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Abstract Objective Previous observational studies have indicated associations between various inflammatory cytokines and diabetic nephropathy (DN) caused by type 2 diabetes mellitus (T2DM). However, the causality remains unclear. We aimed to further evaluate the causal association between 91 inflammatory cytokines and DN using bidirectional two-sample Mendelian randomization (MR) analysis. Method Summary statistics for DN were obtained from a publicly available genome-wide association study (GWAS) analysis. Data pertaining to inflammatory cytokines were derived from a GWAS protein quantitative trait locus (pQTL) study. The primary analytical approach employed the inverse variance weighted (IVW) method, complemented by MR-Egger regression, weighted mode (WM), and weighted median (WME) methods to evaluate the causal association between inflammatory cytokines and DN. Sensitivity analyses were conducted to validate the robustness of the findings. Result Among individuals of European ancestry, the IVW method results revealed a positive causal association between the gene expression of tumor necrosis factor ligand superfamily member 14 (TNFSF14), and TNF-related activation-induced cytokine (TRANCE) with DN. Conversely, a negative causal association was observed between the gene expression of interleukin-1-alpha (IL-1α), and transforming growth factor-alpha (TGF-α) with DN. Among individuals of East Asian ancestry, the IVW method results indicated a negative causal association between the gene expression of glial cell line-derived neurotrophic factor (GDNF) and DN. Notably, these findings persisted without evidence of horizontal pleiotropy or heterogeneity, ensuring their robustness and reliability. Conclusion The MR analysis underscores a causal association between inflammatory cytokines and DN, providing an important reference and evidence for the study of DN.

ObjectivePrevious observational studies suggest a potential link between gut microbiota, metabolites, and diabetic nephropathy. However, the exact causal relationship among these factors remains unclear.MethodWe conducted a two-sample bidirectional Mendelian randomization study using summary statistics from the IEU OpenGWAS Project database to investigate gut microbiota, metabolites, and diabetic nephropathy. A range of methods, including inverse variance weighting, MR-Egger, weighted median, and simple median, were applied to examine causal associations. Sensitivity analyses were performed to assess the robustness of the results. Additionally, reverse Mendelian randomization analysis was conducted, treating significant gut microbiota as the outcome, to evaluate effects and perform sensitivity testing. This comprehensive approach provided an in-depth assessment of the interactions among gut microbiota, metabolites, and diabetic nephropathy.ResultThe Inverse Variance Weighted estimates revealed that the abundance of Lachnospiraceae, Parasutterella, and Eubacterium exhibited negative causal effects on diabetic nephropathy, while Coprococcus, Sutterella, Faecalibacterium prausnitzii, and Bacteroides vulgatus showed protective causal effects against the condition. However, reverse Mendelian randomization analysis did not identify any significant associations between diabetic nephropathy and the identified gut microbiota. Furthermore, the estimates indicated that Cholesterol, Pyridoxate, Hexanoylcarnitine, X-12007, Octanoylcarnitine, 10-nonadecenoate (19:1n9), X-12734, and the average number of double bonds in a fatty acid chain had negative causal effects on diabetic nephropathy. In contrast, Methionine, Glycodeoxycholate, X-06351, 1-stearoylglycerol (1-monostearin), 5-dodecenoate (12:1n7), X-13859, 2-hydroxyglutarate, Glycoproteins, Phospholipids in IDL, and the concentration of small HDL particles demonstrated protective causal effects. Notably, sensitivity analyses did not detect any heterogeneity or horizontal pleiotropy, ensuring the robustness of the findings.ConclusionModulating gut microbiota diversity and composition offers a promising strategy for improving the incidence and prognosis of diabetic nephropathy. This highlights the need for future clinical trials focusing on microbiome-based interventions, potentially utilizing microbiome-dependent metabolites. Such approaches could transform the treatment and management of diabetic nephropathy and its associated risk factors, paving the way for more effective therapeutic strategies to combat this debilitating condition.

