white adipose tissue. In vitro, AGDMP1 could increase glucose uptake and insulin sensitivity of adipocytes by activating the IRS-1/AKT/GLUT4 signaling pathway under basal, insulin-stimulated, and insulin-resistant conditions, respectively. Mechanistically, we found that AGDMP1 could bind to HSP60 to dampen its effects on AKT signaling and pro-inflammatory response, which was reversed in the present of recombinant HSP60 protein. AGDMP1 ameliorated adipose insulin resistance and inflammation by targeting HSP60 and activating the IRS-1/AKT/GLUT4 signaling pathway. These data supported AGDMP1 with therapeutic potential in GDM and associated pathologies., (© 2025 Federation of American Societies for Experimental Biology.)

Gestational diabetes mellitus (GDM) significantly disrupts placental structure and function, leading to complications such as intrauterine growth restriction (IUGR) and preeclampsia. This study aimed to investigate the effects of GDM on placental histology, angiogenesis, and oxidative stress, as well as evaluate metformin's protective role in mitigating these changes. A total of 60 pregnant Sprague-Dawley rats were divided into four groups: control, metformin-treated, GDM, and GDM with metformin. GDM was induced using streptozotocin (STZ) at 40 mg/kg, and metformin was administered at 200 mg/kg from gestational day (GD) 4 to GD17. Blood glucose and insulin levels were assessed, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was calculated. Placentae were weighed and subjected to histological, immunohistochemical, and molecular analyses, focusing on key angiogenesis markers (VEGF, VEGFR, CD31, KLF2) and oxidative stress indicators (MDA, eNOS). GDM increased placental weight, angiogenesis (elevated VEGF, VEGFR, CD31), and oxidative stress (elevated MDA, eNOS). Histopathological changes included villous edema, membrane rupture, and hemosiderin deposition. Metformin treatment reduced placental weight; normalized VEGF, KLF2, and PlGF expression; and improved placental architecture. Additionally, oxidative stress was significantly reduced in metformin-treated GDM rats. In conclusion, GDM induces placental abnormalities, promoting excessive angiogenesis and oxidative stress, potentially leading to IUGR and other complications. Metformin showed protective effects by reducing placental overgrowth and restoring vascular and oxidative balance. These findings suggest that metformin may play a therapeutic role in improving placental health in GDM pregnancies, warranting further investigation into its long-term effects on fetal development and maternal health., Competing Interests: Declarations. Conflicts of interest: The authors declare no competing interests. The authors reported no conflict of interest. The authors have no competing interests as defined by Springer, or other interests that might be perceived to influence the results and/or discussion reported in this paper. Ethical approval: IRP no.: 00012098- serial no.: 0305326- FWA no.: 00018699., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Overweight and obesity (OWO) are linked to dyslipidemia and low-grade chronic inflammation, which is fueled by lipotoxicity and oxidative stress. In the context of pregnancy, maternal OWO has long been known to negatively impact on pregnancy outcomes and maternal health, as well as to imprint a higher risk for diseases in offspring later in life. Emerging research suggests that individual lipid metabolites, which collectively form the lipidome, may play a causal role in the pathogenesis of OWO-related diseases. This can be applied to the onset of pregnancy complications such as gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP), which in fact occur more frequently in women affected by OWO. In this review, we summarize current knowledge on maternal lipid metabolites in pregnancy and highlight associations between the maternal lipidome and the risk to develop GDM, HDP and childhood OWO. Emerging data underpin that dysregulations in maternal triglyceride, phospholipid and polyunsaturated fatty acid (PUFA) metabolism may play a role in modulating the risk for adverse pregnancy outcomes and childhood OWO, but it is yet premature to convert currently available insights into clinical guidelines. Well-designed large-scale lipidomic studies, combined with translational approaches including animal models of obesity, will likely facilitate the recognition of underling pathways of OWO-related pregnancy complications and child's health outcomes, based on which clinical guidelines and recommendations can be updated., Competing Interests: Declarations. Illustrations: All figures were designed or modified using InDesign, Adobe Photoshop and Adobe Acrobat Pro. Images in Fig. 3 are copyrighted by BioRender. Figure 5 was created in GraphPad PRISM (version 10.2.3). Competing interests: PA is the Editor-in-Chief of this Journal. Thus, an independent Editor has had the responsibility to supervise the peer review process. This manuscript has not been given priority and has undergone the same peer review process as other manuscripts in this Journal. The other authors have no competing interests to declare that are relevant to the content of this article., (© 2025. The Author(s).)

Background: Neonicotinoids (NEOs) are well-designed highly selective pesticides that target nicotinic acetylcholine receptors. However, their extensive use, accumulation, and biomagnification pose significant risks to humans. Increasing evidence has suggested that NEOs may affect glucose homeostasis, but little research has linked NEOs exposure to gestational diabetes mellitus (GDM), which is the most common disease in pregnancy. We here aimed to investigate the association between NEOs exposure and GDM occurrence., Methods: 100 pregnant women who completed a 75 g oral glucose tolerance test (OGTT) at 24-28 weeks of gestation were enrolled. Urinary concentrations of seven widely used NEOs were quantified using ultra-high performance liquid chromatography multiple reaction monitoring mass spectrometry (UHPLC-MRM-MS/MS). Correlation analysis revealed the associations between NEOs concentrations and glucose homeostasis parameters. The toxic effects of thiamethoxam (TMX) and clothianidin (CLO) were assessed using pregnant mice, and the potential mechanism in impairing glucose disposition regarding brown adipose tissue (BAT) thermogenesis has been elucidated., Results: Among the 100 urine samples, 88 % were contaminated by NEOs with concentrations ranging from 2.50 to 491.34 nmol/L. TMX and CLO were the most frequently detected NEOs, highly detected in women with GDM. Moreover, we found statistically significant associations between TMX concentrations and 1hBG, and 2hBG. Exposure to mixed NEOs during gestation resulted in elevated glucose levels and impaired insulin sensitivity in normal pregnant and GDM mice models. In addition, we found the metabolic disorders induced by NEOs were linked to the deterioration of BAT thermogenesis in vivo., Conclusion: In general, we demonstrated that prenatal exposures to NEOs were associated with an increased risk of GDM by deteriorating the thermogenic capacity of BAT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Gestational diabetes mellitus (GDM) is linked to a greater risk of various maternal and fetal complications, including the possibility of long-term metabolic issues in offspring. Our initial research suggests that the Traditional Chinese Medicine formula, Shenling Guchang prescription (SLGP), may have an impact on the gut microbiota. However, the specific mechanisms through which it affects intestinal barrier inflammation in GDM are still not fully understood. This study explored SLGP's mechanisms in GDM. Firstly, network pharmacology predicted key bioactive constituents targeting toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB), guiding experimental design. Subsequently, the pregnant female rats were induced with GDM through intraperitoneal streptozotocin injection and then divided into control, model, metformin, and SLGP treatment groups. Blood samples were collected for ELISA analysis to measure levels of inflammatory markers, intestinal tissues were examined histologically using hematoxylin-eosin (HE) staining, and western blot analysis was conducted to evaluate TLR4 and NF-κB expression. Relative to control rats, model group animals exhibited significant increases in the levels of inflammatory markers (IL-1β, IL-6, TNF-α, TGF-β, CRP), as well as enhanced TLR4 and p-NF-κB p65 expression, along with intestinal histopathological changes. Treatment with SLGP notably reduced inflammatory markers and protein expression in the colonic tissue of GDM rats, leading to a decrease in histopathological damage. Overall, SLGP was found to modulate the TLR4/NF-κB pathway, resulting in enhancements in insulin resistance and a reduction in inflammatory responses in GDM rats, thereby providing protection for the intestines. This study demonstrates the potential therapeutic effectiveness of SLGP in addressing intestinal inflammation linked to GDM.

