Search

This study aimed to explore associations of serum cluster of differentiation 44 (CD44) levels and its genetic variants in early pregnancy with gestational diabetes mellitus (GDM). We conducted a 1:1 case-control study (n = 414) nested in a prospective cohort of 22,302 pregnant women recruited from 2010 to 2012 in Tianjin, China. Blood samples were collected at the first antenatal care visit (at a median of 10 th gestational week). Binary conditional logistic regressions were performed to examine associations of serum CD44 levels and its genetic variants with increased risk of GDM. In this study, we found that serum CD44 levels in early pregnancy was associated with GDM risk in a U-shaped manner. High serum CD44 levels and its genetic risk score in early pregnancy were associated with markedly increased risk of GDM after adjustment for traditional confounders (OR: 1.95, 95%CI: 1.12-3.40 & 1.95, 1.05-3.61). Furthermore, after adjustment for serum CD44 levels, the OR of CD44 genetic risk score for GDM was slightly attenuated but not significant (1.84, 0.98-3.48). In conclusion, serum CD44 levels and its genetic variants in early pregnancy were associated with GDM risk in Chinese pregnant women, with the effect of CD44 genetic variants being accounted for by serum CD44. SIGNIFICANCE: Recent studies suggested that pregnant women with GDM may have abnormal levels of CD44 and abnormal expression of CD44 gene, but it is uncertain whether abnormal CD44 plays a causal role in occurrence of GDM. Specifically, it remains unknown whether serum CD44 levels in early pregnancy and its genetic variants can predict the later occurrence of GDM. In this study, we found that high serum CD44 levels in early pregnancy and its genetic variants were associated with markedly increased risk of GDM in Chinese pregnant women, with the effect of CD44 genetic variants being largely accounted for by serum CD44 levels. Our study is the first reporting that serum CD44 levels and its genetic variants were associated with markedly increased risk of GDM. These multi-omics risk markers may be useful for identification of women at high risk of GDM in early pregnancy. Our findings also provide new insights into the disease mechanisms., Competing Interests: Declaration of competing interest The authors declared no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Observational studies have revealed associations between maternal lipid metabolites and gestational diabetes mellitus (GDM). However, whether these associations are causal remain uncertain., Objective: To evaluate the causal relationship between lipid metabolites and GDM., Methods: A two-sample Mendelian randomization (MR) analysis was performed based on summary statistics. Sensitivity analyses, validation analyses and reverse MR analyses were conducted to assess the robustness of the MR results. Additionally, a phenome-wide MR (Phe-MR) analysis was performed to evaluate potential side effects of the targeted lipid metabolites., Results: A total of 295 lipid metabolites were included in this study, 29 of them had three or more instrumental variables (IVs) suitable for sensitivity analyses. The ratio of triglycerides to phosphoglycerides (TG_by_PG) was identified as a potential causal biomarker for GDM (inverse variance weighted (IVW) estimate: odds ratio (OR) = 2.147, 95% confidential interval (95% CI) 1.415-3.257, P = 3.26e-4), which was confirmed by validation and reverse MR results. Two other lipid metabolites, palmitoyl sphingomyelin (d18:1/16:0) (PSM(d18:1/16:0)) (IVW estimate: OR = 0.747, 95% CI 0.583-0.956, P = 0.021) and triglycerides in very small very low-density lipoprotein (XS_VLDL_TG) (IVW estimate: OR = 2.948, 95% CI 1.197-5.215, P = 0.015), were identified as suggestive potential biomarkers for GDM using a conventional cut-off P-value of 0.05. Phe-MR results indicated that lowering TG_by_PG had detrimental effects on two diseases but advantageous effects on the other 13 diseases., Conclusion: Genetically predicted elevated TG_by_PG are causally associated with an increased risk of GDM. Side-effect profiles indicate that TG_by_PG might be a target for GDM prevention, though caution is advised due to potential adverse effects on other conditions., (© 2024. The Author(s).)

Background: Gestational diabetes mellitus (GDM) has a strong genetic predisposition. Integrating metabolomics with Mendelian randomisation (MR) analysis offers a potent method to uncover the metabolic factors causally linked to GDM pathogenesis., Objectives: This study aims to identify specific metabolites and metabolic pathways causally associated with GDM susceptibility through a comprehensive MR analysis. Additionally, it seeks to explore the potential of these identified metabolites as circulating biomarkers for early GDM detection and risk assessment. Furthermore, it aims to evaluate the implicated metabolic pathways as potential therapeutic targets for preventive or interventional strategies against GDM., Methods: A two-sample MR study was conducted using summary statistics from a metabolite genome-wide association study (GWAS) of 8299 individuals and a GDM GWAS comprising 13,039 cases and 197,831 controls. Rigorous criteria were applied to select robust genetic instruments for 850 metabolites., Results: MR analysis revealed 47 metabolites exhibiting putative causal associations with GDM risk. Among these, five metabolites demonstrated statistically significant associations after multiple-testing correction: Beta-citrylglutamate, Isobutyrylcarnitine (c4), 1,2-dilinoleoyl-GPC (18:2/18:2), Alliin and Cis-3,4-methyleneheptanoylcarnitine. Importantly, all these metabolites exhibited protective effects against GDM development. Additionally, metabolic pathway enrichment analysis implicated the methionine metabolism and spermidine and spermine biosynthesis pathways in the pathogenesis of GDM., Conclusion: This comprehensive MR study has robustly identified specific metabolites and metabolic pathways with causal links to GDM susceptibility. These findings provide novel insights into the metabolic underpinnings of GDM aetiology and offer promising translational implications. The identified metabolites could serve as potential circulating biomarkers for early detection and risk stratification, while the implicated metabolic pathways may represent therapeutic targets for preventive or interventional strategies against GDM., (© 2024 John Wiley & Sons Ltd.)

Objective: Women with a history of gestational diabetes mellitus (GDM) are at increased risk of developing type 2 diabetes (T2D). It remains unclear whether genetic information improves prediction of incident T2D in these women., Research Design and Methods: Using five independent cohorts representing four different ancestries (n = 1,895), we investigated whether a genome-wide T2D polygenic risk score (PRS) is associated with increased risk of incident T2D. We also calculated the area under the receiver operating characteristics curve (AUROC) and continuous net reclassification improvement (NRI) following the incorporation of T2D PRS into clinical risk models to assess the diagnostic utility., Results: Among 1,895 women with previous history of GDM, 363 (19.2%) developed T2D in a range of 2 to 30 years. T2D PRS was higher in those who developed T2D (-0.08 vs. 0.31, P = 2.3 × 10-11) and was associated with an increased risk of incident T2D (odds ratio 1.52 per 1-SD increase, 95% CI 1.05-2.21, P = 0.03). In a model that includes age, family history of diabetes, systolic blood pressure, and BMI, the incorporation of PRS led to an increase in AUROC for T2D from 0.71 to 0.74 and an intermediate improvement of NRI (0.32, 95% CI 0.15-0.49, P = 3.0 × 10-4). Although there was variation, a similar trend was observed across study cohorts., Conclusions: In cohorts of GDM women with diverse ancestry, T2D PRS was significantly associated with future development of T2D. A significant but small improvement was observed in AUROC when T2D PRS was integrated into clinical risk models to predict incident T2D., (© 2024 by the American Diabetes Association.)

Gestational Diabetes Mellitus (GDM) presents a significant health concern globally, necessitating a comprehensive understanding of its metabolic intricacies for effective management. MicroRNAs (miRNAs) have emerged as pivotal regulators in GDM pathogenesis, influencing glucose metabolism, insulin signaling, and lipid homeostasis during pregnancy. Dysregulated miRNA expression, both upregulated and downregulated, contributes to GDM-associated metabolic abnormalities. Ethnic and temporal variations in miRNA expression underscore the multifaceted nature of GDM susceptibility. This review examines the dysregulation of miRNAs in GDM and their regulatory functions in metabolic disorders. We discuss the involvement of specific miRNAs in modulating key pathways implicated in GDM pathogenesis, such as glucose metabolism, insulin signaling, and lipid homeostasis. Furthermore, we explore the potential diagnostic and therapeutic implications of miRNAs in GDM management, highlighting the promise of miRNA-based interventions for mitigating the adverse consequences of GDM on maternal and offspring health., 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 B.V. All rights reserved.)

Gestational diabetes mellitus (GDM) represents a prevalent complication during pregnancy, exerting both short-term and long-term impacts on maternal and offspring health. This review offers a comprehensive outline of DNA methylation modifications observed in various maternal and offspring tissues affected by GDM, emphasizing the intricate interplay between DNA methylation dynamics, gene expression, and the pathogenesis of GDM. Furthermore, it explores the influence of environmental pollutants, maternal nutritional supplementation, and prenatal gut microbiota on GDM development through alterations in DNA methylation profiles. Additionally, this review summarizes recent advancements in DNA methylation-based diagnostics and predictive models in early GDM detection and risk assessment for subsequent type 2 diabetes. These insights contribute significantly to our understanding of the epigenetic mechanisms underlying GDM development, thereby enhancing maternal and fetal health outcomes and advocating further efforts in this field.