BackgroundCardiometabolic index (CMI) is a novel marker that can assess metabolic status. Studies have found that people with diabetes mellitus (DM) are at high risk of developing frailty. However, there is a lack of evidence between CMI and the risk of frailty in patients with DM. Therefore, the aim of this study was to investigate the association between CMI and frailty in patients with DM.MethodsThis study utilized data from the 2005-2018 National Health and Nutrition Examination Survey (NHANES). Weighted multivariate logistic regression was conducted in this study to explore the association between CMI and frailty status in patients with DM. In addition, subgroup analyses and interaction analyses were conducted to assess heterogeneity between different subgroups. Subsequently, restricted cubic spline (RCS) was also used to test for non-linear relationships.ResultsThis study ultimately included 2,761 patients with DM. Weighted multivariate logistic regression showed that, after adjusting all covariates, an increase in the level of CMI was associated with an increased risk of being in a frailty status in patients with DM (OR = 1.12, 95% CI = 1.04–1.22, p = 0.005). Dividing CMI into tertiles, the risk of frailty in patients in the highest tertile (Q3) was higher than that of patients in Q1 (OR = 1.56, 95% CI = 1.18–2.07, p = 0.002). The non-linear relationship between CMI and the risk of frailty in DM patients was further confirmed by RCS analysis.ConclusionThis study found that the higher the CMI, the higher the risk of frailty in DM patients. Maintaining a healthy low-fat dietary pattern and properly controlling blood lipid levels may reduce the risk of frailty in patients with DM.

ObjectiveTo systemically assess the relationship between serum osteocalcin levels and the progression of diabetic kidney disease (DKD) in the Chinese population.MethodsThe PubMed, Web of Science, CNKI, Wanfang Database, VIP and Chinese Medical Journal full-text Database were searched. Two investigators independently reviewed the literature and extracted data based on predetermined inclusion and exclusion criteria. The Newcastle-Ottawa scale was used to assess the quality of the literature. The statistical analysis was performed using Stata16 software.ResultsA total of 20 case-control studies encompassed 4 565 cases, consisting of 643 healthy controls (CN), 1 649 individuals with simple diabetes mellitus (DM), 1 305 with microalbuminuria (MI), and 968 with macroalbuminuria (MA). The meta-analysis results indicated that the serum osteocalcin levels in MI group were significantly lower than those in CN group and DM group [SMD = -1.15, 95% CI (-1.46, -0.85), P < 0.01; and SMD = -0.53, 95% CI (-0.69, -0.37), P < 0.01, respectively], and lower in the MA group compared to the CN group [SMD = -1.28, 95% CI (-1.79, -0.76), P < 0.01]. In the MA group, the serum osteocalcin levels were considerably lower compared to those in DM group and MI group [SMD = -0.93, 95% CI (-1.28, -0.58), P < 0.01; and SMD = -0.41, 95% CI (-0.65, -0.17), P < 0.01, respectively].ConclusionThe serum osteocalcin levels are typically reduced and show a negative correlation with the severity of proteinuria in Chinese patients with DKD. This indicates a decline in bone formation at early-stage in DKD patients, which worsens as the disease progresses.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/,identifier CRD42024580324.

Objective Previous observational studies have indicated associations between various immune cells and diabetic nephropathy (DN). However, the causality remains unclear. We aimed to further evaluate the causal association between immune cells and DN using bidirectional two-sample Mendelian randomization (MR) analysis.Method The DN data were retrieved from the IEU OpenGWAS Project database, while the data for 731 immune cells were sourced from GWAS summary statistics by Orru ̀ et al. The investigation into the causal relationship between immune cells and DN employed the inverse variance weighted (IVW), weighted median (WME), and MR-Egger methods. The stability and reliability of the findings underwent evaluation through Cochran’s Q test, MR-Egger intercept’s P-value, MR-PRESSO, and Leave-One-Out (LOO) method.Result The IVW estimates suggested a positive causal effect of CD25 on IgD-CD38dim B cell, CD25 on naive-mature B cell, CD127 on granulocyte, SSC-A on HLA DR + Natural Killer, HLA DR on plasmacytoid Dendritic Cell, and HLA DR on Dendritic Cell on DN. Conversely, the abundance of Myeloid Dendritic Cell, CD62L- Dendritic Cell %Dendritic Cell, CD86+ myeloid Dendritic Cell %Dendritic Cell, CD14- CD16-, CX3CR1 on CD14- CD16-, and SSC-A on CD4+ T cell had negative causal effects on DN. However, after correcting the P value for significant causality results using the FDR method, it was concluded that only Myeloid Dendritic Cells had a causal relationship with DN (FDR-p = 0.041), while the other immune cells showed no significant association with DN, so their relationship was suggestive. The results were stable with no observed horizontal pleiotropy and heterogeneity. Reverse MR analysis indicated no causal relationship between DN and the increased risk of positively identified immune cells.Conclusion This study provides an initial insight into the genetic perspective of the causal relationship between immune cells and DN. It establishes a crucial theoretical foundation for future endeavors in precision medicine and individualized treatment.