Gestational diabetes mellitus (GDM), a transient form of diabetes that resolves postpartum, is a major risk factor for type 2 diabetes (T2D) in women. While the progression from GDM to T2D is not fully understood, it involves both genetic and environmental components. By integrating clinical, metabolomic, and genome-wide association study (GWAS) data, we identified associations between decreased sphingolipid biosynthesis and future T2D, in part through the rs267738 allele of the CERS2 gene in Hispanic women shortly after a GDM pregnancy. To understand the impact of the CERS2 gene and risk allele on glucose regulation, we examined whole-body Cers2 knockout and rs267738 knock-in mice. Both models exhibited glucose intolerance and impaired insulin secretion in vivo. Islets isolated from these models also demonstrated reduced β cell function, as shown by decreased insulin secretion ex vivo. Overall, reduced circulating sphingolipids may indicate a high risk of GDM-to-T2D progression and reflect deficits in CERS2 activity that negatively affect glucose homeostasis and β cell function.

Gestational diabetes mellitus (GDM), a common pregnancy disease, has long-term negative effects on offspring health. Epigenetic changes may have important contributions to that, but the underlying mechanisms are not well understood. Here, we report the influence of GDM on DNA methylation of offspring (GDF1) oocytes and the possible mechanisms. Our results show that GDM induces genomic hyper-methylation of offspring oocytes, and at least a part of the altered methylation is inherited by F2 oocytes, which may be a reason for the inheritance of metabolic disorders. We further find that GDM exposure increases the expression of Ezh2 in oocytes. Ezh2 regulates DNA methylation via DNMT1, and Ezh2 knockdown reduces the genomic methylation level of GDF1 oocytes. These results suggest that GDM may induce oocyte genomic hyper-methylation of offspring via enhancing the Ezh2 expression recruiting more DNMT1 into nucleus., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Aim: To synthesise the evidence from clinical trials and observational studies using omics techniques to investigate the impact of diet and lifestyle factors on metabolite profile in pregnancy, and in the prevention and management of gestational diabetes mellitus (GDM)., Materials and Methods: A systematic literature search was performed using PubMed, Ovid, CINAHL, and Web of Science databases in October 2023 and updated in September 2024. Inclusion criteria were randomised controlled trials (RCT) or non-RCTs in pregnant women with or without GDM, that measured diet and lifestyle factors, and which applied post-transcriptional omics approaches. Risk of bias was assessed using the ROBINS-I for non-RCTs and ROB-2 tool for RCTs. The results of all studies are narratively synthesised., Results: Of 6293 studies identified, eight observational studies and three RCTs comprising 2639 pregnant women were included. Three studies reported on changes in diet-related metabolic phenotypes during pregnancy; however, the impact of certain foods on the metabolome and risk for GDM was less clear. Compared with women without GDM, women with GDM had a worse deterioration in metabolites, including saturated fatty acids, branched chain amino acids and purine degradation metabolites. There is limited evidence that conventional dietary treatment for GDM may modify the metabolome in women with GDM., Conclusions: Metabolome profiles in pregnancy may be altered by certain dietary choices; however, it is inconclusive whether improved diet related metabolite profiles have a beneficial impact in the prevention or management of GDM. High quality studies with larger sample sizes are needed to better understand the role that maternal nutrition plays in modulating the maternal metabolome, not only for a healthy pregnancy but also for the prevention and management of GDM., (© 2025 The Author(s). Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Human milk oligosaccharides (HMOs) are bioactive components which play an important role in infant health. HMO composition is vulnerable to changes of maternal conditions including lactation stages and maternal phenotypes. Pregnant diseases such as gestational diabetes mellitus (GDM) are commonly found in women during pragnancy, and may cause disorder in maternal physiological metabolism which is harmful to infants. Unfortunately, anlysis of oligosaccharides from women with GDM is limited. To address this issue, we analyzed HMO compositions and profiles in breast milk from women with GDM using an established 96-well plate permethylation platform and MALDI-TOF-MS. We enrolled 127 women with GDM, and investigated HMO abundances in colostrum, transition milk, and mature milk respectively. We found that GDM affected HMO compositions in breast milk, and the level of fucosylation became higher over the course of lactation for all the women with GDM. Interestingly, the relative abundances of fucosylated HMOs in different lactation stages were affected differentially by GDM, with the most pronounced effect in colostrum. In particular, the relative abundances of H3N1F1 and H3N1F2 sharply decreased over time, showing very low levels in late lactation. These differences in our findings need further investigation to develop optimal feeding for mothers with GDM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Gestational diabetes mellitus (GDM) is the first type of diabetes induced by abnormal maternal glucose metabolism after pregnancy. Long non-coding RNA (lncRNA) has been found to be of great value in the study of its pathogenesis and treatment. This study aimed to explore the expression and diagnostic value of lncRNA HCG18 in GDM., Material and Methods: The expression levels of HCG18 in serum of participating GDM patients and healthy controls were detected by polymerase chain reaction (RT-qPCR). The correlation between the expression of HCG18 and the blood glucose level was clarified by the detection of blood glucose levels in GDM patients. The receiver operating characteristic curve (ROC) was used to evaluate the clinical diagnostic value of HCG18 for GDM. Furthermore, multivariate logistic analysis was used to verify the diagnostic value of HCG18 in GDM., Results: This study concluded that the expression level of HCG18 was upregulated in the serum of GDM patients compared with the control group. ROC curve showed that the AUC was 0.916, the sensitivity was 80.5%, the specificity was 90.2%, and multivariate logistic regression analysis verified that HCG18 (OR = 6.984, 95% CI = 3.751-13.005, p < 0.001) was significantly associated with GDM, which suggesting that HCG18 has diagnostic significance for GDM. In addition, the expression of HCG18 was positively correlated with fasting blood glucose, 1h blood glucose and 2 h blood glucose of patients., Conclusions: LncRNA HCG18 was elevated in patient serum and might serve as a diagnostic biomarker for GDM.

