Ube2L6 promotes M1 macrophage polarization in HFD-fed obese mice via ISGylation of STAT1 to trigger STAT1 activation

Introduction: In obesity-related type 2 diabetes mellitus (T2DM), M1 macrophages aggravate chronic inflammation and insulin resistance. ISG15-conjugation enzyme E2L6 (Ube2L6) has been demonstrated as a promoter of obesity and insulin resistance. This study investigated the function and mechanism of Ube2L6 in M1 macrophage polarization in obesity. Methods: Obesity was induced in Ube2L6AKO mice and age-matched Ube2L6flox/flox control mice by high-fat diet (HFD). Stromal vascular cells (SVCs) were isolated from epididymal white adipose tissue of mice. Polarization induction was performed in mouse bone marrow-derived macrophages (BMDMs) by exposure to IFN-γ, lipopolysaccharide (LPS), or IL-4. F4/80 expression was assessed by immunohistochemistry staining. Expression of M1/M2 macrophage markers and target molecules was determined by flow cytometry, RT-qPCR, and Western blotting, respectively. Protein interaction was validated by co-immunoprecipitation (Co-IP) assay. The release of TNF-α and IL-10 was detected by ELISA. Results: The polarization of pro-inflammatory M1 macrophages together with an increase in macrophage infiltration were observed in HFD-fed mice, which could be restrained by Ube2L6 knockdown. Additionally, Ube2L6 deficiency triggered the repolarization of BMDMs from M1 to M2 phenotypes. Mechanistically, Ube2L6 promoted the expression and activation of signal transducer and activator of transcription 1 (STAT1) through interferon-stimulated gene 15 (ISG15)-mediated ISGlylation, resulting in M1 macrophage polarization. Conclusion: Ube2L6 exerts as an activator of STAT1 via post-translational modification of STAT1 by ISG15, thereby triggering M1 macrophage polarization in HFD-fed obese mice. Overall, targeting Ube2L6 may represent an effective therapeutic strategy for ameliorating obesity-related T2DM

Genome-wide association study of fasting proinsulin, fasting insulin, 2-hour postprandial proinsulin, and 2-hour postprandial insulin in Chinese Han people

Introduction: Fasting proinsulin (FPI) and fasting insulin (FI) have been demonstrated to be associated with impaired b cell function, T2DM, and insulin resistance. This genome-wide association study (GWAS) was performed to contribute to our understanding of the genetic basis of FPI, FI, 2-hour postprandial proinsulin (2hPI), and 2-hour postprandial insulin (2hI) of the pathophysiology of prediabetes in the Chinese population. Material and methods: The levels of fasting plasma glucose (FPG), FPI, FI, 2hPI, and 2hI were examined by an automatic biochemical analyser. The Applied BiosystemsTM AxiomTM Precision Medicine Diversity Array, the Gene Titan Multi-Channel instrument, and Axiom Analysis Suite 6.0 Software were used for genotyping. Imputation was performed with IMPUTE 2.0 software from HapMap, 1000 Genomes Phase 3 as a reference panel. Results: Six single nucleotide polymorphisms (SNPs) in DLG1-AS1, SORCS1, and CTAGE11P for FPI, and 27 SNPs in ZNF718, MARCHF2, and HNRNPM for 2hPI reached genome-wide significance. Genome-wide significance was reached for associations of 6 SNPs in KRT71 to FI. Also, 14 SNPs in UBE2U, ABO, and GRID1-AS1 were genome-wide significant in their relationship with 2hI. Among these, the genetic loci of CTAGE11P, MARCHF2, KRT71, and ABO have the strongest association with FPI, 2hPI, FI, and 2hI. Conclusions: The genetic variants of CTAGE11P, MARCHF2, KRT71, and ABO are significantly correlated with FPI, 2hPI, FI, and 2hI, respectively, in Chinese Han people. These genetic variants may serve as new biomarkers for the prevention of prediabetes

MRPS6 modulates glucose-stimulated insulin secretion in mouse islet cells through mitochondrial unfolded protein response