ObjectivePrevious observational studies have suggested associations between various inflammatory cytokines with type 2 diabetes mellitus and diabetic nephropathy. However, the causal association remains uncertain.MethodSummary statistics for type 2 diabetes mellitus and diabetic nephropathy were obtained from a publicly available genome-wide association study. Data on inflammatory cytokines were sourced from a genome-wide association study on protein quantitative trait loci. The inverse variance-weighted method was applied as the primary method for causal inference. MR-Egger, weighted mode, and weighted median method were employed as supplementary analyses. Sensitivity analyses were performed to detect heterogeneity and potential horizontal pleiotropy in the study.ResultGenetic evidence indicated that elevated levels of fibroblast growth factor 19 levels promoted the occurrence of type 2 diabetes mellitus, and increased concentrations of fibroblast growth factor 21 levels, C-C motif chemokine 19 levels, eotaxin levels, and interleukin-10 mitigated the risk of developing type 2 diabetes mellitus, while type 2 diabetes mellitus did not exert a significant influence on said proteins. Elevated levels of tumor necrosis factor ligand superfamily member 14 and TNF-related activation-induced cytokine were associated with an increased risk of diabetic nephropathy, and increased concentrations of interleukin-1-alpha and transforming growth factor-alpha were potentially correlated with a diminished risk of diabetic nephropathy. Sensitivity analyses further ensure the robustness of our findings.ConclusionMendelian randomization analysis highlights a causal association between inflammatory cytokines with type 2 diabetes mellitus and diabetic nephropathy, offering valuable evidence and reference for future research.

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is a leading public health problem worldwide. Approximately one fourth of patients with nonalcoholic fatty liver (NAFL) progress to nonalcoholic steatohepatitis (NASH), an advanced stage of NAFLD. Hence, there is an urgent need to make a better understanding of NAFLD heterogeneity and facilitate personalized management of high-risk NAFLD patients who may benefit from more intensive surveillance and preventive intervene. Methods In this study, a series of bioinformatic methods were performed to identify NAFLD progression-specific pathways and genes, and three machine learning approaches were combined to construct a risk-stratification gene signature to quantify risk assessment. In addition, bulk RNA-seq, single-cell RNA-seq (scRNA-seq) transcriptome profiling data and whole-exome sequencing (WES) data were comprehensively analyzed to reveal the genomic alterations and altered pathways between distinct molecular subtypes. Results Two distinct subtypes of NAFL were identified with the NAFLD progression-specific genes, and one subtype has a high similarity of the inflammatory pattern and fibrotic potential with NASH. The established risk-stratification gene signature could discriminate advanced samples from overall NAFLD. COL1A2, one key gene closely related to NAFLD progression, is specifically expressed in fibroblasts involved in hepatocellular carcinoma (HCC), and significantly correlated with EMT and angiogenesis in pan-cancer. Moreover, the β-catenin/COL1A2 axis might play a critical role in fibrosis severity and inflammatory response during NAFLD-HCC progression. Conclusion In summary, our study provided evidence for the necessity of molecular classification and established a risk-stratification gene signature to quantify risk assessment of NAFLD, aiming to identify different risk subsets and to guide personalized treatment.