Aims: Gestational diabetes mellitus (GDM) poses a significant risk for developing type 2 diabetes mellitus (T2D) and exhibits heterogeneity. However, understanding the link between different types of post-GDM individuals without diabetes and their progression to T2D is crucial to advance personalised medicine approaches., Materials and Methods: We employed a discovery-based unsupervised machine learning clustering method to generate clustering models for analysing metabolomics, clinical, and biochemical datasets. For this analysis, we selected 225 women who later developed T2D during the 12-year follow-up period from the cohort of 1010 women who returned to a non-diabetic state at 6-9 weeks (study baseline) after a GDM pregnancy based on 2-h 75 g research OGTTs. The optimal model was selected by assessing Bayesian Information Criterion values, class separation performance, and the potential for clinically distinguishable clusters, accounting for participant prenatal and early postpartum characteristics., Results: The selected model comprises three clusters: pancreatic beta cell dysfunction (cluster-β: median HOMA-B 161.3 and median HOMA-IR 3.8), insulin-resistance (cluster-IR: median HOMA-B 630.5 and median HOMA-IR 16.8), and a mixed cluster (cluster-mixed: median HOMA-B 307.2 and median HOMA-IR 8.6). These clusters are distinguishable based on postpartum blood test parameters such as glucose tolerance, HOMA indices, and fasting lipid profiles including triglycerides, leptin, HDL-c, and adiponectin, as well as participant age and BMI. Metabolomic analysis identified unique molecular signatures for each cluster. However, the time to T2D onset was not statistically significant among the three clusters (p = 0.22)., Conclusion: This study enhances our understanding of the heterogeneity of early postpartum metabolic profiles that characterise the future onset of T2D diabetes in a diverse cohort of women with GDM, revealing insights into distinct mechanisms and personalised intervention strategies for the prevention of T2D., (© 2025 The Author(s). Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Background: Gestational diabetes mellitus (GDM) is a metabolic disorder that arises during pregnancy and heightens the risk of placental dysplasia. Ginsenoside Re (Re) may stabilize insulin and glucagon to regulate glucose levels, which may improve diabetes-associated diseases. Purpose: This study aims to investigate the mechanism of Re in high glucose (HG)-induced apoptosis of trophoblasts through endoplasmic reticulum stress (ERS)-related protein CHOP/GADD153. Research Design: Human trophoblast cells HTR-8/SVneo were treated with HG to simulate the HG environment in vitro , while normal glucose (NG) was used as the control. Study Sample: NG (5 mM) or HG (25 mM)-cultured HTR-8/SVneo cells were treated with 10, 20 or 40 μM Re. HG-cultured cells were treated with 5 mM ERS inducer 2-Deoxy-D-glucose (2-DG) and transfected with oe- CHO. Data Collection and/or Analysis: Cell viability and apoptosis were detected by CCK-8 and flow cytometry; LDH release, superoxide dismutase (SOD), malonaldehyde (MDA) and glutathione (GSH) levels were detected using kits; the apoptosisrelated proteins and ERS-related proteins were assessed by western blot. Results: Re (10, 20 or 40 μM) had no significant effect on NG-treated HTR-8/SVneo cell viability. Re (20 or 40 μM) could enhance the viability of HG-treated trophoblasts. Re (40 μM) inhibited apoptosis of HGtreated trophoblasts, ERS and alleviated oxidative stress evidenced by suppressed phosphorylation of PERK, IRE1α, reduced protein expression of ATF6, CHOP/GADD153, and inhibited MDA accumulation, GSH and SOD loss. ERS activation or CHOP/GADD153 overexpression reversed Re's inhibition on HG-induced apoptosis of trophoblasts. Conclusions: Re repressed HG-induced placental trophoblast apoptosis by mediating ERS-related protein CHOP/GADD153., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The Lingguizhugan decoction (LGZGD) is a promising traditional Chinese medicine for the treatment of gestational diabetes mellitus (GDM). However, its bioactive compounds and therapeutic mechanisms remain unknown. The main chemical composition of LGZGD was analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Furthermore, the underlying mechanisms of LGZGD against GDM were elucidated through network pharmacology and molecular docking. The therapeutic efficacy and targets of LGZGD were further confirmed via an in vitro GDM model (high glucose [HG]-treated HTR-8/SVneo cells). Four compounds of LGZGD, namely, cinnamaldehyde, glycyrrhizic acid, 2-atractylenolide, and pachymic acid, were detected. A total of 26 targets for LGZGD treating GDM were obtained, which were mainly involved in oxidative stress and the PI3K-AKT signaling pathway. The protein-protein interaction (PPI) network unveiled that AKT1, TLR4, TP53, and NOS3 were hub therapeutic targets. Molecular docking showed that these targets had strong affinity with key compounds. In vitro experiments confirmed that LGZGD treatment promoted HG-induced cell viability, migration, and invasion ability while inhibited the apoptosis rate and oxidative stress. Mechanically, western blot revealed that LGZGD may protect HG-treated cells by activating the PI3K-AKT pathway and suppressing TLR4 expression. Our study preliminarily explored the mechanism of LGZGD in GDM treatment, providing a scientific basis for the clinical application of LGZGD., (© 2024 John Wiley & Sons Ltd.)

Introduction: Gestational diabetes mellitus (GDM) is defined as glucose intolerance during pregnancy. We aimed to investigate the potential effects of betatrophin and ApoC2 in GDM, focusing on their roles in LPL (lipoprotein lipase) regulation and their relationship with hPL to elucidate the possible impact of hPL on lipid metabolism and its potential contribution to the development of GDM., Methods: Thirty pregnant women with normal glucose tolerance and 29 with gestational diabetes mellitus (diagnosed by 75g OGTT between 24 and 28 weeks) were included in the study. Serum betatrophin, hPL, and ApoC2 were measured by Elisa and HOMA-IR was calculated., Results: In the GDM group, hPL levels correlated with betatrophin and ApoC2 (r = 0.552, p < 0.05; r = 0.588, p < 0.05 respectively) while betatrophin correlated with the ApoC2 (r = 0.584, p < 0.05). A linear relationship between hPL and betatropin and also between hPL and ApoC2 values in the control group (r = 0.454, p < 0.05; r = 0.779, p < 0.01 respectively) were observed. ApoC2 levels in the GDM group (n = 20) with HOMA-IR cut-off >2.5 were significantly higher than the control group (n = 10) (p < 0.05). There was also a positive relationship between betatrophin and ApoC2 (r = 0.591) (p < 0.05)., Discussion: GDM patients may have impaired LPL enzyme regulation in addition to insulin resistance, with hPL potentially contributing to this disruption. Impaired lipoprotein lipase activity and its dysregulation secondary to genetic disorders may play a role in the etiopathogenesis of GDM. Further investigation into the correlation between betatrophin, ApoC2, and other LPL modulators in patients with various forms of diabetes could be beneficial for understanding this interaction more comprehensively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Gestational diabetes mellitus is one of the most common complications during pregnancy. Its prevalence is rapidly increasing worldwide. Gestational diabetes mellitus is leading to an elevated risk for the development of endothelial dysfunction and cardiovascular diseases both in the mother and the child in later life. The underlying pathophysiological mechanisms are not well-understood. Therefore, we aimed to characterize the endothelial function in fetal placental vessels from mothers with gestational diabetes mellitus. In this study, we distinguished between insulin-treated and diet-controlled gestational diabetes mothers and compared them to a normoglycemic control group. The clinical data confirmed pre-conceptional overweight as a risk factor in women with insulin-treated gestational diabetes mellitus. The insulin-treated gestational diabetes group was also characterized by a recent family history of diabetes compared to mothers of the control or diet-controlled gestational diabetes group. Analyses of blood serum from umbilical cords suggested a reduced fetal insulin metabolism in the insulin-treated gestational diabetes group. Vascular function analysis in fetal placental vessels revealed an altered substance P-induced vasorelaxation in vessels from patients with insulin-dependent gestational diabetes. Inhibition of nitric oxide synthase affected only fetal vessel segments from the control group or diet-controlled gestational diabetes group, but not from insulin-dependent gestational diabetes. Finally, we found a significantly decreased substance P receptor (TACR1) mRNA expression in fetal vessel segments from patients with insulin-treated gestational diabetes. In conclusion, we provide evidence that different pathophysiological mechanisms might be responsible for the development of insulin-treated versus diet-controlled gestational diabetes. Only in fetal vessels from patients with insulin-treated gestational diabetes were we able to detect an endothelial dysfunction and a reduced fetal insulin conversion. This provides novel insights into the pathophysiology of the subtypes of gestational diabetes., Competing Interests: Declarations. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional ethics committee of the participating center and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All patients received detailed verbal and written information about the study and gave written informed consent. The study was approved by the Ethics Committee of the TUD Dresden University of Technology (EK 277–07-2018 (BO), extension 2022). Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: The placenta uses lipids and other nutrients to support its own metabolism hence impacting the type and amount of these substrates available to the growing fetus. Maternal obesity and gestational diabetes (GDM) can disrupt placental lipid metabolism and thus lead to altered fetal growth contributing to adverse pregnancy outcomes and developmentally programing the offspring for disease in later life. Understanding obesity and GDM driven changes in placental lipid metabolism is thus important., Methods: We collected maternal plasma and placental villous tissue following elective cesarean section at term from women who were lean (pre-pregnancy BMI 18.5-24.9), obese (BMI>30) or obese with type A2 GDM n = 8 each group (4 male and 4 female placentas). Fatty acid composition of different lipid classes was analyzed by LC-MS/MS analysis. Significant changes in GDM vs obese, GDM vs lean, and obese vs lean were determined in both a fetal sex-dependent and independent manner., Results: In placenta 436 lipids were identified, among which 85 showed significant changes. We report significant changes in placental triglyceride, phosphatidylcholine, and phosphatidylinositol lipids containing essential fatty acids- DHA and AA in GDM, with male placentas driving these changes. In maternal plasma, 284 lipids were identified with 14 showing significant changes, but we observed no changes based on fetal sex., Discussion: Maternal obesity and GDM impact placental lipid composition in a sexually dimorphic manner. The alteration in specific lipid classes can impact cellular energetics and placental function., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aims: To investigate immunometabolic associations of CD4 + T cell phenotypes with gestational diabetes mellitus (GDM)., Methods: A nested case-control study was conducted comprising 53 pairs of GDM patients and matched controls within a prospective cohort. Metabolomic signatures related to both CD4 + T cell phenotypes and glycemic traits among pregnant women were investigated by weighted gene co-expression network analysis (WGCNA). Multivariable-adjusted generalized linear models were used to explore the associations of CD4 + T cell phenotypes and selected metabolites with GDM. Mediation analysis was conducted to evaluate the mediating effect of selected metabolites on the relationship between CD4 + T cell phenotypes and glycemic traits., Results: Higher levels of Treg cells (OR per SD increment (95%CI): 0.57 (0.34, 0.95), p = 0.031) and increased expression of Foxp3 (OR per SD increment (95%CI): 0.59 (0.35, 0.97), p = 0.039) and GATA3 (OR per SD increment (95%CI): 0.42 (0.25, 0.72), p = 0.002) were correlated with a decreased risk of GDM. Plasma pyruvaldehyde, S-adenosylhomocysteine (SAH), bergapten, and 9-fluorenone mediated the association between Tregs and fasting plasma glucose (FPG), with mediation proportions of 46.9%, 39.6%, 52.4%, and 56.9%, respectively., Conclusions: Treg cells and Foxp3 expressions were inversely associated with GDM risk, with potential metabolic mechanisms involving metabolites such as pyruvaldehyde and SAH., Competing Interests: Declarations. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Research Committee of the Obstetrics and Gynecology Hospital of Fudan University (Ethics Approval number 2017-74). Consent to participate: Informed consent was obtained from all individual participants included in the study. Conflict of interest: The authors declare that they have no conflict of interest., (© 2024. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Background: m6A modification plays a vital role in gestational diabetes mellitus (GDM) progression. However, the role of METTL3 and differential m6A-modified circRNAs in GDMremainsto be investigated., Methods: Placental tissue samples from GDM patients and normal controls (NC) were collected to measure changes in m6A modification levels. MeRIP-seq on placental tissue was performed to detect differential m6A-modified circRNAs.High glucose (HG)-treated JEG3 cells were used to establish the GDM cell model. Differentially expressed circRNAs levels in GDM and NC groups were measured by qRT-PCR. We knocked down METTL3 to study its function. Additionally, we conducted functional recovery experiments. Dot blot assay was utilized to assess changes in m6A levels. MeRIP-qPCR was performed to evaluate the effect of knocking down METTL3 on m6A modification of hsa&#95;circ&#95;0072380 in JEG3 cells., Results: Compared with the NC group, the GDM group exhibited increased levels of m6A modification and METTL3 expression. Differences in m6A modification of circRNAs exist between the GDM and NC groups. Hsa&#95;circ&#95;0000994, hsa&#95;circ&#95;0058733, and hsa&#95;circ&#95;0072380 were significantly down-regulated in the GDM group while hsa&#95;circ&#95;0036376, hsa&#95;circ&#95;0000471, and hsa&#95;circ&#95;0001173 showed no significant differences between two groups. HG treatment promoted METTL3 expression and m6A level of JEG3 cells, and inhibited cell proliferation, migration, and invasion abilities. Knocking down METTL3 reversed these effects. After HG treatment, hsa&#95;circ&#95;0072380 was significantly down-regulated. Knocking down METTL3 led to up-regulation of hsa&#95;circ&#95;0072380, while knocking down hsa&#95;circ&#95;0072380 restored the function of SiMETTL3. Additionally, knocking down METTL3 significantly reduced the m6A modification of hsa&#95;circ&#95;0072380., Conclusion: METTL3 mediated m6A modification of hsa&#95;circ&#95;0072380 to regulate GDM progression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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.