Pregestational diabetes mellitus (PGDM) has an impact on fetal bone formation, but the underlying mechanism is still obscure. Although miRNAs have been extensively investigated throughout bone formation, their effects on fetal bone development caused by PGDM still need clarification. This study intends to examine the mechanism by which hyperglycemia impairs the bone formation of offspring via miR-322-5p (miR-322). In this study, miR-322 was selected by systemically screening utilizing bioinformatics and subsequent validation experiments. Using streptozotocin (STZ)-induced diabetic mice and ATDC5 cell lines, we found that miR-322 was abundantly expressed in the proliferative and hypertrophic zones of the growth plate, and its expression pattern was disturbed in the presence of hyperglycemia, suggesting that miR-322 is involved in the chondrocyte proliferation and differentiation in absence/presence of hyperglycemia. This observation was proved by manipulating miR-322 expression in ATDC5 cells by transfecting mimic and inhibitor of miR-322. Furthermore, Adamts5, Col12a1, and Cbx6 were identified as the potential target genes of miR-322, verified by the co-transfection of miR-322 inhibitor and the siRNAs, respectively. The evaluation criteria are the chondrocyte proliferation and differentiation and their relevant key gene expressions (proliferation: Sox9 and PthIh; differentiation: Runx2 and Col10a1) after manipulating the gene expressions in ATDC5 cells. This study revealed the regulative role miR-322 on chondrocyte proliferation and differentiation of growth plate by targeting Adamts5, Col12a1, and Cbx6 in hyperglycemia during pregnancy. This translational potential represents a promising avenue for advancing our understanding of bone-related complications in diabetic pregnancy and mitigating bone deficiencies in diabetic pregnant individuals, improving maternal and fetal outcomes., (© 2024. The Author(s).)

Objective: Our aim was to explore the relationship between serum uric acid (UA) levels in early pregnancy and the development of gestational diabetes mellitus (GDM), and to further explore whether there is a causal relationship., Methods: 684 pregnant women with GDM and 1162 pregnant women without GDM participated in this study. 311 pregnant women with GDM and 311 matched controls were enrolled in a 1:1 case-control study. We used conditional logistic regression to explore the relationship between UA levels and the risk of developing GDM. The causal relationship between the two was examined by two-sample Mendelian randomization (MR) analysis., Results: In the 1:1 matched population, the odds ratio (OR) of developing GDM compared with the extreme tertiles of UA levels was 1.967 (95% confidence interval [CI]: 1.475-2.625; P < 0.001). Restricted cubic spline analyses showed a linear relationship between UA and GDM when UA exceeded 222 µmol/L. GDM and UA levels maintained a statistically significant positive correlation in different stratified regression analyses (P < 0.001). However, no evidence of a causal relationship between uric acid and GDM was found by MR analyses with an OR of 1.06 (95% CI: 0.91-1.25) per unit increase in UA., Conclusion: There is a positive correlation between UA levels in early pregnancy and the subsequent risk of developing GDM. However, no genetic evidence was found to support a cause-effect relationship between UA and GDM., (© 2024. The Author(s).)

Background: Gestational diabetes mellitus (GDM) is one of the most prevalent pregnancy problems, and there is still debate over the relationship between vitamin D and GDM., Objectives: Our objective is to investigate the correlation between vitamin D and GDM by employing Mendelian randomization (MR) with summary data obtained from genome-wide association studies (GWAS)., Methods: Data on exposures and outcomes, namely vitamin D, vitamin D insufficiency, and GDM, were acquired from the IEU OpenGWAS Project. Bidirectional MR analysis was performed utilizing the inverse variance weighted (IVW) method as the principal analytical approach. The complementary approaches employed in this study encompassed weighted median, simple mode, weighted mode, and MR-Egger regression. A series of sensitivity analysis were conducted in order to assess the reliability of the obtained results., Results: The data were acquired from the IEU OpenGWAS Project. Following the application of the three assumptions of MR, 13 single nucleotide polymorphisms (SNPs) were included in the MR analysis for vitamin D levels and vitamin D deficiency on GDM, and 10 and 26 SNPs were included for GDM on vitamin D levels and deficiency, respectively. The findings from the IVW analysis revealed a significant positive correlation between vitamin D levels and GDM (OR = 1.057, 95% CI: 1.011-1.104, p = 0.015). Conversely, a negative correlation was seen between vitamin D deficiency and GDM (OR = 0.979, 95% CI: 0.959-0.999, p = 0.039). The results of the reverse MR study revealed no evidence of reverse causation between GDM and vitamin D. The findings from multiple MR approaches were in line with the direction of IVW analysis. Sensitivity analysis revealed no evidence of heterogeneity, pleiotropy, or outliers, suggesting the robustness of the results., Conclusions: There exists a causal association between vitamin D and GDM, whereby vitamin D levels serve as a risk factor for GDM.

Background: Extracellular vesicles (EVs) are membrane-enclosed structures containing lipids, proteins, and RNAs that play a crucial role in cell-to-cell communication. However, the precise mechanism through which circulating EVs disrupt hepatic glucose homeostasis in gestational diabetes mellitus (GDM) remains unclear., Results: Circulating EVs isolated from human plasma were co-cultured with mammalian liver cells to investigate the potential induction of hepatic insulin resistance by GDM-EVs using glucose output assays, Seahorse assays, metabolomics, fluxomics, qRT-PCR, bioinformatics analyses, and luciferase assays. Our findings demonstrated that hepatocytes exposed to GDM-EVs exhibited increased gluconeogenesis, attenuated energy metabolism, and upregulated oxidative stress. Particularly noteworthy was the discovery of miR-1299 as the predominant miRNA in GDM-EVs, which directly targeting the 3'-untranslated regions (UTR) of STAT3. Our experiments involving loss- and gain-of-function revealed that miR-1299 inhibits the insulin signaling pathway by regulating the STAT3/FAM3A axis, resulting in increased insulin resistance through the modulation of mitochondrial function and oxidative stress in hepatocytes. Moreover, experiments conducted in vivo on mice inoculated with GDM-EVs confirmed the development of glucose intolerance, insulin resistance, and downregulation of STAT3 and FAM3A., Conclusions: These results provide insights into the role of miR-1299 derived from circulating GDM-EVs in the progression of insulin resistance in hepatic cells via the STAT3/FAM3A axis and downstream metabolic reprogramming., (© 2024. The Author(s).)

Gestational diabetes mellitus (GDM) presents varied manifestations throughout pregnancy and poses a complex clinical challenge. High-depth cell-free DNA (cfDNA) sequencing analysis holds promise in advancing our understanding of GDM pathogenesis and prediction. In 299 women with GDM and 299 matched healthy pregnant women, distinct cfDNA fragment characteristics associated with GDM are identified throughout pregnancy. Integrating cfDNA profiles with lipidomic and single-cell transcriptomic data elucidates functional changes linked to altered lipid metabolism processes in GDM. Transcription start site (TSS) scores in 50 feature genes are used as the cfDNA signature to distinguish GDM cases from controls effectively. Notably, differential coverage of the islet acinar marker gene PRSS1 emerges as a valuable biomarker for GDM. A specialized neural network model is developed, predicting GDM occurrence and validated across two independent cohorts. This research underscores the high-depth cfDNA early prediction and characterization of GDM, offering insights into its molecular underpinnings and potential clinical applications., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Numerous studies have examined whether vitamin D is associated with gestational diabetes mellitus (GDM). Nevertheless, it is still challenging to determine the causality, due to a number of shortcomings in observational research and randomized controlled trials., Objective: Mendelian randomization (MR) with two samples was conducted to investigate the potential causative association between 25-hydroxyvitamin D (25(OH)D), vitamin D binding protein (VDBP) and GDM risk., Methods: Publicly accessible summary data from independent cohorts were used for two-sample MR. For 25(OH)D, we obtained data from UK Biobank, IEU and EBI, then performed a meta-analysis to enhance the statistical power (via METAL); for VDBP, data were obtained from the INTERVAL study; for GDM, data were obtained from FinnGen. The inverse variance weighted (IVW) approach was performed as the main analysis, together with several sensitivity analyses, such as MR-Egger, maximum likelihood, weighted median, and weighted mode., Results: The IVW results revealed a weak negative causal connection between 25(OH)D and GDM risk [OR (95% CI) = 0.71 (0.50, 0.99), p = 0.046]. However, the causal association was unstable according to sensitivity analyses, and Cochran's Q test revealed significant heterogeneity. After removing BMI-related IVs, the causal association between 25(OH)D and GDM disappeared [OR (95% CI) = 0.76 (0.55, 1.06), p = 0.101]. In addition, our study found no proof to support the assumption that VDBP level was related to GDM risk causally [OR (95% CI) = 0.98 (0.93, 1.03), p = 0.408]., Conclusions: According to this study, a weak negative causal association between 25(OH)D and GDM risk was found, while we had little proof to support the link between VDBP and GDM. To further explore whether total or free 25(OH)D levels and GDM are causally related, GWAS data with an emphasis on women of reproductive age and other ethnic groups are required.

