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Background: Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy. The mechanism underlying the crosstalk between long non-coding RNAs (lncRNAs) and N6-methyladenine (m6A) modification in GDM remain unclear.Methods: We generated a lncRNA-mediated competitive endogenous RNA (ceRNA) network using comprehensive data from the Gene Expression Omnibus database, published data, and our preliminary findings. m6A-related lncRNAs were identified based on Pearson correlation coefficient (PCC) analysis using our previous profiles. An integrated pipeline was established to constructed a m6A-related subnetwork thereby predicting the potential effects of the m6A-related lncRNAs.Results: The ceRNA network was composed of 16 lncRNAs, 17 microRNAs, 184 mRNAs, and 338 edges. Analysis with the Kyoto Encyclopedia of Genes and Genomes database demonstrated that genes in the ceRNA network were primarily involved in the development and adverse outcomes of GDM, such as those in the fatty acid-metabolism pathway, the peroxisome proliferator-activated receptor signaling pathway, and thyroid hormone signaling pathway. Four m6A-related lncRNAs were involved in the ceRNA network, including LINC00667, LINC01087, AP000350.6, and CARMN. The m6A-related subnetwork was generated based on these four lncRNAs, their ceRNAs, and their related m6A regulators. Genes in the subnetwork were enriched in certain GDM-associated hormone (thyroid hormone and oxytocin) signaling pathways. LINC00667 was positively correlated with an m6A "reader" (YTHDF3; PCC = 0.95) and exhibited the highest node degree in the ceRNA network. RIP assays showed that YTHDF3 directly bind LINC00667. We further found that MYC possessed the highest node degree in a protein-protein interaction network and competed with LINC00667 for miR-33a-5p. qPCR analysis indicated that LINC00667, YTHDF3 and MYC levels were upregulated in the GDM placentas, while miR-33a-5p was downregulated. In a support-vector machine classifier, an m6A-related module composed of LINC00667, YTHDF3, MYC, and miR-33a-5p showed excellent classifying power for GDM in both the training and the testing dataset, with an accuracy of 76.19 and 71.43%, respectively.Conclusions: Our results shed insights into the potential role of m6A-related lncRNAs in GDM and have implications in terms of novel therapeutic targets for GDM. [ABSTRACT FROM AUTHOR]

Objective: We aimed to investigate the impact of insulin resistance (IR), as determined by the homeostasis model assessment of insulin resistance (HOMA-IR), on cardiometabolic risk factors (CMRFs), and develop an anthropometry-based predictive nomogram for IR among adolescents in China. Design: Data were acquired from a cross-sectional study with a stratified cluster sampling method, conducted among adolescents in Northeast China. Participants: A total of 882 adolescents (aged 12–16 years, 468 boys) were included. Measurements: All participants underwent anthropometric and biochemical examinations. The thresholds of IR included the 90th percentile of the HOMA-IR for adolescents with a normal body mass index (BMI) and fasting plasma glucose (FPG) level within each sex group (Cutoff A), and the 75th percentile for all participants of the same sex (Cutoff B). Results: The HOMA-IR was associated with CMRFs. IR, as defined by both cutoffs A and B, was significantly associated with most CMRFs, except decreased HDL-C levels. Excellent concordance (κ = 0.825) was found between these two criteria in diagnosing IR. However, IR using cutoff A, was more closely associated with cardiometabolic risk. The incidence of IR, as defined by cutoff A, was 18.93% and increased from 10.99% to 43.87% based on the different BMI categories. Further, an anthropometry-based predictive model for IR, incorporating sex, age, waist-to-hip ratio, weight and BMI, was developed and presented as a nomogram. Conclusions: IR among adolescents is strongly related to cardiometabolic risk. We developed an anthropometry-based predictive nomogram for IR among adolescents, which may facilitate health counselling and self-risk assessments. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to reveal the potential crosstalk between immune infiltration and N6- methyladenosine (m6A) modification in the placentas of patients with gestational diabetes mellitus (GDM), and to construct a model for the diagnosis of GDM. Methods: We analyzed imbalanced immune infiltration and differentially expressed m6A-related genes (DMRGs) in the placentas of patients with GDM, based on the GSE70493 dataset. An immune-related DMRG signature, with significant classifying power and diagnostic value, was identified using a least absolute shrinkage and selection operator (LASSO) regression. Based on the selected DMRGs, we developed and validated a nomogram model using GSE70493 and GSE92772 as the training and validation sets, respectively. Results: Infiltration of monocytes was higher in GDM placentas than in control samples, while the infiltration of macrophages (M1 and M2) in GDM placentas was lower than in controls. A total of 14 DMRGs were strongly associated with monocyte infiltration, seven of which were significant in distinguishing patients with GDM from normal controls. These genes were CD81 , CFH , FABP5 , GBP1 , GNG11 , IL1RL1 , and SLAMF6. The calibration curve, decision curve, clinical impact curve, and receiver operating characteristic curve showed that the nomogram recognized GDM with high accuracy in both the training and validation sets. Conclusions: Our results provide clues that crosstalk between m6A modification and immune infiltration may have implications in terms of novel biomarkers and therapeutic targets for GDM. [ABSTRACT FROM AUTHOR]