Abstract Lack of efficient insulin secretion from the pancreas can lead to impaired glucose tolerance (IGT), prediabetes, and diabetes. We have previously identified two IGT-associated single nucleotide polymorphisms (SNPs) rs62212118 and rs13052524 located at two overlapping genes: MRPS6 and SLC5A3. In this study, we show that MRPS6 but not SLC5A3 regulates glucose-stimulated insulin secretion (GSIS) in primary human β-cell and a mouse pancreatic insulinoma β-cell line. Data mining and biochemical studies reveal that MRPS6 is positively regulated by the mitochondrial unfolded protein response (UPRmt), but feedback inhibits UPRmt. Disruption of such feedback by MRPS6 knockdown causes UPRmt hyperactivation in high glucose conditions, hence elevated ROS levels, increased apoptosis, and impaired GSIS. Conversely, MRPS6 overexpression reduces UPRmt, mitigates high glucose-induced ROS levels and apoptosis, and enhances GSIS in an ATF5-dependent manner. Consistently, UPRmt up-regulation or down-regulation by modulating ATF5 expression is sufficient to decrease or increase GSIS. The negative role of UPRmt in GSIS is further supported by analysis of public transcriptomic data from murine islets. In all, our studies identify MRPS6 and UPRmt as novel modulators of GSIS and apoptosis in β-cells, contributing to our understanding of the molecular and cellular mechanisms of IGT, prediabetes, and diabetes

Contribution of body mass index, waist circumference, and 25-OH-D3 on the risk of pre-diabetes mellitus in the Chinese population

AbstractThis study aimed to investigate the associations between body mass index (BMI), waist circumference (WC), 25-hydroxy-vitamin D3 (25-OH-D3), and the risk of pre-diabetes mellitus (PDM), as well as their predictive values in identifying PDM. A total of 1688 participants were included in this cross-sectional investigation. Spearman’s correlation analysis was used to assess the relationships between candidate indicators and PDM. The impact of indicators on PDM risk was determined by multivariate logistic regression. The receiver operating characteristic (ROC) analysis was performed to evaluate the prognostic value of indicators. Our study indicated a positive correlation between WC, BMI, and 25-OH-D3 and PDM. WC (OR = 1.05, 95% CI = 1.04–1.06, p  80.5 cm predicted PDM with both good sensitivity and specificity. Additionally, the cut-off value of waist circumference (WC) for men with prediabetes was 86.500, while for women with prediabetes, it was 76.500

LASSO-based machine learning algorithm to predict the incidence of diabetes in different stages

AbstractBackground Formal risk assessment is crucial for diabetes prevention. We aimed to establish a practical nomogram for predicting the risk incidence of prediabetes and prediabetes conversion to diabetes.Methods A cohort of 1428 subjects was collected to develop prediction models. The LASSO was used to screen for important risk factors in prediabetes and diabetes and was compared with other algorithms (LR, RF, SVM, LDA, NB, and Treebag). Multivariate logistic regression analysis was used to construct the prediction model of prediabetes and diabetes, and drawn the predictive nomogram. The performance of the nomograms was evaluated by receiver-operating characteristic curve and calibration.Results These findings revealed that the other six algorithms were not as good as LASSO in terms of diabetes risk prediction. The nomogram for individualized prediction of prediabetes included “Age,” “FH,” “Insulin_F,” “hypertension,” “Tgab,” “HDL-C,” “Proinsulin_F,” and “TG” and the nomogram of prediabetes to diabetes included “Age,” “FH,” “Proinsulin_E,” and “HDL-C”. The results showed that the two models had certain discrimination, with the AUC of 0.78 and 0.70, respectively. The calibration curve of the two models also indicated good consistency.Conclusions We established early warning models for prediabetes and diabetes, which can help identify prediabetes and diabetes high-risk populations in advance

Table_1_Genome-wide association study of blood lipid levels in Southern Han Chinese adults with prediabetes.xlsx

BackgroundDyslipidemia is highly prevalent among individuals with prediabetes, further exacerbating their cardiovascular risk. However, the genetic determinants underlying diabetic dyslipidemia in Southern Han Chinese remain largely unexplored.MethodsWe performed a genome-wide association study (GWAS) of blood lipid traits in 451 Southern Han Chinese adults with prediabetes. Fasting plasma lipids, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were assayed. Genotyping was conducted using the Precision Medicine Diversity Array and Gene Titan platform, followed by genotype imputation using IMPUTE2 with the 1000 Genomes Project (Phase 3, Southern Han Chinese) as reference. Single nucleotide polymorphisms (SNPs) associated with lipid levels were identified using mixed linear regression, with adjustment for covariates.ResultsWe identified 58, 215, 74 and 81 novel SNPs associated with TG, TC, HDL-C and LDL-C levels, respectively (P -5). Several implicated loci were located in or near genes involved in lipid metabolism, including SRD5A2, PCSK7, PITPNC1, IRX3, BPI, and LBP. Pathway enrichment analysis highlighted lipid metabolism and insulin secretion.ConclusionThis first GWAS of dyslipidemia in Southern Han Chinese with prediabetes identified novel genetic variants associated with lipid traits. Our findings provide new insights into genetic mechanisms underlying heightened cardiovascular risk in the prediabetic stage. Functional characterization of implicated loci is warranted.</p