Background: Gestational diabetes mellitus (GDM) significantly impacts maternal and infant health both immediately and over the long term, yet effective early diagnostic biomarkers are currently lacking. Thus, it is essential to identify early diagnostic biomarkers for GDM risk screening. Extrachromosomal circular DNA (eccDNA), being more stable than linear DNA and involved in disease pathologies, is a viable biomarker candidate for diverse conditions. In this study, eccDNA biomarkers identified for early diagnosis and assessment of GDM risk were explored., Methods: Using Circle-seq, we identified plasma eccDNA profiles in five pregnant women who later developed GDM and five matched healthy controls at 11-13 weeks of gestation. These profiles were subsequently analyzed through bioinformatics and validated through outward PCR combined with Sanger sequencing. Furthermore, candidate eccDNA was validated by quantitative PCR (qPCR) in a larger cohort of 70 women who developed GDM and 70 normal glucose-tolerant (NGT) subjects. A ROC curve assessed the eccDNA's diagnostic potential for GDM., Results: 2217 eccDNAs were differentially detected between future GDM patients and controls, with 1289 increased and 928 decreased in abundance. KEGG analysis linked eccDNA genes mainly to GDM-related pathways such as Rap1, MAPK, and PI3K-Akt, and Insulin resistance, among others. Validation confirmed a significant decrease in eccDNA PRDM16 circle in the plasma of 70 women who developed GDM compared to 70 NGT women, consistent with the eccDNA-seq results. PRDM16 circle showed significant diagnostic value in 11-13 weeks of gestation (AUC = 0.941, p < 0.001)., Conclusions: Our study first demonstrats that eccDNAs are aberrantly produced in women who develop GDM, including PRDM16 circle , which can predict GDM at an early stage of pregnancy, indicating its potential as a biomarker., Trial Registration: ChiCTR2300075971, http://www.chictr.org.cn . Registered 20 September 2023., (© 2024. The Author(s).)

Background: Polygenic risk scores (PRS) serve as valuable tools for connecting initial genetic discoveries with clinical applications in disease risk estimation. However, limited studies have explored the association between PRS and gestational diabetes mellitus (GDM), particularly in predicting GDM risk among Chinese populations., Aim: To evaluate the relationship between PRS and GDM and explore the predictive capability of PRS for GDM risk in a Chinese population., Methods: A prospective cohort study was conducted, which included 283 GDM and 2,258 non-GDM cases based on demographic information on pregnancies. GDM was diagnosed using the oral glucose tolerance test (OGTT) at 24-28 weeks. The strength of the association between PRS and GDM odds was assessed employing odds ratios (ORs) with 95% confidence intervals (CIs) derived from logistic regression. Receiver operating characteristic curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were employed to evaluate the improvement in prediction achieved by the new model., Results: Women who developed GDM exhibited significantly higher PRS compared to control individuals (OR = 2.01, 95% CI = 1.33-3.07). The PRS value remained positively associated with fasting plasma glucose (FPG), 1-hour post-glucose load (1-h OGTT), and 2-hour post-glucose load (2-h OGTT) (all p < 0.05). The incorporation of PRS led to a statistically significant improvement in the area under the curve (0.71, 95% CI: 0.66-0.75, p = 0.024) and improved discrimination and classification (IDI: 0.007, 95% CI: 0.003-0.012, p < 0.001; NRI: 0.258, 95% CI: 0.135-0.382, p < 0.001)., Conclusions: This study highlights the increased odds of GDM associated with higher PRS values and modest improvements in predictive capability for GDM., 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 Cheng, Meng, Li, Kong and Zhou.)

The aetiological mechanism of gestational diabetes mellitus (GDM) has still not been fully understood. The aim of this study was to explore the associations between functional genetic variants screened from a genome-wide association study (GWAS) and GDM risk among 554 GDM patients and 641 healthy controls in China. Functional analysis of single nucleotide polymorphisms (SNPs) positively associated with GDM was further performed. Univariate regression and multivariate logistic regression analyses were used to screen clinical risk factors, and a predictive nomogram model was established. After adjusting for age and prepregnancy BMI, rs9283638 was significantly associated with GDM susceptibility (P < 0.05). Moreover, an obvious interaction between rs9283638 and clinical variables was detected (P interaction  < 0.05). Functional analysis confirmed that rs9283638 can regulate not only target gene transcription factor binding, but it also regulates the mRNA levels of SAMD7 (P < 0.05). The nomogram model constructed with the factors of age, FPG, 1hPG, 2hPG, HbA1c, TG and rs9283638 revealed an area under the ROC curve of 0.920 (95% CI 0.902-0.939). Decision curve analysis (DCA) suggested that the model had greater net clinical benefit. Conclusively, genetic variants can alter women's susceptibility to GDM by affecting the transcription of target genes. The predictive nomogram model constructed based on genetic and clinical variables can effectively distinguish individuals with different GDM risk factors., (© 2024. The Author(s).)

Background: Gestational diabetes mellitus (GDM) poses significant health risks for both mothers and children, contributing to long-term complications such as type 2 diabetes and cardiovascular disease. This study explores the potential of microRNAs (miRNAs) as biomarkers for GDM by analyzing peripheral blood samples from GDM patients., Method: Ten samples, including peripheral blood from 5 GDM patients and 5 controls, were collected to perform the RNA sequencing analysis. Differentially expressed miRNAs were further validated by quantitative real-time polymerase chain reaction., Results: A total of 2287 miRNAs were identified, 229 of which showed differential expression. Validation by qRT-PCR confirmed significant up-regulation of miR-5193, miR-5003-3p, miR-3127-5p, novel-miR-96, miR-6734-5p, and miR-122-5p, while miR-10395-3p was down-regulated. Bioinformatics analyses revealed the involvement of these miRNAs in pathways associated with herpes simplex virus 1 infection., Conclusion: This study provides insights into the differential expression of miRNAs in GDM patients and their potential roles in disease pathogenesis. It suggests that the differentially expressed miRNAs could serve as potential biomarkers for GDM, shedding light on the complex molecular mechanisms involved., (© 2024. The Author(s).)

Background: Gestational diabetes mellitus (GDM) is a pregnancy-related diabetic condition that may cause serious complications. However, its pathogenesis remains unclear. Placental damage due to GDM may lead to several health issues that cannot be ignored. Thus, we aimed to identify the mechanisms underlying GDM by screening differentially expressed genes (DEGs) related to vascular endothelial cells in the GDM databases and verify the expression of these DEGs in the placentas of women afflicted by GDM. Methods: We used GDM microarray datasets integrated from the Gene Expression Omnibus (GEO) database. Functional annotation and protein-protein interaction (PPI) analyses were used to screen DEGs. Placental tissues from 20 pregnant women with GDM and 20 healthy pregnant women were collected, and differential gene expression in the placental tissues was verified via qRT-PCR, western blotting, and immunofluorescence. Results: Bioinformatics analysis revealed three significant DEGs: SNAIL2 , PAPP-A , and TGFβ1 . These genes were all predicted to be underexpressed in patients with GDM. The results of qRT-PCR, western blot, and immunofluorescence analyses indicated that SNAIL2 and PAPP-A in the placenta tissue of patients with GDM were significantly underexpressed. However, TGF β 1 in the placenta tissues of GDM was significantly overexpressed. Conclusion: SNAIL2, TGF β 1, and PAPP-A may affect the placentas of pregnant women with GDM, warranting further investigation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Yujing He et al.)

Background: Gestational diabetes mellitus (GDM) is associated with DNA methylation and lifestyle. The effects of DNA methylation on GDM, and the interaction between DNA methylation and lifestyle factors are not well elucidated. The objective of this study was to explore the association between GDM, DNA methylation and lifestyle factors., Methods: A nest case-control design was performed. Sociodemographic data, dietary intake and daily physical activity information of pregnant women were collected. Bisulfate pyrosequencing was used to detect the DNA methylation level of PPARGC1A, HLA-DQA1, and ADCY3 genes. The differences of DNA methylation levels between the GDM group and the control group were compared. The correlation between clinical characteristics, dietary, physical activity and DNA methylation level was analyzed., Results: A total of 253 pregnant women were enrolled, of which, 60 participants (GDM: 30; control: 30) were included in the final analysis. There were no significant differences in DNA methylation levels of six methylated sites between the two groups in this study (P > 0.05). Daily intake of potato and poultry were associated with DNA methylation level of the CpG 1 site of the ADCY3 gene in all participants and the control group (P < 0.05). Duration of folic acid intake before pregnancy was correlated with the methylation level of the CpG 1 site of the ADCY3 gene in all participants (r = 0.341, P = 0.04) and the control group (r = 0.431, P = 0.025). Daily oil intake was correlated with the methylation level of CpG 2 (r = 0.627, P = 0.016) and CpG 3 (r = 0.563, P = 0.036) of PPARGC1A in the GDM group., Conclusion: The association between the DNA methylation levels and GDM wasn't validated. There were associations between dietary and DNA methylation in pregnant women. A large-sample-sized and longitudinal study is warranted to further investigate the impacts of lifestyle on DNA methylation., (© 2024. The Author(s).)