Background and Aims: Hyperglycaemia during gestational diabetes (GD) predisposes women and their offspring to later cardiometabolic disease. The hyperglycaemia-mediated epigenetic changes remain to be elucidated. Methyltransferase MLL1-induced trimethylation of histone 3 at lysine 4 (H3K4me3) activates inflammatory and oxidative phenotype. This epigenetic mark in GD women and its transmission to the offspring were investigated., Methods: Peripheral blood mononuclear cells (PBMC) were collected from GD and control (C) women and also from adolescents born to women of both groups. Endothelial human umbilical vein endothelial cells (HUVEC) and cord blood mononuclear cells (CBMC) were from umbilical cords. The NF-κBp65 and NOX4 expressions were investigated by reverse transcription quantitative polymerase chain reaction and immunofluorescence (IF). MLL1 and H3K4me3 were investigated by immunoblotting and IF. H3K4me3 on NF-κBp65 and NOX4 promoters was studied by chromatin immunoprecipitation. Superoxide anion generation was measured by electron spin resonance spectroscopy. Plasma cytokines were measured by enzyme-linked immunosorbent assay. To investigate the role of MLL1, HUVEC were exposed to inhibitor MM102 or siRNA transfection., Results: PBMC, CBMC, and HUVEC showed an increase of NF-κBp65, IL-6, ICAM-1, MCP-1, and VCAM-1 mRNAs. These findings were associated with H3K4me3 enrichment in the promoter of NF-κBp65. Elevated H3K4me3 and cytokine levels were observed in GD adolescents. MLL1 drives H3K4me3 not only on NF-kB p65, but also on NOX4 promoter. Inhibition of MLL1 blunted NF-κBp65 and NOX4 by modulating inflammatory and oxidative phenotype., Conclusions: Such proof-of-concept study shows persistence of MLL1-dependent H3K4me3 in offspring born to GD women, suggesting an epigenetic-driven transmission of maternal phenotype. These findings may pave the way for pharmacological reprogramming of adverse histone modifications to mitigate abnormal phenotypes underlying early ASCVD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Gestational diabetes mellitus (GDM) has been associated with several fetal complications, such as macrosomia and fetal growth restriction (FGR). Infants from GDM associated FGR are at increased risk for adult-onset obesity and associated metabolic disorders. However, the underlying mechanisms of GDM associated FGR remain to be explored., Methods: We analyzed placentas from GDM patients with FGR for ferroptosis markers and GLUT1 expression. High glucose conditions were established by adding different concentrations of D-Glucose to the 1640 cell culture medium. RSL3 were used to test ferroptosis sensitivity in trophoblast cells. GLUT1 was inhibited using siRNA or its inhibitor WZB117 to assess its impact on ferroptosis inhibition in HTR8/SVneo cell line. Mechanistic studies explored the effects of GLUT1 on AMPK and ACC phosphorylation, which in turn impacted lipid metabolism and ferroptosis. In mouse models, streptozotocin (STZ)-induced GDM was treated with WZB117 and the ferroptosis inhibitor liproxstatin-1 (Lip-1). Finally, AMPK and ACC phosphorylation levels were evaluated in GDM patient samples., Results: In this study, placentas from GDM patients with FGR showed signs of ferroptosis and upregulation of GLUT1. In cell models, high glucose conditions sensitized trophoblast cells to ferroptosis and induced GLUT1 expression. Interestingly, GLUT1 inhibition significantly suppressed ferroptosis in trophoblast cells under high glucose conditions. Mechanistically, elevated GLUT1 inhibited AMPK phosphorylation and reduced ACC phosphorylation, thereby promoting lipid synthesis and facilitating ferroptosis. In pregnant mice, STZ-induced hyperglycemia led to FGR, and treatment with either the GLUT1 inhibitor WZB117 or the ferroptosis inhibitor Lip-1 alleviated the FGR phenotype. Moreover, in vivo elevation of GLUT1 increased ferroptosis markers, decreased AMPK/ACC phosphorylation, and resulted in altered lipid metabolism, which likely contributed to the observed phenotype. Finally, placental samples from GDM patients showed reduced AMPK and ACC phosphorylation., Conclusions: Our findings suggest a potential role of ferroptosis in GDM associated FGR and indicate that the dysregulated GLUT1-AMPK-ACC axis may be involved in the pathogenesis of GDM associated FGR in clinicals., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University (ID: 2024-291-01) and informed consent was obtained from all subjects. All procedures were performed in accordance with the principles stated in the Declaration of Helsinki. Animal experiments were performed in accordance with in accordance with the Guide for the Care and Use of Laboratory Animals. All animal experiments were conducted with approval from the Animal Experimental Ethical Committee of Chongqing Medical University (ID: IACUC-CQMU-2024-02026). Consent for publication: All authors have agreed to the content of the manuscript and agree to this submission. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: Gestational diabetes mellitus (GDM) is a common complication during pregnancy and increases the risk of metabolic diseases in offspring. We hypothesize that the poor intrauterine environment in pregnant women with GDM may lead to chromosomal DNA damage and telomere damage in umbilical cord blood cells, providing evidence of an association between intrauterine programming and increased long-term metabolic disease risk in offspring., Methods: We measured telomere length (TL), serum telomerase (TE) activity, and oxidative stress markers in umbilical cord blood mononuclear cells (CBMCs) from pregnant women with GDM (N=200) and healthy controls (Ctrls) (N=200) and analysed the associations of TL with demographic characteristics, biochemical indicators, and blood glucose levels., Results: The length of telomeres in umbilical CBMCs in the GDM group was significantly shorter than that in the Ctrl group (P<0.001), and the shortening of telomeres in male infants in the GDM group was more significant than that in the Ctrl group (P<0.001) after adjustment for Pre-pregnancy body mass index (PBMI), Pregnancy weight gain (PGW), and Triglyceride (TG) as confounding factors. In addition, the TE expression level in the GDM group was lower after adjustment. There was no statistically significant difference in oxidative stress hydroxydeoxyguanosine (8-OHdG), malondialdehyde (MDA) and superoxide dismutase (SOD) between the two groups. TL was positively correlated with TE activity, and both were negatively correlated with blood glucose levels. There was no correlation between TL and Gestational age (GA), PBMI, PGW, or TG levels., Conclusion: The poor intrauterine environment in pregnant women with GDM increases telomere attrition and reduces TE activity, which may be potential genetic risk factors for an increased risk of metabolic diseases in offspring later in life due to intrauterine reprogramming., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Xu, Cheng, Liu, Zhang, Chen and Zheng.)