BackgroundGut microbiota (GM) homeostasis in the human body is closely associated with health, which can be used as a regulator for preventing the onset and progression of disease. Diabetic microvascular complications bring about not only a huge economic burden to society, but also miserable mental and physical pain. Thus, alteration of the GM may be a method to delay diabetic microvascular complications.ObjectiveA two-sample Mendelian randomization (MR) analysis was conducted to reveal the causal inference between GM and three core diabetic microvascular complications, namely, diabetic kidney disease (DKD), diabetic retinopathy (DR), and diabetic neuropathy (DNP).MethodsFirst, genome-wide association study (GWAS) summary statistics for GM from the MiBioGen consortium and three main diabetic microvascular complications acquired from the FinnGen research project were assessed. Second, a forward MR analysis was conducted to assess the causality of GM on the risk of DKD, DR, and DNP. Third, a series of sensitivity studies, such as heterogeneity tests, pleiotropy evaluations, and leave-one-out analyses, were further conducted to assess the accuracy of MR analysis. Finally, Steiger tests and reverse MR analyses were performed to appraise the possibility of reverse causation.ResultsA total of 2,092 single-nucleotide polymorphisms related to 196 bacterial traits were selected as instrumental variables. This two-sample MR analysis provided strongly reasonable evidence that 28 genetically predicted abundance of specific GM that played non-negligible roles in the occurrence of DKD, DR, and DNP complications were causally associated with 23 GM, the odds ratio of which generally ranged from 0.9 to 1.1. Further sensitivity analysis indicated low heterogeneity, low pleiotropy, and high reliability of the causal estimates.ConclusionThe study raised the possibility that GM may be a potential target to prevent and delay the progression of diabetic microvascular complications. Further experiments of GM therapy on diabetic microvascular complications are warranted to clarify their effects and specific mechanisms.

Objective: This study aims to explore the causal relationships between 1400 serum metabolites (SMs) and five autoimmune diseases (Myasthenia gravis [MG], Multiple sclerosis [MS], Systemic lupus erythematosus [SLE], Type 1 diabetes mellitus [T1DM], and Ulcerative colitis [UC]) through Mendelian randomization analysis. Method: Data on MG, MS, SLE, T1DM, and UC were obtained from the IEU OpenGWAS Project database, while information on 1400 SMs was extracted from GWAS summary statistics provided by Chen et al. Causal relationships were assessed using the inverse variance weighted (IVW), MR-Egger, Weighted Median (WME), and Simple median (SME) methods. The robustness of instrumental variables was verified through computation of the F-statistic. Heterogeneity was evaluated using Cochran's Q test and the leave-one-out (LOO) method. Horizontal pleiotropy was assessed using MR-Egger regression and MR-PRESSO. Result: Following correction of the IVW P values using the False Discovery Rate (FDR) method, it was found that increased levels of 5-methyluridine (ribothymidine) (OR = 1.191, 95%CI 1.086–1.307, FDR-P = 0.000) and 2′-deoxyuridine (OR = 1.337, 95%CI 1.127–1.586, FDR-P = 0.001) were found to be correlated with a higher risk of MS. Conversely, the ratio of S-adenosylhomocysteine (SAH) to 5-methyluridine (ribothymidine) (OR = 0.771, 95%CI 0.649–0.916, FDR-P = 0.007) was linked to a decreased risk of MS. Levels of 1,2-dilinoleoyl-GPE (18:2/18:2) (OR = 0.877, 95%CI 0.791–0.974, FDR-P = 0.003) appear to be a protective factor for T1DM. No notable correlations between SMs and MG, SLE, or UC. The study detected no heterogeneity or horizontal pleiotropy. Conclusion: Levels of 5-methyluridine (ribothymidine), 2′-deoxyuridine, and the ratio of S-adenosylhomocysteine (SAH) to 5-methyluridine (ribothymidine) can serve as predictors for MS. Similarly, 1,2-dilinoleoyl-GPE (18:2/18:2) levels can be used to predict T1DM. However, no significant causal relationships were found between SMs and MG, SLE, or UC. This observation holds significant clinical implications for crafting tailored preventive and therapeutic approaches for ADs.