Objective: To explore the causal association between coagulation function, including von Willebrand factor (vWF), a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13), activated partial thromboplastin time (aPTT), coagulation factor Ⅷ (FⅧ), coagulation factor Ⅺ (FⅪ), coagulation factor Ⅶ (FⅦ), coagulation factor Ⅹ (FⅩ), endogenous thrombin potential (ETP), plasminogen activator inhibitor-1 (PAI-1), protein C, and plasmin, and gestational diabetes mellitus (GDM) using two-sample two-way Mendelian randomization (MR), and to provide genetic evidence for the association between coagulation function and the pathogenesis of GDM., Methods: The IEU OpenGWAS database was accessed using the R package TwoSampleMR (v 0.5.6) to obtain the statistical data of the genome-wide association study (GWAS) summary of GDM. MR analysis of the causal association between 11 coagulation function and GDM was performed by the inverse-variance weighted method (IVW), the MR-Egger method, and the weighted median method (WM)., Results: In this study, the GWAS summary statistics of GDM (covering 5 687 cases and 117 892 controls) were used for MR analysis. It was found that there was a causal relationship between the predicted plasma FⅧ level and the risk for GDM (IVW: [odds ratio, OR]=0.28, 95% confidence interval [CI]: 0.10-0.75, P <0.001; WM: OR=0.30, 95% CI: 0.09-0.98, P <0.001). There was no causal relationship between other coagulation function and the risk for GDM ( P >0.05)., Conclusion: There is a significant causal relationship between the plasma FⅧ level and the risk for GDM. This finding highlights the complex interaction between coagulation function and glucose metabolism during pregnancy, but further research on this finding is warranted., Competing Interests: 利益冲突　所有作者均声明不存在利益冲突, (© 2024《四川大学学报（医学版）》编辑部 版权所有Copyright ©2024 Editorial Office of Journal of Sichuan University (Medical Sciences).)

Objective: The relationship between diabetes mellitus (DM) and autism spectrum disorder (ASD) remains controversial. This study aimed to analyze the causal relationship between different types of DM and ASD by bidirectional Mendelian randomization (MR)., Methods: Single nucleotide polymorphisms for type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM), and ASD were obtained from genome-wide association studies. Subsequently, inverse variance weighted, MR-Egger, and weighted median were used to test the exposure-outcome causality. Finally, MR-Egger's intercept, Cochran's Q, and leave-one-out method were used to assess horizontal pleiotropy, heterogeneity, and sensitivity of the results, respectively., Results: The positive analysis showed that T2DM was associated with an increased risk of ASD, whereas neither T1DM nor GDM was associated with the risk of ASD. The reverse analysis showed that ASD was associated with an increased risk of T2DM, while it was not associated with the risk of either T1DM or GDM. MR-Egger intercept showed no horizontal pleiotropy ( p > 0.05) for these results. Cochran's Q showed no heterogeneity expect for the results of T1DM on the risk of ASD, and leave-one-out sensitivity analysis showed these results were robust., Conclusion: This MR analysis suggests that T2DM and ASD are reciprocal risk factors and that they may create an intergenerational risk cycling in female patients. Aggressive prevention and treatment of T2DM and ASD help to break the trap of this risk cycling. Additionally, this study does not support a causal relationship between T1DM and ASD, as well as GDM and ASD. And more studies are needed in the future to continue to explore the interactions and underlying mechanisms between different types of DM and ASD., 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 Yu, Yang, Hu, Tong, Wu and Yu.)

Gestational diabetes mellitus (GDM) is a common condition during pregnancy and is associated with an increased risk of pre-eclampsia. The methylenetetrahydrofolate reductase (MTHFR) gene plays a crucial role in folate metabolism and has been implicated in GDM. To investigate the relationship between the MTHFR C677T gene polymorphism and the conditions of GDM and gestational prediabetes in pregnant women. A case-control study was conducted in 114 pregnant women with GDM and 96 pregnant women without GDM, from the first trimester to the prenatal examination at Can Tho Obstetrics Hospital. The pregnant women underwent a 1-hour (G1) and 2-hour (G2) oral glucose tolerance test (OGTT) and genetic polymorphism analysis based on real-time PCR technique. In pregnant women with GDM, weight, concentrations of G0, G1, G2, and folic acid were higher than those in the non-GDM group, with P < .05. When analyzing the subgroup without gestational diabetes, we found that the rate of prediabetes was 16.6% (16/96 pregnant women). In this group, blood glucose levels at 1 hour and 2 hours during the OGTT were higher compared to the normal glucose group (P < .05). A 2-hour post-OGTT glucose level of 7.78 mmol/L had a sensitivity of 93.8%, a specificity of 100%, and an area under the curve of 0.987 for diagnosing gestational prediabetes (P < .001). However, there were no statistically significant differences in the CC, CT, and TT polymorphisms of the MTHFR C677T gene among pregnant women with or without pre-gestational and GDM. Both fasting blood glucose and 2-hour glucose concentrations during the OGTT, as well as folic acid concentrations, were higher in both the pre-gestational and GDM groups compared to the non-gestational diabetes cohort. However, the analysis of MTHFR C677T polymorphisms revealed no statistically significant differences among the groups, highlighting the necessity for more extensive investigations to gain deeper insights into this relationship., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Gestational diabetes mellitus (GDM) has been found to be a common complication in pregnant women, known to escalate the risk of negative obstetric outcomes. In our study, we genotyped 1,566 Chinese pregnant women for two single nucleotide polymorphisms (SNPs) in the LINGO2 gene and one SNP in the GLIS3 gene, utilizing targeted next-generation sequencing. The impact of two interacting genes, and the interaction of genes with the environment─including exposure to particulate matter (PM 2.5 ), ozone (O 3 ), and variations in prepregnancy body mass index (BMI)─on the incidence of GDM were analyzed using logistic regression. Our findings identify the variants LINGO2 rs10968576 ( P = 0.022, OR = 1.224) and rs1412239 ( P = 0.018, OR = 1.231), as well as GLIS3 rs10814916 ( P = 0.028, OR = 1.172), as risk mutations significantly linked to increased susceptibility to GDM. Further analysis underscores the crucial role of gene-gene and gene-environment interactions in the development of GDM among Chinese women ( P < 0.05). Particularly, the individuals carrying the rs10968576 G-rs1412239 G-rs10814916 C haplotype exhibit increased susceptibility to GDM during the prepregnancy period when interacting with PM 2.5 , O 3 , and BMI ( P = 8.004 × 10 -7 , OR = 1.206; P = 6.3264 × 10 -11 , OR = 1.280; P = 9.928 × 10 -7 , OR = 1.334, respectively). In conclusion, our research emphasizes the importance of the interaction between specific gene variations─ LINGO2 and GLIS3 ─and environmental factors in influencing GDM risk. Notably, we found significant associations between these gene variations and GDM risk across various environmental exposure periods.

Milk fat globule membrane proteins (MFGMP) in human milks have positive effects on infant's health. As gestational diabetes mellitus (GDM) causes variations in MFGMP, it is essential to understand the effects of GDMon MFGMP. This study aims to investigate and compare the MFGMP (>3 months postpartum) of GDM and non-GDM (NGDM) women using four-dimensional-data-independent-acquisition proteomics technology. Principal component analysis shows significant differences in the MFGMP of GDM and NGDM women. A total of 4747 MFGMP were identified in maturehuman milk of GDM and NGDM women. Among these proteins, 174 differentially expressed proteins (DEPs) were identified in MFGM of GDM and NGDM women. Albumin (FC = 7.96) and transthyretin (FC = 2.57) which are related to insulin resistance and involved in thyroid hormone synthesis, are significantly up-regulated in MFGMP of GDM mothers indicating insulin resistance, imbalance of glucose homeostasis and poor glucose metabolism might persist in postpartum period., 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 Ltd.. All rights reserved.)

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.)

Background: Gestational diabetes mellitus (GDM) is a prevalent pregnancy complication during pregnancy. We aimed to evaluate a risk prediction model of GDM based on traditional and genetic factors., Methods: A total of 2744 eligible pregnant women were included. Face-to-face questionnaire surveys were conducted to gather general data. Serum test results were collected from the laboratory information system. Independent risk factors for GDM were identified using univariate and multivariate logistic regression analyses. A GDM risk prediction model was constructed and evaluated with the Hosmer-Lemeshow goodness-of-fit test, goodness-of-fit calibration plot, receiver operating characteristic curve and area under the curve., Results: Among traditional factors, age ≥30 years, family history, GDM history, impaired glucose tolerance history, systolic blood pressure ≥116.22 mmHg, diastolic blood pressure ≥74.52 mmHg, fasting plasma glucose ≥5.0 mmol/L, 1-hour postprandial blood glucose ≥8.8 mmol/L, 2-h postprandial blood glucose ≥7.9 mmol/L, total cholesterol ≥4.50 mmol/L, low-density lipoprotein ≥2.09 mmol/L and insulin ≥11.5 mIU/L were independent risk factors for GDM. Among genetic factors, 11 single nucleotide polymorphisms (SNPs) (rs2779116, rs5215, rs11605924, rs7072268, rs7172432, rs10811661, rs2191349, rs10830963, rs174550, rs13266634 and rs11071657) were identified as potential predictors of the risk of postpartum DM among women with GDM history, collectively accounting for 3.6% of the genetic risk., Conclusions: Both genetic and traditional factors contribute to the risk of GDM in women, operating through diverse mechanisms. Strengthening the risk prediction of SNPs for postpartum DM among women with GDM history is crucial for maternal and child health protection.