Macrosomia, which is frequently associated with gestational diabetes mellitus (GDM), is linked to maternal glycemic control during gestation. When GDM is complicated by macrosomia (GDMM), the placenta exhibits increased mass, underscoring its role as a critical nexus for maternal-fetal nutrient exchange. Despite this recognized correlation, the underlying mechanisms propelling placental hypertrophy have remained elusive. Our study leveraged single-cell RNA transcriptome sequencing of GDMM placental tissues to pinpoint the specific syncytiotrophoblast (SCT) subsets that regulate placental dimensions. Notably, we observed pronounced upregulation of the epidermal growth factor receptor (EGFR) and its corresponding ligands, with a particular emphasis on the autoregulatory cascade involving the glycoprotein hormone alpha subunit (CGA), EGFR, and the transcription factor GATA binding protein 2 (GATA2), as well as perturbations in hormonal homeostasis within the SCT. Furthermore, our cell interaction analysis revealed an enhanced interplay between myeloid cells and SCT3, augmenting the EGFR signaling pathway. These molecular exchanges underscore the pivotal role of the placental immune microenvironment in the etiology of macrosomia, shedding light on the pathophysiology of GDMM and paving the way for novel therapeutic approaches., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Women with gestational diabetes mellitus (GDM) are more likely to give birth to large for gestational age (LGA) infants, due to abnormalities in glucose metabolism during pregnancy. Although previous studies have explored the risk factors for LGA delivery in GDM women, the results are quite different and still lack of unified understanding., Objective: To explore the elements linked to LGA delivery in GDM women, and thus provide a reference for medical staff to formulate relevant clinical interventions., Methods and Analysis: Systematic search of seven electronic databases (PubMed, Scopus, Cochrane Library, Web of Science, EMBASE, OVID and CINAHL) will be undertaken between the inception of the database to 1 August 2024. Quantitative studies published in English and focused on the risk factors for LGA delivery in GDM women will be included. Two researchers will independently screen the literature and any disagreements will be resolved by a third-party researcher. Joanna Briggs's Institutional Critical Appraisal Tools will be used for the quality assessment of included studies. RevMan V.5.4 software will be used for data processing and summarising. To ensure the reliability and stability of the results, Q test and I 2 test will be used to identify the heterogeneity between studies, while subgroup analysis and sensitivity analysis will be performed based on study quality., Ethics and Dissemination: This systematic review and meta-analysis will be based on published literature, and the findings will be published in a peer-reviewed journal and presented at major conferences focused on clinical nursing., Prospero Registration Number: CRD42024559013., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Gut microbiome dysbiosis is associated with gestational diabetes mellitus (GDM), and its modulation represents a promising approach for enhancing glycemic control. In this study, we aimed to discover specific alterations in the gut microbiome through lifestyle management. We performed metagenome sequencing on fecal samples and measured short-chain fatty acid (SCFA) in plasma samples from 27 well-controlled GDM pregnancies before and after glycemic control. At the same time, 38 normal glucose tolerance (NGT) samples served as controls. Additionally, we employed two-sample Mendelian Randomization (MR) to validate our findings against Genome-Wide Association Study (GWAS) database. Our dynamic analysis revealed Bifidobacterium genus increased in GDM patients after intervention. The MR analysis confirmed that the family of Bifidobacteriaceae (OR 0.929, 95% CI, 0.886-0.975; P = 0.003) was the only negatively associated family with GDM. Further analysis indicated the increased abundance of Bifidobacterium species were negatively correlated with glycemic traits (Spearman rho mean - 0.32 ± 0.34) but positively correlated with plasma SCFA levels (Spearman rho mean 0.24 ± 0.19). Functional analysis revealed that the quorum-sensing pathway had the strongest effect on the ability of Bifidobacterium to promote glucose homeostasis (Spearman rho = -0.34), suggesting its role in regulating intestinal microbiota. Finally, the multivariable MR analysis demonstrated that two pathways, COLANSYN PWY and PWY 7323, responsible for cell surface compound synthesis in gram-negative bacteria, mediated 14.83% (P = 0.017) and 16.64% (P = 0.049) of the protective effects of Bifidobacteriaceae against GDM, respectively. In summary, Bifidobacterium is an effective gut microbiota regulator for GDM-related glucose homeostasis., Competing Interests: Declarations. Ethics approval and consent to participate: This project was approved by the Ethics Committee of Peking University First Hospital (V2.0/201504.20), and informed consent was obtained from all participants. Consent for publication: Not applicable. Clinical trial number: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Not much is currently known about disturbances in insulin signaling and glucose transport in leukocytes of women with gestational diabetes mellitus (GDM) during and after pregnancy. In this study, the expression of insulin signaling ( INSR , IRS1 , IRS2 and PIK3R1)- and glucose transporter ( SLC2A1 , SLC2A3 and SLC2A4 )-related genes in the leukocytes of 92 pregnant women was assayed using quantitative RT-PCR. The cohort consisted of 44 women without GDM (NGT group) and 48 with GDM (GDM group) at 24-28 weeks of gestation. GDM women were then tested again one year after childbirth (pGDM group: 14 women (29.2%) with abnormal glucose tolerance (AGT) and 34 women (70.8%) with normoglycemia). The GDM and NGT groups were closely matched for gestational age and parameters of obesity, such as pre-pregnancy body mass index (BMI), pregnancy weight, and gestational weight gain (GWG) ( p > 0.05). Compared to the NGT group, the GDM and pGDM groups were hyperglycemic, but the GDM group featured a more highly insulin-resistant condition than the pGDM group, as reflected by higher fasting insulin (FI) levels and the values of the homeostasis model assessment for insulin resistance (HOMA-IR) ( p < 0.05). In leukocytes from the GDM and pGDM groups, PIK3R1 , SLC2A1 , and SLC2A3 were upregulated and IRS1 was downregulated, with a larger magnitude in fold change (FC) values for PIK3R1 and IRS1 in the GDM group and for SLC2A1 and SLC2A3 in the pGDM group. The expression of SLC2A4 was unchanged in the GDM group but upregulated in the pGDM group, where it was inversely correlated with HOMA-IR ( rho = -0.48; p = 0.007). Although the INSR and IRS2 levels did not significantly differ between the groups, the IRS2 transcript positively correlated with pregnancy weight, fasting plasma glucose, FI, and HOMA-IR in the GDM group. Our findings indicate that pronounced quantitative changes exist between the GDM and pGDM groups with respect to the expression of certain genes engaged in insulin signaling and glucose transport in leukocytes, with insulin resistance of a variable degree. These data also highlight the relationship of leukocyte SLC2A4 expression with insulin resistance in the postpartum period.