ObjectiveThis study sought to elucidate the causal association between gut microbiota (GM) composition and type 2 diabetes mellitus (T2DM) through a comprehensive two-sample bidirectional Mendelian randomization analysis.MethodT2DM data were sourced from the IEU OpenGWAS Project database, complemented by 211 gut microbiota (GM) datasets from the MiBioGen Federation. The primary analytical approach employed was inverse variance weighted (IVW), supplemented by MR-Egger regression and weighted median (WME) methods to investigate their potential interplay. Results were assessed using odds ratios (OR) and 95% confidence intervals (CI). The robustness and reliability of the findings were confirmed through leave-one-out analysis, heterogeneity testing, and assessment of horizontal pleiotropy. Furthermore, we explored the potential mediating role of metabolites in the pathway linking GM to T2DM.ResultA set of 11 Single Nucleotide Polymorphisms (SNPs) linked to GM were identified as instrumental variables (IVs). The IVW analysis revealed that increased abundance of the genus Actinomyces, genus Bilophila, genus Lachnoclostridium, genus Ruminococcus gnavus group, and genus Streptococcus corresponded to a heightened risk of T2DM. Conversely, higher levels of genus Eubacterium oxidoreducens group, genus Oscillospira, genus Ruminococcaceae UCG003, genus Ruminococcaceae UCG010, and genus Sellimonas were associated with a reduced risk of T2DM. However, following false discovery rate (FDR) correction, only the abundance of genus Lachnoclostridium retained a significant positive correlation with T2DM risk (OR = 1.22, q value = 0.09), while the other ten GM showed suggestive associations with T2DM. Reverse MR analysis did not reveal any causal relationship between T2DM and the increased risk associated with the identified GM. Additionally, metabolites did not exhibit mediating effects in this context.ConclusionThis study effectively pinpointed specific GM associated with T2DM, potentially paving the way for novel biomarkers in the prevention and treatment of this condition. The findings suggested that probiotics could emerge as a promising avenue for managing T2DM in the future. Furthermore, the analysis indicated that metabolites do not appear to act as mediators in the pathway from GM to T2DM.

Background: Diabetic kidney disease (DKD) is one of the most serious microvascular complications of diabetes, with the incidence rate increasing yearly, which is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease. Abelmoschus Manihot capsule, as a proprietary Chinese patent medicine, is widely used for treating CKD in China. Currently, the combination of Abelmoschus Manihot (AM) capsule and renin-angiotensin-aldosterone system inhibitor (RASI) has gained popularity as a treatment option for DKD, with more and more randomized control trials (RCTs) in progress. However, the high-quality clinical evidence supporting its application in DKD is still insufficient.Aim of the study: To comprehensively and systematically evaluate the efficacy and safety of AM capsule combined with RASI in the treatment of DKD.Materials and methods: English and Chinese databases such as Pubmed, Cochrane Library, Embase, CNKI, SinoMed, WF, and VIP were searched to collect the RCTs of AM capsule in treatment of DKD. Then Two investigators independently reviewed and extracted data from the RCTs which met the inclusion criteria. The quality of the data was assessed using the Cochrane risk of bias assessment tool, and meta-analysis was performed using RevMan 5.4 software.Results: 32 RCTs with a total of 2,881 DKD patients (1,442 in the treatment group and 1,439 in the control group) were included. The study results showed that AM capsule combined with RASI could be more effective in decreasing 24h-UTP [MD = −442.05, 95% CI (−609.72, −274.38), p < 0.00001], UAER [MD = −30.53, 95% CI (−39.10, −21.96), p < 0.00001], UACR [MD = −157.93, 95% CI (−288.60, −27.25), p < 0.00001], Scr [MD = −6.80, 95% CI (−9.85, −3.74), p < 0.0001], and BUN [MD = −0.59, 95% CI (−1.07, −0.12), p = 0.01], compared to using RASI alone. According to the subgroup analyses, the combination of AM and ARB seems to be more effective in reducing UAER than the combination of ACEI, and the addition of AM may achieve a more significant clinical effect on decreasing Scr for DKD patients with 24h-UTP>2 g or Scr>110–133 μmol/L and >133 μmol/L. Furthermore, no additional adverse reactions were observed in the combination group [OR = 1.06; 95%CI: (0.66, 1.69), p = 0.82].Conclusion: Combining AM with RASI may be a superior strategy for DKD treatment compared to RASI monotherapy. However, due to significant heterogeneity, the results should be interpreted with great caution, and more high-quality RCTs with multi-centers, different stages of DKD, large sample sizes, and long follow-up periods are still needed to improve the evidence quality of AM for DKD in the future.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/#recordDetails; Identifier CRD42022351422