Gestational Diabetes Mellitus (GDM) is a medical complication during the gestational period in which woman who had never been diagnosed with diabetes develops hyperglycemia. Prior studies have demonstrated that the advancement of GDM and its consequences arises from a disparity between oxidants and antioxidants in the cells. The observed outcomes can be attributed to an excessive formation of reactive oxygen species (ROS) within the cells, coupled with a reduced activity of anti-oxidative enzymes. Glutathione S-transferase (GSTs) is recognized as an antioxidant enzyme that is belong to as a phase II family member of detoxifying enzymes. These metabolic multigene catalysts are found into the cytoplasm of the cell. GSTs play a vital part in the elimination of cellular ROS or free radicals. The study involves total 300 pregnant women, (150 GDM cases and 150 healthy controls). The polymorphism study of GSTs genes (GSTM1 and GSTT1) was determined by conventional Polymerase Chain Reaction (PCR). The mRNA expression study of GSTM1 and GSTT1 genes analysed by qPCR/ RT-PCR (quantitative PCR/Real-Time PCR) followed by statistical analysis done using Prism8 software (version 8.01). The study revealed statistically significant variations in biochemical parameters between GDM cases and controls. It was found GSTM1-null (GSTM1-/-) polymorphism significantly (P < 0.0001) most prevalent in GDM cases (56.7%) when compared to healthy control (28%). However, no significant difference was observed for GSTT1 null and present polymorphism (P = 0.906). The gene expression levels of both GSTM1 and GSTT1 were found considerably downregulated in individuals with GDM as compared to the control group (P < 0.0001). The downregulation of gene expression has a significant (P<0.0001) association with the null/deletion polymorphism of both GSTM1/ GSTT1 genes respectively. Null/deletion genotype of GSTM1 gene and its expression showed significant association with GDM. Therefore, this gene variant has the potential to be used as a prognostic biomarker for GDM. However, there is need to study this gene variant in larger sample size and different ethnicity., 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 B.V. All rights reserved.)

The current study sought to investigate the associations of common genetic risk variants with gestational diabetes mellitus (GDM) risk in the north Indian population and to evaluate their utility in identifying GDM cases. A case-control study, including 300 pregnant women, was included, and clinical and pathological information was collected. The amplification-refractory mutation system (ARMS) was used for genotyping four single nucleotide polymorphisms (SNPs), namely FTO (rs9939609), PPARG2 (rs1801282), SLC30A8 (rs13266634), and TCF7L2 (rs12255372). The odds ratio and confidence interval were determined for each SNP in different genetic models. Further, attributable risk, population penetrance, and relative risk were also calculated. The risk allele A of FTO (rs9939609) poses a two times higher risk of GDM (p = 0.02, OR = 2.5). The CG and GG genotypes of PPARG2 (rs1801282) have half a lower risk of GDM. In SLC30A8 (rs13266634), the recessive model analysis showed a two times higher risk of having GDM, while the recessive model (TT vs. GG + GT) analysis in TCF7L2 (rs12255372) indicates a lower risk of GDM. Finally, the relative risk, population penetrance, and attributable risk for risk allele in all four variants was higher in GDM mothers. All four polymorphisms were found to be significantly associated with BMI, HbA1c, and insulin. Our study first time confirmed a significant association with GDM for four variants, FTO, PPARG2, SLC30A8, and TCF7L2, in the North Indian population., 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 B.V. All rights reserved.)

Background: Gestational Diabetes Mellitus (GDM) poses significant risks to maternal and fetal health, yet its precise etiology remains unclear. Observational studies have demonstrated a link between specific inflammatory cytokines and the occurrence of GDM, but the causal relationships remain uncertain., Methods: Utilizing publicly accessible genetic data, we performed a bidirectional two-sample mendelian randomization (MR) analysis to elucidate the causal association between 91 inflammatory cytokines and GDM. Sensitivity analysis was carried out to evaluate the robustness, heterogeneity, and potential presence of horizontal pleiotropy within the results., Results: Elevated levels of Interleukin-7 (IL7) and Neurturin (NRTN) (OR=1.104, 95 % CI=1.003-1.216, p = 0.042; OR=1.102, 95 % CI=1.023-1.187, p = 0.010), along with decreased levels of Glial cell line-derived neurotrophic factor (GDNF), Interleukin-12 subunit beta (IL12β), and Interleukin-20 (IL20) (OR=0.911, 95 % CI=0.849-0.979, p = 0.010;OR=0.955, 95 % CI=0.916-0.996, p = 0.033; OR=0.892, 95 % CI=0.819-0.971, p = 0.008), are associated with increased GDM risk. Additionally, GDM occurrence correlates with increased Matrix metalloproteinase-10 (MMP-10) and decreased Interleukin-20 receptor subunit alpha (IL-20Rα) levels (OR=1.042, 95 % CI=1.002-1.084, p = 0.038; OR=0.949, 95 % CI=0.909-0.992, p = 0.021). Sensitivity analyses detected no significant heterogeneity or pleiotropy., Conclusion: This study has clarified the causal link between inflammatory cytokines and GDM, thereby enhancing our comprehension of the potential mechanisms involved in GDM pathogenesis. These findings offer new insights into the etiology, diagnosis, and therapeutic strategies for 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 B.V. All rights reserved.)

Background: Several studies have identified associations between some of circulating inflammatory cytokines and gestational diabetes mellitus (GDM). However, the causal role of these associations remains unclear and unsystematic. We aimed to provide evidence for the causal relationships between circulating inflammatory cytokines and gestational diabetes mellitus., Methods: We performed bidirectional two-sample Mendelian randomization (2SMR) to investigate the causal connection between circulating inflammatory cytokines and gestational diabetes mellitus. Publicly accessible data for circulating inflammatory cytokines (8,293 individuals) and gestational diabetes mellitus (123,579 individuals) were obtained from genome-wide association study (GWAS)., Results: Only one causal association was identified between circulating inflammatory cytokines and GDM. The inverse variance weighting (IVW) method showed that macrophage migration inhibitory factor (MIF) increased the risk of GDM (OR 1.162, 95%CI 1.044,1.293). Moreover, two causal associations were detected between GDM and circulating inflammatory cytokines. GDM was negatively correlated with interferon gamma-induced protein 10 (IP10) (Beta -0.129, 95%CI -0.236,-0.231) and interleukin-18 (IL18) (Beta -0.133, 95%CI -0.241,-0.026)., Conclusion: Mendelian randomization study revealed MIF as a risk factor for gestational diabetes mellitus. This finding offers a new and valuable insight into the pathophysiological mechanisms underlying 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 Ltd. All rights reserved.)

Background: This study aimed to assess whether the Haptoglobin (Hp) genotype influences the relationship between hemoglobin (Hb) levels and the development of gestational diabetes mellitus (GDM). Additionally, it sought to evaluate the interaction and joint association of Hb levels and Hp genotype with GDM risk., Methods: This retrospective study involved 358 women with GDM and 1324 women with normal glucose tolerance (NGT). Peripheral blood leukocytes were collected from 360 individuals at 14-16 weeks' gestation for Hp genotyping. GDM was diagnosed between 24-28 weeks' gestation. Interactive moderating effect, joint analysis, and mediation analysis were performed to evaluate the crosslink of Hb levels and Hp genotype with GDM risk., Results: Women who developed GDM had significantly higher Hb levels throughout pregnancy compared to those with NGT. Increase first-trimester Hb concentration was associated with a progressive rise in GDM incidence, glucose levels, glycosylated hemoglobin levels, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) values, cesarean delivery rates, and composite neonatal outcomes. Spline regression showed a significant linear association of GDM incidence with continuous first-trimester Hb level when the latter exceeded 122 g/L. Increased first-trimester Hb concentration was an independent risk factor for GDM development after adjusting for potential confounding factors in both the overall population and a matched case-control group. The Hp2-2 genotype was more prevalent among pregnant women with GDM when first-trimester Hb exceeded 122 g/L. Significant multiplicative and additive interactions were identified between Hb levels and Hp genotype for GDM risk, adjusted for age and pre-pregnancy BMI. The odds ratio (OR) for GDM development increased incrementally when stratified by Hb levels and Hp genotype. Moreover, first-trimester Hb level partially mediated the association between Hp genotype and GDM risk., Conclusion: Increased first-trimester Hb levels were closely associated with the development of GDM and adverse pregnancy outcomes, with this association moderated by the Hp2-2 genotype., (© 2024. The Author(s).)