Importance: Gestational diabetes (GD) is linked to health risks for the birthing parent and infant. The outcomes of GD on human milk composition are mostly unknown., Objective: To determine associations between GD, the human milk metabolome, and infant growth and body composition., Design, Setting, and Participants: Cohort study using data from the Mothers and Infants Linked for Healthy Growth and the Maternal Milk, Metabolism, and the Microbiome studies at the University of Oklahoma and University of Minnesota, large prospective US cohorts with a high proportion of exclusive breastfeeding. Participants were mother-infant dyads recruited between October 2014 and August 2019 who planned to exclusively breastfeed for 3 or more months. Data were analyzed from July 2022 to August 2024., Exposure: GD diagnosed via oral glucose tolerance test., Main Outcomes and Measures: The milk metabolome was assessed by untargeted liquid chromatography-gas chromatography-mass spectrometry at 1 month post partum. Infant growth (weight for length z score, length for age z score, and rapid weight gain) and body composition (percentage body fat and fat-free mass index) from 0 to 6 months were assessed. Linear regression analyses tested associations between GD and milk metabolites, with adjustment for covariates and potential confounders., Results: Among 348 dyads (53 with GD), 27 (51%) of the GD-exposed infants were female and 157 (53%) of nonexposed infants were male; 10 (19%) were Asian, 2 (4%) were Black or African American, and 37 (70%) were White. The mean (SD) age was higher in the GD group (with GD, 34.0 [4.3] years; without GD, 30.7 [4.1] years). In adjusted models, GD was associated with differential levels of 9 metabolites of 458 tested (FDR<0.05); 3 were higher (2-hydroxybutyric acid, 3-methylphenylacetic acid, and pregnanolone sulfate) and 6 were lower in women with GD (4-cresyl sulfate, cresol, glycine, P-cresol sulfate, phenylacetic acid, and stearoylcarnitine). Phenylacetic acid was associated with length for age z score (β = 0.27; SE, 0.13; 95% CI, 0.02 to 0.16), 2-hydroxybutryic acid with percentage body fat (β = -1.50; SE, 0.66; 95% CI, -2.79 to -4.82), and stearoylcarnitine with greater odds of rapid weight gain (odds ratio, 1.66; 95% CI, 1.23 to 2.25). GD was associated with greater length for age z scores (β = 0.48; SE, 0.22; 95% CI, 0.04 to 0.91)., Conclusions and Relevance: In this observational cohort study, GD was associated with altered concentrations of several human milk metabolites. The associations between these metabolites and infant growth suggest that milk compositional differences in mothers with GD may beneficially moderate the growth and body composition of their infants.

Gestational diabetes mellitus (GDM) is prevalent among pregnant individuals and is linked to increased risks for both mothers and fetuses. Although GDM is known to cause disruptions in gut microbiota and metabolites, their potential transmission to the fetus has not been fully explored. This study aimed to characterize the similarities in microbial and metabolic signatures between mothers with GDM and their neonates as well as the interactions between these signatures. This study included 89 maternal-neonate pairs (44 in the GDM group and 45 in the normoglycemic group). We utilized 16S rRNA gene sequencing and untargeted metabolomics to analyze the gut microbiota and plasma metabolomics of mothers and neonates. Integrative analyses were performed to elucidate the interactions between these omics. Distinct microbial and metabolic signatures were observed in GDM mothers and their neonates compared to those in the normoglycemic group. Fourteen genera showed similar alterations across both groups. Metabolites linked to glucose, lipid, and energy metabolism were differentially influenced in GDM, with similar trends observed in both mothers and neonates in the GDM group. Network analysis indicated significant associations between Qipengyuania and metabolites related to bile acid metabolism in mothers and newborns. Furthermore, we observed a significant correlation between several genera and metabolites and clinical phenotypes in normoglycemic mothers and newborns, but these correlations were disrupted in the GDM group. Our findings suggest that GDM consistently affects both the microbiota and metabolome in mothers and neonates, thus elucidating the mechanism underlying metabolic transmission across generations. These insights contribute to knowledge regarding the multiomics interactions in GDM and underscore the need to further investigate the prenatal environmental impacts on offspring metabolism., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Fetal development is dependent on placenta and affected by multiple factors including maternal diabetes. Here we aimed to identify maternal diabetes-associated changes in placentas and analyzed placental gene expression to understand its modulation by maternal diabetes and birth mode., Methods: Placental RNAseq transcriptome analyses were performed on maternally-derived decidua and fetal-derived villous tissue from pregnancies of mothers with type 1 diabetes (n = 14), gestational diabetes (n = 6) and without diabetes (n = 14). Information on delivery mode and anesthesia were included as covariables. Analyses were performed separately for decidua and fetal tissues and adjusted for sex., Results: Substantial placenta gene expression variation was associated with factors other than maternal diabetes, including site, sex, anesthesia type and delivery mode. Two dominant gene expression clusters aligned to anesthesia and delivery mode were observed for decidua and villous tissue. Upregulation of genes within pathways related to organ morphogenesis and downregulation of immune response to steroid- and hypoxia pathway genes was characteristic of placentas from primary cesarean section deliveries with spinal anesthesia. Opposite profiles were observed for placentas from secondary cesarean and epidural anesthesia deliveries. Placentas from vaginal delivery had intermediate gene expression profiles. More subtle changes were associated with maternal diabetes: upregulation of ribosome activity, down-regulation of maternally-derived decidua chemokine signaling pathways and for gestational diabetes, alteration in hypoxia response genes., Discussion: The findings reveal suppression of immune pathways and upregulation of ribosome activity in the placenta by maternal diabetes highlighting the importance of confounding factors when examining cell and tissue expression profiles. Further studies should determine whether the observed gene expression differences are related to underlying causes for cesarean section deliveries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Asiaticoside (AS) has been reported to improve the changes induced by high glucose stimulation, and it may have potential therapeutic effects on gestational diabetes mellitus (GDM). This study aims to explore the effect of AS on the cell model of GDM and the action mechanism of the PI3K/AKT pathway., Methods: The GDM model was established in HTR-8/Svneo cells with a high glucose (HG) medium. After the cytotoxicity assay of AS, cells were divided into the control group, HG group and HG + AS group to conduct control experiment in cells. The cell proliferation and migration were detected by CCK-8 assay and scratch test, respectively. The mRNA levels of PI3K, AKT2, mTORC1, and GLUT4 in PI3K/AKT signalling pathway were measured by RT-PCR, and the protein expressions of these signalling molecules were monitored by western blot., Results: AS showed a promotion effect on the cell proliferation rate of HTR-8/Svneo cells, and 80 μmol/L AS with a treatment time of 48 h had no cytotoxicity. The cell proliferation rate, migration rate, mRNA levels and protein expressions of PI3K, AKT2, mTORC1, and GLUT4 in the HG group were significantly lower than those in the control group, which were significantly increased in the HG + AS group ( p  < 0.05)., Conclusions: AS can facilitate the cell proliferation and migration in the cell model of GDM, and might play a role in GDM treatment via PI3K/AKT pathway.