Image_1_Genome-wide association study of blood lipid levels in Southern Han Chinese adults with prediabetes.tif

BackgroundDyslipidemia is highly prevalent among individuals with prediabetes, further exacerbating their cardiovascular risk. However, the genetic determinants underlying diabetic dyslipidemia in Southern Han Chinese remain largely unexplored.MethodsWe performed a genome-wide association study (GWAS) of blood lipid traits in 451 Southern Han Chinese adults with prediabetes. Fasting plasma lipids, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were assayed. Genotyping was conducted using the Precision Medicine Diversity Array and Gene Titan platform, followed by genotype imputation using IMPUTE2 with the 1000 Genomes Project (Phase 3, Southern Han Chinese) as reference. Single nucleotide polymorphisms (SNPs) associated with lipid levels were identified using mixed linear regression, with adjustment for covariates.ResultsWe identified 58, 215, 74 and 81 novel SNPs associated with TG, TC, HDL-C and LDL-C levels, respectively (P -5). Several implicated loci were located in or near genes involved in lipid metabolism, including SRD5A2, PCSK7, PITPNC1, IRX3, BPI, and LBP. Pathway enrichment analysis highlighted lipid metabolism and insulin secretion.ConclusionThis first GWAS of dyslipidemia in Southern Han Chinese with prediabetes identified novel genetic variants associated with lipid traits. Our findings provide new insights into genetic mechanisms underlying heightened cardiovascular risk in the prediabetic stage. Functional characterization of implicated loci is warranted.</p

Duplicated adrenal veins in primary aldosteronism misdiagnosed with ectopic aldosteronoma due to apparent bilateral aldosterone suppression

Background Primary aldosteronism (PA) is considered the number one aetiology for secondary hypertension. Apart from confirmatory tests and localisation of PA determined by computed tomography (CT), adrenal venous sampling (AVS) is used to define whether aldosterone hypersecretion occurs inside one or both adrenal glands. However, even correctly-performed AVS may lead to undiagnostic results such as apparent bilateral adrenal suppression (apparent bilateral aldosterone suppression), in which the adrenal aldosterone-to-cortisol ratios (AC ratios) are decreased bilaterally compared to the peripheral blood sample, with several causes contributing to it. Case description Here, we describe the case of a 48-year-old man who was referred to our department for further investigation with a history of refractory hypertension, hypokalaemia, and aortic dissection. His hypertension and hypokalaemia were initially attributed to ectopic aldosteronoma due to his adrenal CT scan and AVS results. However, the correct diagnosis of an adenoma with duplicated right adrenal veins (duplicated adrenal veins) due to apparent bilateral aldosterone suppression was confirmed during surgery. Conclusion AVS is the gold standard accepted for PA subtyping, but sometimes when apparent bilateral aldosterone suppression is present, it can give ambiguous results. Duplicated right adrenal veins, may impact results, thus, AVS may not accurately provide evidence of unilateral hypersecretion for all PA patients. Repeat AVS or adrenal surgery can provide worthwhile diagnostic conclusions

The correlation between proinsulin, true insulin, proinsulin: True insulin ratio, 25(OH) D3, waist circumference and risk of prediabetes in Hainan Han adults.

PurposeDiabetes mellitus is a kind of highly prevalent chronic disease in the world. The intervention measures on the risk factors of prediabetes contribute to control and reduce the occurrence of diabetes. This study aimed to investigate the correlation between proinsulin (PI), true insulin (TI), PI/TI, 25(OH) D3, waist circumference (WC), and risk of prediabetes.MethodsIn this cross-sectional study, 1662 subjects including 615 prediabetes and 1047 non-prediabetes were recruited. Spearman's correlation analysis was used to explore the association of PI, TI, PI/TI, 25(OH) D3, and waist circumference with prediabetes. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by logistic regression. Receiver-Operator Characteristic (ROC) curve was used to evaluate the risk of prediabetes.ResultsOur study showed that FPI, 2hPI, FTI, 2hTI, FPI/FTI, and WC could enhance the risk of prediabetes (OR 1.034; OR 1.007; OR 1.005; OR 1.002; OR 3.577, OR 1.053, respectively; all pConclusionThe FPI, 2hPI, FTI, 2hTI, FPI/FTI, and WC significantly associated with an increased risk of prediabetes. The combination of FPI, FTI, 2hPI, 2hTI, 25(OH) D3, and WC might be used as diagnostic indicators for prediabetes