Gestational diabetes mellitus (GDM) is an intolerance of carbohydrate of any degree, which appears for the first time or is diagnosed during pregnancy. The objective of this study is to assess the differences in circular RNA (circRNA) in a Polish pregnant population with and without GDM. A total of 62 pregnant women, 34 with GDM and 28 controls, were enrolled in the study. Total RNAs were extracted from plasma and reverse transcription to complementary DNA (cDNA) was performed. A panel covering 271 amplicons, targeting both linear and circular as well as negative control gene transcripts, was used. Next-generation sequencing was used to evaluate the circRNA quantity. Data analysis was performed using the Coverage Analysis plugin in the Torrent Suite Software (Torrent Suite 5.12.3). A two-step normalization was performed by dividing each transcript read count by the total number of reads generated for the sample, followed by dividing the quantity of each transcript by β-actin gene expression. Both circular and linear forms of RNAs were independently evaluated. A total of 57 transcripts were dysregulated between pregnant women with GDM and controls. Most of the targets (n = 25) were downregulated (cut-off ratio below 0.5), and one target showed a trend toward strong upregulation (ratio 1.45). A total of 39 targets were positively correlated with fasting plasma glucose (FPG), but none of the tested targets were correlated with insulin, CRP or HOMA-IR levels. Among the pregnant women with gestational diabetes, the relative quantity of hsa&#95;circ&#95;0002268 ( PHACTR1 ) was approximately 120% higher than among healthy pregnant women: 0.046 [0.022-0.096] vs. 0.021 [0.007-0.047], respectively, ( p = 0.0029). Elevated levels of hsa&#95;circ&#95;0002268 (PHACTR1) might be specific to the Polish population of pregnant women with GDM, making it useful as a potential molecular biomarker in the management of GDM in Poland.

Background: The causality between frailty and gestational diabetes mellitus (GDM) has not yet been fully explored. A potential bidirectional causality was also needed to be confirmed., Methods: A bidirectional two-sample Mendelian randomization (MR) was conducted, with frailty-related data was collected from UK Biobank and TwinGen and GDM-related data was collected from the FinnGen consortium. We performed univariable and multivariable-adjusted MR with adjustments for body mass index (BMI). Several methodologies of MR were conducted to confirm the robustness of results., Results: Frailty was significantly associated with elevated risks of GDM (OR, 3.563; 95% CI, 1.737 to 7.309; P< 0.001) and GDM was also significantly associated with elevated risks of frailty ( β , 0.087; 95% CI, 0.040 to 0.133; P< 0.001). There is no evidence demonstrating the existence of horizontal pleiotropy and heterogeneity. This association was robust after adjustments for BMI. The sensitivity analyses with Weighted median, Maximum likelihood, Penalised weighted median, MR Egger and MR PRESSO methods indicated consistent results., Conclusion: Our study provides evidence of the bidirectional causal association between frailty and GDM from genetic perspectives, signaling that the identification and assessment of frailty should become a standard strategy during the early stages and care of gestational diabetes., 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 Li and Xiong.)

Lactylation is a novel post-translational modification of proteins. Although the histone lactylation modification has been reported to be involved in glucose metabolism, its role and molecular pathways in gestational diabetes mellitus (GDM) are still unclear. This study aims to elucidate the histone lactylation modification landscapes of GDM patients and explore lactylation-modification-related genes involved in GDM. We employed a combination of RNA-seq analysis and chromatin immunoprecipitation sequencing (ChIP-seq) analysis to identify upregulated differentially expressed genes (DEGs) with hyperhistone lactylation modification in GDM. We demonstrated that the levels of lactate and histone lactylation were significantly elevated in GDM patients. DEGs were involved in diabetes-related pathways, such as the PI3K-Akt signaling pathway, Jak-STAT signaling pathway, and mTOR signaling pathway. ChIP-seq analysis indicated that histone lactylation modification in the promoter regions of the GDM group was significantly changed. By integrating the results of RNA-seq and ChIP-seq analysis, we found that CACNA2D1 is a key gene for histone lactylation modification and is involved in the progression of GDM by promoting cell vitality and proliferation. In conclusion, we identified the key gene CACNA2D1, which upregulated and exhibited hypermodification of histone lactylation in GDM. These findings establish a theoretical groundwork for the targeted therapy of GDM.

Gestational diabetes mellitus (GDM) is a common metabolic condition during pregnancy, posing risks to both mother and fetus. CircRNAs have emerged as important players in various diseases, including GDM. We aimed to investigate the role of newly discovered circRNA, hsa&#95;circ&#95;0042260, in GDM pathogenesis. Using GSE194119 dataset, hsa&#95;circ&#95;0042260 was identified and its expression in plasma, placenta, and HG-stimulated HK-2 cells was examined. Silencing hsa&#95;circ&#95;0042260 in HK-2 cells assessed its impact on cell viability, apoptosis, and inflammation. Bioinformatics analysis revealed downstream targets of hsa&#95;circ&#95;0042260, namely miR-4782-3p and LAPTM4A. The interaction between hsa&#95;circ&#95;0042260, miR-4782-3p, and LAPTM4A was validated through various assays. hsa&#95;circ&#95;0042260 was upregulated in plasma from GDM patients and HG-stimulated HK-2 cells. Silencing hsa&#95;circ&#95;0042260 improved cell viability, suppressed apoptosis and inflammation. Hsa&#95;circ&#95;0042260 interacted with miR-4782-3p, which exhibited low expression in GDM patient plasma and HG-stimulated cells. MiR-4782-3p targeted LAPTM4A, confirmed by additional assays. LAPTM4A expression increased in GDM patient plasma and HG-induced HK-2 cells following hsa&#95;circ&#95;0042260 knockdown or miR-4782-3p overexpression. In rescue assays, inhibition of miR-4782-3p or overexpression of LAPTM4A counteracted the effects of hsa&#95;circ&#95;0042260 downregulation on cell viability, apoptosis, and inflammation. In conclusion, the hsa&#95;circ&#95;0042260/miR-4782-3p/LAPTM4A axis plays a role in regulating GDM progression in HG-stimulated HK-2 cells., (© 2024 Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

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.

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.

Introduction: This study aimed to screen circRNAs involved in gestational diabetes mellitus (GDM)-related macrosomia. One differentially expressed circRNA (DEC), hsa&#95;circ&#95;0024838, was further tested for its potential role and mechanism in trophoblasts., Methods: DECs in GDM were selected through GSE182737 and GSE194119. The targets were predicted for DECs and microRNAs (miRNAs), to complete the construction of the circRNA-miRNA-gene network. Functional annotation and related biological pathway enrichment analysis were performed on the target genes of miRNAs in the network. Subsequently, the expression levels of hsa&#95;circ&#95;0024838, miR-543, and HIF1A mRNA were identified by real-time quantitative real-time PCR (RT-qPCR) in GDM patients. Trophoblast activity was assessed via CCK-8 assay, apoptosis assay, and Matrigel invasion assay. Finally, interactions between miR-543 and either hsa&#95;circ&#95;0024838 or HIF1A were confirmed using dual-luciferase reporter assays., Results: A GDM-related circRNA-miRNA-genes interaction network was constructed, consisting of 35 circRNAs, 46 miRNAs, and 122 target genes. Functional enrichment revealed that the enriched pathways were involved in GDM. Hsa&#95;circ&#95;0024838 and HIF1A mRNA expression levels were upregulated in GDM, while miR-543 expression levels were downregulated. A significant positive correlation between hsa&#95;circ&#95;0024838 and newborn weight was observed. Both hsa&#95;circ&#95;0024838 and HIF1A possessed binding sites for miR-543. Overexpressing hsa&#95;circ&#95;0024838 in high-glucose (HG)-cultured trophoblasts can partially reverse HG-induced reduction in trophoblast cell proliferation/migration and increase apoptosis. But this reversal can be negated by co-transfection with miR-543 mimics. The effects of miR-543 can be counteracted by HIF1A., Discussion: Hsa&#95;circ&#95;0024838 can regulate the expression of HIF1A by interacting with miR-543. This regulates the HIF1A signaling pathway and enhance vitality in trophoblast cells., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Reduced insulin sensitivity (insulin resistance) is a hallmark of normal physiology in late pregnancy and also underlies gestational diabetes mellitus (GDM). We conducted transcriptomic profiling of 434 human placentas and identified a positive association between insulin-like growth factor binding protein 1 gene (IGFBP1) expression in the placenta and insulin sensitivity at ~26 weeks gestation. Circulating IGFBP1 protein levels rose over the course of pregnancy and declined postpartum, which, together with high gene expression levels in our placenta samples, suggests a placental or decidual source. Higher circulating IGFBP1 levels were associated with greater insulin sensitivity (lesser insulin resistance) at ~26 weeks gestation in the same cohort and in two additional pregnancy cohorts. In addition, low circulating IGFBP1 levels in early pregnancy predicted subsequent GDM diagnosis in two cohorts of pregnant women. These results implicate IGFBP1 in the glycemic physiology of pregnancy and suggest a role for placental IGFBP1 deficiency in GDM pathogenesis., (© 2024. The Author(s).)