Purpose: Secreted frizzled-related protein 5 (SFRP5) is a novel anti-inflammatory adipokine that has been associated with various metabolic diseases. However, such relationship among adolescents remains unclear. The purpose of this study was to clarify the relationship between SFRP5 and the components of metabolic syndrome in Chinese adolescents. Patients and Methods: In this cross-sectional study, we included a total of 684 adolescents aged 11– 16 years old from Liaoyang city, Liaoning province, China. The ELISA kits were implemented to measure the plasma SFRP5 and high-sensitivity C-reactive protein. Serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C), serum uric acid (UA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting plasma glucose (FPG), and fasting serum insulin (FINS) were also measured. Results: The multivariate logistic regression analysis showed that low SFRP5 level were an independent risk factor of high FPG [odds ratio (OR)=5.31, 95% confidence interval (CI): 1.85– 15.22, P< 0.01] and high TC (OR=1.73, 95% CI: 1.01-2.96, P< 0.05) when adjusting for age, sex, family history of diabetes, body mass index, and high-sensitivity C-reactive protein. Conclusion: The lower level of SFRP5 is strongly related to lipid and glucose metabolism among adolescents in Northeast China. The risk of high fasting plasma glucose and high total cholesterol increases significantly as the plasma SFRP5 level decreases. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is a metabolic disorder whose major pathophysiological basis is demonstrated as placental insulin resistance (IR), while Smad4 always functions in the signal transduction of transforming growth factor beta (TGF‐β) pathway. Our study aims to figure out the role of Smad4 in an insulin resistance (IR) cellular model using placental trophoblast cell line. Importantly, HTR8‐Svneo cells, in the status of IR, indicated a significant increase in the expression of Smad4. Subsequently, the HTR8‐Svneo cell line with up‐regulated or depleted Smad4 was respectively achieved by the effective over‐expressed plasmid or siRNA of Smad4. We found out that the deficiency of Smad4 could promote the insulin sensitivity and restrict the inflammatory response in IR group of cells with significant augment in glucose uptake, up‐regulation of insulin signalling‐related molecules and attenuation in inflammatory biomarker expressions. On the contrary, the over‐expression of Smad4 showed a reversal effect on these alterations in IR group of cells. Besides, the positive effect of Smad4 on cell viability was also observed in our study. Significance of the study: Gestational diabetes mellitus (GDM) is a metabolic disorder whose major pathophysiological basis is demonstrated as insulin resistance (IR). Importantly, our findings indicate that the deficiency of Smad4 significantly improves the insulin sensitivity and relieves the inflammation in the cellular model of IR. Besides, the positive effect of Smad4 on cell viability was also observed in our study. Our present findings provide novel insights for the investigation on molecular details about the GDM pathogenesis. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study is to investigate the potential of using the tortuosity of branch retinal artery as a more promising indicator for early detection and accurate assessment of diabetic retinopathy (DR)., Design and Method: The diagnoses, consisting of whether DR or not as well as DR severity, were given by ophthalmologists upon the assessment of those fundus images from 495 diabetic patients. Meanwhile, benefiting from those good contrast and high optical resolution fundus images taken by confocal scanning laser ophthalmoscope, the branch arteries, branch veins, main arteries and main veins in retina can be segmented independently, and the tortuosity values of them were further extracted to investigate their potential correlations with DR genesis and progress based on one-way ANOVA test., Results: For both two comparisons, i.e., between non-DR group and DR group as well as among groups with different DR severity levels, larger tortuosity increments were always observed in retinal arteries and the increments in branch retinal vessels were even larger. Furthermore, it was newly found that branch arterial tortuosity was significantly associated with both DR genesis (p=0.030) and DR progress (p<0.001)., Conclusion: Based on this cohort study of 495 diabetic patients without DR and with different DR severity, the branch arterial tortuosity has been found to be more closely associated with DR genesis as well as DR progress. Therefore, the branch arterial tortuosity is expected to be a more direct and specific indicator for early detection of DR as well as accurate assessment of DR severity, which can further guide timely and rational management of DR to prevent from visual impairment or even blindness resulting from DR., 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 © 2022 Song, Zhou, Liu, Du, Zhou, Zhu and Chen.)

Objectives: The aim of this study was to evaluate the effects of fasudil on insulin resistance (IR) in HTR-8/SVneo cells., Methods: HTR-8/SVneo cells were treated with insulin or/and fasudil. Cell proliferation, apoptosis, inflammation and related signalling pathways were assessed., Key Findings: Insulin treatment significantly enhanced the protein expressions of RhoA and Rho kinase (ROCK1 and ROCK2), but decreased glucose consumption. Administration of fasudil effectively promoted glucose uptake. Moreover, fasudil enhanced cell viability and the level of proliferating cell nuclear antigen (PCNA). Insulin-mediated cell apoptosis was inhibited by fasudil via the down-regulation of bax and cleaved-caspase-3, and the up-regulation of bcl-2. At the same time, fasudil led to the reduction of IL-1β, TNF-α, IL-6 and IL-8 mRNA levels in insulin-treated cells. In addition, RhoA, ROCK2 and phosphorylated myosin phosphatase target subunit-1 (p-MYPT-1) expressions were down-regulated by fasudil. Importantly, fasudil activated insulin receptor substrate-1 (IRS-1) through increasing p-IRS-1 (Tyr612) and p-Akt expressions. The nuclear NF-κB p65 and p-IκB-α levels were reduced via the administration of fasudil in insulin-treated cells., Conclusions: Fasudil mitigated IR by the promotion of cell proliferation, inhibition of apoptosis and inflammation and regulation of RhoA/ROCK/insulin/NF-κB signalling pathway through in vitro studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)