Diagnosing a pregnant woman's glucose intolerance is referred to as gestational diabetes mellitus (GDM). Diabetes has been linked to enhanced oxidative stress. In this condition, oxidative stress may damage nucleic acids, fats, and proteins, which in turn affects cell and tissue functions. The present study highlights the relationship between oxidative stress and GDM, with a particular focus on the role of hyperglycemia-induced processes during reactive oxygen species (ROS) oversupply, followed by it discusses the oxidative stress biomarkers and assesses the effects of antioxidant supplements on glycemic control, inflammatory processes, and oxidative stress among individuals with GDM. Two reviewers conducted a comprehensive literature search utilizing the PubMed®, Web of Science™, and Scopus® databases. Only items published in the English language up until June 2024 were taken into account. We conducted a thorough search of research databases to identify articles that had the terms "oxidative stress" or "antioxidant" and "GDM". From this search, we selected 55 relevant papers to be included in this narrative review. Pregnancy-induced hypertension, postpartum bleeding, lower birth weight, a higher risk of hyperbilirubinemia in their neonates, fetal growth retardation, and birth asphyxia were revealed to be outcomes of women enduring major oxidative stress during pregnancy. Furthermore, tight glycemic control both before and throughout pregnancy as well as oxidative stress treatment may help women highly prone to GDM., Competing Interests: Compliance with Ethical Standards Conflict of Interest The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Neuregulin 4 (Nrg4) is a brown adipose tissue-derived adipokine that greatly affects systemic metabolism and improves metabolic derangements. Although abnormal circulating levels of Nrg4 are common in obesity, it remains elusive whether low or elevated levels of this batokine are associated with the onset of metabolic diseases., Aim: To assess Nrg4 levels and its role as a feasible biomarker to predict the severity of obesity, gestational diabetes mellitus (GDM), type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases (CVD)., Methods: A search for relevant studies was performed systematically using prominent search engines, including PubMed, Google Scholar, and Embase, by following PRISMA guidelines., Results: Ample clinical evidence reported low serum/plasma levels of Nrg4 in obesity and these were inversely proportional to the indices of metabolic syndrome, including body mass index, waist circumference, triglycerides, fasting plasma glucose, and homoeostatic model assessment for insulin resistance as well as high-sensitivity C-reactive protein. Low circulating Nrg4 levels may aid in the prediction of morbid obesity, and subsequent GDM, T2DM, NAFLD, and CVD., Conclusion: Current clinical evidence emphasizes that the circulating levels of Nrg4 are decreased in morbid obesity, and it also highlights that Nrg4 May serve as a potential prognostic biomarker for obesity-related metabolic diseases.

This research aimed to obtain gestational diabetes mellitus (GDM) related hub genes, providing new targets for clinical diagnosis and treatment of GDM. The microarray data of GSE9984 and GSE103552 were obtained from the Gene Expression Omnibus (GEO). The dataset GSE9984 contained placental gene expression profiles of 8 GDM patients and four healthy specimens. The dataset GSE103552 contained 20 specimens from GDM patients and 17 normal specimens. The differentially expressed genes (DEGs) were identified by GEO2R online analysis. DAVID database was applied to conduct functional enrichment analysis of the DEGs. The Search Tool for the Retrieval of Interacting Genes (STRING) database was adopted to acquire protein-protein interaction (PPI) networks. A total of 195 up-regulated and 371 down-regulated DEGs were selected in the GSE9984, and total of 191 up-regulated and 229 down-regulated DEGs were selected in the GSE103552. In the two datasets, 24 common differential genes were obtained and named co-DEGs. The Gene Ontology (GO) annotation analysis indicated the DEGs participated in multi-multicellular organism process, endocrine hormone secretion, long-chain fatty acid biosynthetic process, cell division, unsaturated fatty acid biosynthetic process, cell adhesion and cell recognition. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that GSE9984 and GSE103552 were related to vitamin digestion and absorption, tryptophan metabolism, steroid hormone biosynthesis, Ras signaling pathway, protein digestion and absorption, PPAR signaling pathway, PI3K-Akt signaling pathway, p53 signaling pathway. PPI was constructed in string database, and six hub genes were selected, including CCNB1, APOA2, AHSG and IGFBP1. Four critical genes were identified to be considered as therapeutic potential biomarkers of GDM, including CCNB1, APOA2, AHSG and IGFBP1.

Objective: Gestational diabetes mellitus (GDM) is a metabolic disorder that occurs in 3-5% of pregnancies. The inflammatory response is essential to the development of GDM. Resistant dextrin is a natural fiber and exhibits an antidiabetic effect against diabetes. We investigate resistant dextrin's preventive role and underlying mechanism against STZ-induced GDM., Material and Method: Female Wistar rats were utilized, and GDM was induced in pregnant rats using STZ. The levels of glycated hemoglobin (HbA1c), resistin, serum-c-peptide, free fatty acid, antioxidant, hepatic glycogen, lipid, inflammatory cytokines, apoptosis, and inflammatory parameters were estimated. mRNA expression of Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor kappa B (NF-κB) and NOD-like receptor protein 3 (NLRP3) was estimated. We also estimated the histopathology of pancreatic and liver tissue., Result: Body weight, plasma insulin, fetal body weight, and blood glucose levels were all considerably (P < .001) improved by resistant dextrin, while placental weight and blood sugar levels were also decreased. Resistant dextrin significantly (P < .001) suppressed the levels of HbA1c, resistin, serum-c-peptide, and hepatic glycogen and improved the free fatty acid (FFA) level. Resistant dextrin significantly (P < .001) altered the level of adiponectin, leptin, intercellular Adhesion Molecule 1 (ICAM-1), and visfatin; antioxidant parameters such as malonaldehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), glutathione S-transferase GST, inflammatory cytokines like tumor necrosis factor- α (TNF-α), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-2 (IL-2), interferon- γ (INF-γ), interleukin-10 (IL-10); apoptosis parameters include Bcl-2, caspase-3, and Bax, respectively. Resistant dextrin significantly (P < .001) suppressed the mRNA expression of NF-κB, MyD88, NLRP3, and TLR4. Resistant dextrin altered the histopathological changes in the pancreas and hepatic tissue., Discussion and Conclusion: In short, resistant dextrin demonstrated a protective effect against STZ-induced GDM by modulating the TLR4/MyD88/NF-κB signaling pathway.