Background: Associations of liver function with the risk of gestational diabetes mellitus (GDM) remain unclear. This study aimed to examine the relationship and the potential causality between maternal liver biomarkers and the risk of subsequent GDM, as well as to evaluate the interaction between liver biomarkers and lipids on GDM risk., Methods: In an ongoing Zhoushan Pregnant Women Cohort, pregnant women who finished the first prenatal follow-up record, underwent liver function tests in early pregnancy, and completed the GDM screening were included in this study. Logistic regression models were used to investigate the association, and the inverse-variance weighted method supplemented with other methods of two-sample Mendelian randomization (MR) analysis was applied to deduce the causality., Results: Among 9,148 pregnant women, 1,668 (18.2%) developed GDM. In general, the highest quartile of liver function index (LFI), including ALT, AST, GGT, ALP, and hepatic steatosis index, was significantly associated with an increased risk of GDM (OR ranging from 1.29 to 3.15), especially an elevated risk of abnormal postprandial blood glucose level. Moreover, the causal link between ALT and GDM was confirmed by the MR analysis (OR=1.28, 95%CI:1.05-1.54). A significant interaction between AST/ALT and TG on GDM risk was observed ( P interaction = 0.026)., Conclusion: Elevated levels of LFI in early pregnancy were remarkably associated with an increased risk of GDM in our prospective cohort. Besides, a positive causal link between ALT and GDM was suggested., 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, Zhang, Cheng, Chi, Zhuang, Alifu, Zhou, Qiu, Huang, Ainiwan, Si and Yu.)

Context: Pancreatic β-cell function impairment is a key mechanism for developing gestational diabetes mellitus (GDM). Maternal and placental exosomes regulate maternal and placental responses during hyperglycemia. Studies have associated exosomal micro-RNAs (miRNAs) with GDM development. To date, no studies have been reported that evaluate the profile of miRNAs present in maternal and placental exosomes in the early stages of gestation from pregnancies that develop GDM., Objective: We assessed whether early-pregnancy serum maternal and placenta-derived exosomes miRNA profiles vary according to pancreatic β-cell function in women who will develop GDM., Methods: A prospective nested case-control study was used to identify exosomal miRNAs that vary in early-pregnancy stages (<18 weeks of gestation) from women with normoglycemia and those who developed GDM based on their pancreatic β-cell function using the homeostasis model assessment of pancreatic β-cell function (HOMA-%β) index. Early-pregnancy serum maternal and placenta-derived exosomes were isolated to obtain miRNA profiles. Potential target and pathway analyses were performed to identify molecular and metabolic pathways associated with the exosomal miRNAs identified., Results: In early-pregnancy stages, serum maternal exosome size and concentration are modified in GDM group and fluctuate according to HOMA-%β index. Serum maternal exosomal hsa-miR-149-3p and hsa-miR-455-3p in GDM are related to insulin secretion and signaling, lipolysis, and adipocytokine signaling. Early-pregnancy serum placenta-derived exosomes hsa-miR-3665 and hsa-miR-6727-5p in GDM are related to regulating genes involved in response to immunological tolerance of pregnancy and pathways associated with placental dysfunction., Conclusion: Early serum exosomal miRNAs differ depending on their origin (maternal or placental) and pancreatic β-cell function. This research provides insights into the interactions between maternal and placental exosomal miRNAs and may have implications for identifying potential biomarkers or therapeutic targets for GDM., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Gestational diabetes mellitus (GDM) is a prevalent metabolic disorder during pregnancy with potential long-term health implications for the mother and child. The interplay between genetics and GDM susceptibility remains an area of active research. Recently, brain-derived neurotrophic factor (BDNF) was investigated in relation to obesity and impaired glucose metabolism and pathogenesis. We aimed to investigate the association of common BDNF polymorphisms, with GDM risk in Israeli females., Methods: A cohort of 4,025 Israeli women data for BDNF common SNPs was analyzed for potential association with GDM using binary logistic regressions analysis (SPSS 29.0 and R) adjusted for confounding variables (age, T1DM, T2DM, PCOS) under different genetic models., Results: The GDM and Non-GDM genetic frequencies for the BDNF rs925946 Tag-SNP were significantly different. The genetic frequencies were 54.16 %, and 66.91 % for the wild type (GG), 38.88 and 29.64 % for the heterozygotes (TC), and 6.94 and 3.48 % for the risk allele homozygotes (TT) for the GDM non-GDM populations, respectively. Carriers of BDNF rs925946 were significantly associated with higher risk for GDM, following the dominant genetic model (OR=1.7, 95 % CI 1.21-2.39, p=0.002), the recessive genetic model (OR=2.05, 95 % CI 1.04-4.03, p=0.03), and the additive genetic model (OR=1.62, 95 % CI 1.13-2.3, p=0.008). This association persisted after adjusting for age, T1DM, T2DM, and polycystic ovary syndrome (PCOS)., Conclusions: Carrying BDNF rs925946 polymorphism predisposes to a higher risk of GDM pathogenesis. Its role and implications warrant further investigation, especially when considering preventive measures for GDM development., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

Objective: Youth-onset type 2 diabetes (T2D) is physiologically distinct from adult-onset, but it is not clear how the two diseases differ at a molecular level. In utero exposure to maternal type 2 diabetes (T2D) is known to be a specific risk factor for youth-onset T2D. DNA methylation (DNAm) changes associated with T2D but which differ between youth- and adult-onset might delineate the impacts of T2D development at different ages and could also determine the contribution of exposure to in utero diabetes., Methods: We performed an epigenome-wide analysis of DNAm on whole blood from 218 youth with T2D and 77 normoglycemic controls from the iCARE (improving renal Complications in Adolescents with type 2 diabetes through REsearch) cohort. Associations were tested using multiple linear regression models while adjusting for maternal diabetes, sex, age, BMI, smoking status, second-hand smoking exposure, cell-type proportions and genetic ancestry., Results: We identified 3830 differentially methylated sites associated with youth T2D onset, of which 3794 were moderately (adjusted p-value < 0.05 and effect size estimate > 0.01) associated and 36 were strongly (adjusted p-value < 0.05 and effect size estimate > 0.05) associated. A total of 3725 of these sites were not previously reported in the EWAS Atlas as associated with T2D, adult obesity or youth obesity. Moreover, three CpGs associated with youth-onset T2D in the PFKFB3 gene were also associated with maternal T2D exposure (FDR < 0.05 and effect size > 0.01). This is the first study to link PFKFB3 and T2D in youth., Conclusion: Our findings support that T2D in youth has different impacts on DNAm than adult-onset, and suggests that changes in DNAm could provide an important link between in utero exposure to maternal diabetes and the onset of T2D., (© 2024. The Author(s).)

Adverse pregnancy outcomes (APOs) affect a large proportion of pregnancies and represent an important cause of morbidity and mortality worldwide. Yet the pathophysiology of APOs is poorly understood, limiting our ability to prevent and treat these conditions. To search for genetic markers of maternal risk for four APOs, we performed multi-ancestry genome-wide association studies (GWAS) for pregnancy loss, gestational length, gestational diabetes, and preeclampsia. We clustered participants by their genetic ancestry and focused our analyses on three sub-cohorts with the largest sample sizes: European, African, and Admixed American. Association tests were carried out separately for each sub-cohort and then meta-analyzed together. Two novel loci were significantly associated with an increased risk of pregnancy loss: a cluster of SNPs located downstream of the TRMU gene (top SNP: rs142795512), and the SNP rs62021480 near RGMA. In the GWAS of gestational length we identified two new variants, rs2550487 and rs58548906 near WFDC1 and AC005052.1, respectively. Lastly, three new loci were significantly associated with gestational diabetes (top SNPs: rs72956265, rs10890563, rs79596863), located on or near ZBTB20, GUCY1A2, and RPL7P20, respectively. Fourteen loci previously correlated with preterm birth, gestational diabetes, and preeclampsia were found to be associated with these outcomes as well., (© 2024. The Author(s).)

Background: Diabetes in pregnancy is associated with increased risk of long-term metabolic disease in the offspring, potentially mediated by in utero epigenetic variation. Previously, we identified multiple differentially methylated single CpG sites in offspring of women with gestational diabetes mellitus (GDM), but whether stretches of differentially methylated regions (DMRs) can also be identified in adolescent GDM offspring is unknown. Here, we investigate which DNA regions in adolescent offspring are differentially methylated in blood by exposure to diabetes in pregnancy. The secondary aim was to characterize the RNA expression of the identified DMR, which contained the nc886 non-coding RNA., Methods: To identify DMRs, we employed the bump hunter method in samples from young (9-16 yr, n = 92) offspring of women with GDM (O-GDM) and control offspring (n = 94). Validation by pyrosequencing was performed in an adult offspring cohort (age 28-33 years) consisting of O-GDM (n = 82), offspring exposed to maternal type 1 diabetes (O-T1D, n = 67) and control offspring (O-BP, n = 57). RNA-expression was measured using RT-qPCR in subcutaneous adipose tissue and skeletal muscle., Results: One significant DMR represented by 10 CpGs with a bimodal methylation pattern was identified, located in the nc886/VTRNA2-1 non-coding RNA gene. Low methylation status across all CpGs of the nc886 in the young offspring was associated with maternal GDM. While low methylation degree in adult offspring in blood, adipose tissue, and skeletal muscle was not associated with maternal GDM, adipose tissue nc886 expression was increased in O-GDM compared to O-BP, but not in O-T1D. In addition, adipose tissue nc886 expression levels were positively associated with maternal pre-pregnancy BMI (p = 0.006), but not with the offspring's own adiposity., Conclusions: Our results highlight that nc886 is a metastable epiallele, whose methylation in young offspring is negatively correlated with maternal obesity and GDM status. The physiological effect of nc886 may be more important in adipose tissue than in skeletal muscle. Further research should aim to investigate how nc886 regulation in adipose tissue by exposure to GDM may contribute to development of metabolic disease., (© 2024. The Author(s).)

Background: This study investigates the causal relationship between lipid traits and GDM in an effort to better understand the aetiology of GDM., Methods: Employing a two-sample Mendelian Randomization (MR) framework, we used Single Nucleotide Polymorphisms (SNPs) as instrumental variables to examine the impact of lipids and apolipoproteins on GDM. The research comprised univariable and multivariable MR analyses, with a prime focus on individual and combined effects of lipid-related traits. Statistical techniques included the fixed-effect inverse variance weighted (IVW) method and supplementary methods such as MR-Egger for comprehensive assessment., Results: Our findings revealed the following significant associations: apoA-I and HDL cholesterol were inversely correlated with GDM risk, while triglycerides showed a positive correlation. In multivariable analysis, apoA-I consistently exhibited a strong causal link with GDM, even after adjusting for other lipids and Body Mass Index (BMI)., Conclusion: The study demonstrates a significant causal relationship between apoA-I and GDM risk., (© 2024. The Author(s).)

Objective: To investigate the associations of Insulin-like growth factor-II (IGF2) gene, Insulin-like growth factor-II receptor (IGF2R) gene and Insulin-like growth factor-II binding protein 2 (IGF2BP2) gene polymorphisms with the susceptibility to gestational diabetes mellitus (GDM) in Chinese population., Methods: A total of 1703 pregnant women (835 GDM and 868 Non-GDM) were recruited in this case-control study. All participants underwent prenatal 75 g oral glucose tolerance test (OGTT) examinations during 24-28 gestational weeks at the Maternal and Child Health Hospital of Hubei Province from January 15, 2018 to March 31, 2019. Genotyping of candidate SNPs (IGF2 rs680, IGF2R rs416572, IGF2BP2 rs4402960, rs1470579, rs1374910, rs11705701, rs6777038, rs16860234, rs7651090) was performed on Sequenom MassARRAY platform. Logistic regression analysis was conducted to investigate the associations between candidate SNPs and risk of GDM. In addition, multifactor dimensionality reduction (MDR) method was applied to explore the effects of gene-gene interactions on GDM risk., Results: There were significant distribution differences between GDM group and non-GDM group in age, pre-pregnancy BMI, education level and family history of diabetes (P < 0.05). After adjusted for age, pre-pregnancy BMI, education level and family history of diabetes, there were no significant associations of the candidate SNPs polymorphisms and GDM risk (P > 0.05). Furthermore, there were no gene-gene interactions on the GDM risk among the candidate SNPs (P > 0.05). However, the fasting blood glucose (FBG) levels of rs6777038 CT carriers were significantly lower than TT carriers (4.69±0.69 vs. 5.03±1.57 mmol/L, P < 0.01), and the OGTT-2h levels of rs6777038 CC and CT genotype carriers were significantly lower than TT genotype carriers (8.10±1.91 and 8.08±1.87 vs. 8.99±2.90 mmol/L, P < 0.01)., Conclusions: IGF2 rs680, IGF2R rs416572, IGF2BP2 rs4402960, rs1470579, rs11705701, rs6777038, rs16860234, rs7651090 polymorphisms were not significantly associated with GDM risk in Wuhan, China. Further lager multicenter researches are needed to confirm these results., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: In recent years, epidemiological studies have revealed the relationship between gestational diabetes mellitus (GDM) and cardiovascular disease (CVD). In this study, we utilized Mendelian randomization (MR) to investigate the potential causal impact of GDM on cardiovascular disease for the first time., Methods:  We retrieved summary statistics from published genome-wide association studies. MR was first performed using significant SNPs extracted from the eighth data release of the FinnGen study. Next, a replication analysis for coronary artery disease (CAD) was conducted in another European ancestry population to validate our findings. Finally, mediation analysis was carried out to assess potential mediation effects., Results: Our data analysis revealed that genetically predicted GDM was significantly associated with increased CAD risk (OR 1.10, 95% CI 1.02-1.18, p 0.006). Replication analysis confirmed a significant genetic association between GDM and CAD (OR 1.07, 95% CI 1.02-1.12, p 0.003) in another European ancestry population. Mediation analysis indicated no significant mediation effect by type 2 diabetes mellitus (T2DM) on the GDM-CAD relationship (mediation effect β [95% CI]: 0.005 [-0.003, -0.017])., Conclusion: Women with a prior history of GDM face an elevated risk of future CAD. This increased risk of CAD cannot be solely attributed to the subsequent onset of diabetes. Regular CAD risk assessment and primary prevention strategies are of paramount importance for women with a history of GDM., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Vitamin D deficiency is prevalent in pregnancy and has been associated with increased occurrences of preeclampsia, cesarean delivery, neonatal bacterial vaginosis, and gestational diabetes. CYP24A1, recognized as a key factor in vitamin D metabolism homeostasis, encodes 24-hydroxylase responsible for converting 25(OH)D3 and 1,25(OH)2D3 into inactive metabolites. Recently, we have reported CYP24A1 overexpression in patients with gestational diabetes mellitus (GDM) and trophoblast cells exposed to hyperglycemia. In this study, we explored miRNA-mediated regulation of CYP24A1 in GDM progression, validating our findings through silencing experiments in a trophoblast cell line. In silico tools identified miR-125b-5p as a putative target of CYP24A1. Expression analysis revealed downregulation of miR-125b-5p in blood samples from early GDM and GDM compared to healthy pregnant women, positively correlating with vitamin D levels. Hyperglycemic exposure in human trophoblastic cell lines (BeWo) decreased miR-125b-5p expression, concomitant with an increase in CYP24A1. To confirm the regulatory role of miR-125b on CYP24A1, we transfected BeWo cells with antimiR-125b or miR-125b mimic. AntimiR-125b transfection heightened CYP24A1 levels, while miR-125b mimic overexpression resulted in decreased CYP24A1 expression. These findings establish miR-125b as a regulator of CYP24A1. To explore the influence of miR-125b on vitamin D metabolism, trophoblast cells overexpressing miR-125b were treated with 0.1 and 1 µM calcitriol. Hyperglycemic conditions exhibited a reduction in CYP24A1 levels. Collectively, our results indicate that miR-125b may regulate vitamin D metabolism by targeting CYP24A1, contributing to GDM progression. These findings may pave the way for understanding vitamin D resistance in concurrent GDM development and identifying novel miRNAs targeting CYP24A1., Competing Interests: Conflicts of interest The authors declare that they have no competing interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Diabetes that only appears or is diagnosed during pregnancy is referred to as gestational diabetes mellitus (GDM). The maternal physiological immune profile is essential for a positive pregnancy outcome. However, the causal relationship between GDM and immunophenotypes is not fully defined., Methods: Based on the high-density genetic variation data at the genome-wide level, we evaluated the logical associations between 731 specific immune mediators and GDM using bidirectional Mendelian randomization (MR). The inverse variance weighted (IVW) was the main method employed for MR analysis. We performed multiple methods to verify the robustness and dependability of the MR results, and sensitivity measures were applied to rule out potential heterogeneity and horizontal pleiotropy., Results: A substantial causal association between several immune mediators and GDM was detected. After FDR testing, HLA DR++ monocyte %leukocyte and HLA DR on plasmacytoid DC were shown to increase the risk of GDM; in contrast, CD127 on CD28+ CD45RA+ CD8br and CD19 on PB/PC were shown to attenuate the effect of GDM. Moreover, the progression of GDM has been shown to decrease the maternal levels of CD39+ activated Treg AC , CD39+ activated Treg %CD4 Treg , CD39+ resting Treg AC , CD39+ resting Treg %CD4 Treg , and CD39+ CD8BR %T cell ., Conclusions: Our findings support a possible causal association between GDM and various immunophenotypes, thus facilitating the provision of multiple options for preventive recognition as well as for the diagnostic and therapeutic management of GDM in clinical practice., 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 Ji, Zhang, Yuan, He, Zhang, Yang, Xu and Chu.)