Gestational diabetes mellitus is a common medical complication during pregnancy. It creates a hyperglycemic environment and impacts offspring development, increasing the risk of long-term complications, including obesity, impaired glucose metabolism and cardiovascular disease. The impact of gestational diabetes on the prostates of adult offspring has already been described; however, it is not known whether these effects are due only to the maternal condition or whether the offspring develop them throughout life. This investigation evaluated the prostates of neonatal and juvenile offspring of hyperglycemic rats due to diabetes. Diabetes was induced with streptozotocin (50 mg/kg, ip) in pregnant Wistar rats and the prostates of 7- or 30-day-old pups from healthy (PC7, PC30) or diabetic (PD7, PD30) mothers were evaluated. We found reduced body weight in pups of PD7 and PD30 and prostate weight in PD30. Prostate branching was not affected, but a reduction in apoptotic levels was associated with impaired acinar bud canalization in neonates. Additionally, PD7 presented reduced ERK1/2 phosphorylation, cell proliferation and collagen, but fibroblasts were increased. In PD30, there was a reduction in the area of the secretory epithelium and stroma, but the luminal area was increased. Moreover, fibroblasts, smooth muscle cells, collagen and metalloproteinase 2 were decreased in these juvenile pups. These data indicate that maternal hyperglycemia inactivates an important cell proliferation signaling pathway in the prostate in the first postnatal days (which is restored in the juvenile period), but it was not sufficient to avoid epithelial and stromal atrophy. This effect on postnatal gland development may impact the reproductive capacity of the prostate in adult life., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest that could be understood as harmful to the impartiality of the research described in this article., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Introduction: Gestational diabetes mellitus (GDM) presents significant risks during pregnancy, including adverse perinatal outcomes and placental dysfunction. Impaired angiogenesis, involving crucial factors like Vascular Endothelial Growth Factor (VEGF), contributes to these complications. The Nrf2/Keap1 pathway, crucial for vascular redox homeostasis, has been linked to GDM-associated angiogenesis dysregulation., Methods: This study aimed to investigate the molecular mechanisms underlying placental Nrf2 regulation, focusing on angiomiRs, key regulators of angiogenesis in GDM. Computational analysis identified miR-142-5p targeting Nrf2 mRNA. Expression levels of miR-142-5p were assessed in GDM placenta and correlated with Nrf2 expression. Experimental validation utilized human trophoblastic cell lines (BeWo) exposed to hyperglycemic conditions, assessing the effects of anti-miR-142 transfection on Nrf2 expression and angiogenic marker levels., Results: miR-142-5p expression was significantly downregulated in GDM placenta, correlating positively with Nrf2 expression. In BeWo cells exposed to hyperglycemia, anti-miR-142 transfection notably increased Nrf2 expression alongside angiogenic marker levels, confirming the computational predictions., Discussion: Our findings highlight the pivotal role of miRNAs in GDM-associated impaired angiogenesis by modulating Nrf2 expression. Understanding these molecular mechanisms provides insights into potential therapeutic targets for improving pregnancy outcomes in GDM cases., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests Ramkumar KM reports was provided by SRM Institute of Science and Technology., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Gestational diabetes mellitus (GDM) is a common complication during pregnancy. The hyperglycemic stimulation of gestational diabetes inhibits the invasion of the placental trophoblast cells. Some studies have indicated that the senescence of trophoblast cells weakens their invasive capacity, while the mechanism of trophoblast cells senescence in GDM remain elusive., Methods: We performed western blotting and Immunohistochemical staining to investigate AT-Rich Interaction Domain 1A (ARID1A) expression in GDM placental tissues. 5 mM and 30 mM glucose treated HTR-8/SVneo cells to simulate normal glucose (NG) stress and high glucose (HG) stress. Cell proliferation capacity was investigated by CCK8 assay and cell cycle assay. SA-β-gal was used to detect cellular senescence. Chip-seq characterized the binding site of ARID1A to CDKN1A. In conjunction with bioinformatics analysis, co-immunoprecipitation assays, Chip-qPCR and luciferase reporter assays were performed to prove ARID1A recruits GATA2 to CDKN1A., Results: We found that ARID1A has a higher expression levels in GDM placental tissues compared to the control. ARID1A overexpression suppressed cell proliferation, induced cell cycle arrest and promoted cell senescence. Conversely the inhibition of ARID1A significantly rescues HG induced senescence of trophoblast cells. To further characterize the mechanism by which ARID1A regulate the transcription of CDKN1A, co-immunoprecipitation assays, Chip-qPCR and luciferase reporter assay indicate that ARID1A recruits GATA2 to regulate the transcriptional activity of CDKN1A., Discussion: Our study uncovers a ARID1A mediated regulatory mechanism in GDM trophoblast cell senescence and suggests that targeting the placental ARID1A might provide new diagnostic and therapeutic strategies for GDM., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Gestational diabetes mellitus is an endocrine and metabolic disorder that appears for the first time during pregnancy and causes varying degrees of short- and/or long-term effects on the mother and child. The etiology of the disease is currently unknown and isobaric tags for relative and absolute quantitation proteomics approach, the present study attempted to identify potential proteins in placental tissues that may be involved in the pathogenesis of GDM and adverse foetal pregnancy outcomes., Methods: Pregnant women with GDM hospitalised were selected as the experimental group, and pregnant women with normal glucose metabolism as the control group. The iTRAQ protein quantification technology was used to screen the differentially expressed proteins between the GDM group and the normal control group, and the differentially expressed proteins were analysed by GO, KEGG, PPI, etc., and the key proteins were subsequently verified by western blot., Results: Based on the proteomics of iTRAQ, we experimented with three different samples of placental tissues from GDM and normal pregnant women, and the total number of identified proteins were 5906, 5959, and 6017, respectively, which were similar in the three different samples, indicating that the results were reliable. Through the Wayne diagram, we found that the total number of proteins coexisting in the three groups was 4475, and 91 differential proteins that could meet the quantification criteria were strictly screened, of which 32 proteins were up-regulated and 59 proteins were down-regulated. By GO enrichment analysis, these differential proteins are widely distributed in extracellular membrane-bounded organelle, mainly in extracellular exosome, followed by intracellular vesicle, extracellular organelle. It not only undertakes protein binding, protein complex binding, macromolecular complex binding, but also involves molecular biological functions such as neutrophil degranulation, multicellular organismal process, developmental process, cellular component organization, secretion, regulated exocytosis. Through the analysis of the KEGG signaling pathway, it is found that these differential proteins are mainly involved in HIF-1 signaling pathway, Glycolysis/Gluconeogenesis, Central carbon metabolism in cancer, AMPK signaling pathway, Proteoglycans in cancer, Protein processing in endoplasmic reticulum, Thyroid cancer, Alcoholism, Glucagon signaling pathway., Discussion: This preliminary study helps us to understand the changes in the placental proteome of GDM patients, and provides new insights into the pathophysiology of GDM., Competing Interests: Declarations. Conflict of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ethical approval: This study was approved by the ethics committee of the Affiliated Hospital of Guizhou Medical University (Document ID: 2019 Ethical Review No. 221) and was implemented in accordance with the Declaration of Helsinki. Written informed consent was obtained from all Patients to participate in the study., (© 2024. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Incidences of childhood obesity and type 2 diabetes (T2D) are climbing at alarming rates. Evidence points to prenatal exposures to maternal obesity and gestational diabetes mellitus (GDM) as key contributors to these upward trends. Children born to mothers with these conditions face higher risks of obesity and T2D, beyond genetic or shared environmental factors. The underpinnings of this maternal-fetal programming are complex. However, animal studies have shown that such prenatal exposures can lead to changes in brain pathways, particularly in the hypothalamus, leading to obesity and T2D later in life. This article highlights significant findings stemming from research funded by my American Diabetes Association Pathway Accelerator Award and is part of a series of Perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program. This critical support, received more than a decade ago, paved the way for groundbreaking discoveries, translating the neural programming findings from animal models into human studies and exploring new avenues in maternal-fetal programming. Our BrainChild cohort includes >225 children, one-half of whom were exposed in utero to maternal GDM and one-half born to mothers without GDM. Detailed studies in this cohort, including neuroimaging and metabolic profiling, reveal that early fetal exposure to maternal GDM is linked to alterations in brain regions, including the hypothalamus. These neural changes correlate with increased energy intake and predict greater increases in BMI, indicating that early neural changes may underlie and predict later obesity and T2D, as observed in animal models. Ongoing longitudinal studies in this cohort will provide critical insights toward breaking the vicious cycle of maternal-child obesity and T2D., (© 2024 by the American Diabetes Association.)

Introduction: The efficacy of myo-inositol supplementation to treat gestational diabetes remains controversial, and this meta-analysis aims to study the efficacy of myo-inositol supplementation on metabolic status for gestational diabetes., Methods: Several databases including PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systemically searched from inception to October 2021, and we included the randomized controlled trials (RCTs) assessing the effect of myo-inositol supplementation on the outcomes of women with gestational diabetes. Gestational diabetes was diagnosed if at least one threshold of glucose concentration was exceeded and the three thresholds included 92, 180, and 153 mg/dl for 0, 1 and 2 h, respectively, after a 75-g, 2-h glucose tolerance test., Results: Four RCTs and 317 patients were included in this meta-analysis. Compared with routine treatment in pregnant women with gestational diabetes, myo-inositol supplementation could lead to remarkably decreased treatment requirement with insulin (odd ratio [OR] = 0.24; 95% confidence interval [CI] = 0.11-0.52; p  = .0003) and homeostasis model assessment of insulin resistance (HOMA-IR, standard mean difference [SMD]= -1.18; 95% CI= -1.50 to -0.87; p  < .00001), but demonstrated no obvious impact on birth weight (SMD= -0.11; 95% CI= -0.83 to 0.61 g; p  = .76), cesarean section (OR = 0.82; 95% CI = 0.46-1.47; p  = .51) or the need of NICU (OR = 0.88; 95% CI = 0.03-26.57; p  = .94)., Conclusions: Myo-inositol supplementation is effective to decrease the need of insulin treatment and HOMA-IR for gestational diabetes.