Objective. The genuine causal nexus between mitochondrial function-related proteins and diabetic nephropathy remains enigmatic and arduous to delineate conclusively. In this study, we employed a bidirectional two-sample Mendelian randomization analysis, a robust approach, to scrutinize and discern the causal interplay between them. Methods. In this investigation, the datasets pertaining to diabetic nephropathy and mitochondrial function-related proteins were meticulously extracted from the comprehensive IEU OpenGWAS Project database. The principal analytical method employed was the inverse variance weighted approach. In addition, MR-Egger regression, simple median, and weighted median methodologies were utilized as supplementary tools to interrogate the causal associations of mitochondrial function-related proteins with the risk of diabetic nephropathy. Semsitivity analyses were conducted using the Cochran’s Q test and MR-Egger regression intercept. The significance level, as indicated by the P value, was employed as the pivotal metric for interpreting the findings. Result. A total of 90 single nucleotide polymorphisms associated with mitochondrial function-related proteins were meticulously screened as instrumental variables. The inverse variance weighted analysis unveiled a positive causal nexus between mitochondrial glutamate carrier 2, 2,4-dienoyl-CoA reductase mitochondrial levels, 39S ribosomal protein L52 mitochondrial, ATP synthase subunit beta mitochondrial, Serine--tRNA ligase mitochondrial, itochondrial sodium/hydrogen exchanger 9B2, and Esseential MCU regulator mitochondrial, and diabetic nephropathy. Conversely, pyruvate dehydrogenase (acetyl-transferring) kinase isozyme 1 mitochondrial exhibited a negative causal relationship with diabetic nephropathy., the MR-Egger intercept test yielded non-multiplicative results (P > 0.05), affirming the robustness and validity of Mendelian randomization as an effective method for causal inference in this investigation. Furthermore, the reverse Mendelian randomization analysis failed to demonstrate any causal link between diabetic nephropathy and an augmented risk associated with positively identified mitochondrial function-related proteins. Conclusion. Pyruvate dehydrogenase (acetyl-transferring) kinase isozyme 1 mitochondrial stands out as an independent protective factor against diabetic nephropathy. The findings bear significant clinical implications, offering pivotal insights into the development of targeted preventive and therapeutic interventions, tailored specifically for combating diabetic nephropathy.

BackgroundThe diversity of clinical trajectories in diabetic kidney disease (DKD) has made blood and biochemical urine markers less precise, while renal puncture, the gold standard, is almost impossible in the assessment of diabetic kidney disease, and the value of functional magnetic resonance imaging in the evaluation of diabetic pathological alterations is increasingly recognized.MethodsThe literature on functional magnetic resonance imaging (fMRI) for the assessment of renal alterations in diabetic kidney disease was searched in PubMed, Web of Science, Cochrane Library, and Embase databases. The search time limit is from database creation to March 10, 2023. RevMan was used to perform a meta-analysis of the main parameters of fMRIs extracted from DKD patients and healthy volunteers (HV).Results24 publications (1550 subjects) were included in this study, using five functional MRIs with seven different parameters. The renal blood flow (RBF) values on Arterial spin labeling magnetic resonance imaging (ASL-MRI) was significantly lower in the DKD group than in the HV group. The [WMD=-99.03, 95% CI (-135.8,-62.27), P

BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1RAs) significantly reduce postprandial blood glucose, inhibit appetite, and delay gastrointestinal emptying. However, it is controversial that some patients are intolerant to GLP-1RAs.MethodsPubMed, Embase, Web of Science, and Cochrane Library were searched for randomized controlled trials (RCTs) using GLP-1RAs with documented withdrawal due to gastrointestinal adverse reactions (GI AEs) from their inception to September 28, 2022. After extracting the information incorporated into the studies, a random-effects network meta-analysis was performed within a frequentist framework.Results64 RCTs were finally enrolled, which included six major categories of the GLP-1RA. The sample size of the GLP-1RAs treatment group was 16,783 cases. The risk of intolerable gastrointestinal adverse reactions of Liraglutide and Semaglutide was higher than that of Dulaglutide. Meanwhile, the higher the dose of the same GLP-1RA preparation, the more likely to cause these adverse reactions. These intolerable GI AEs were not significantly related to drug homology or formulations and may be related to the degree of suppression of the appetite center.ConclusionDulaglutide caused the lowest intolerable GI AEs, while Liraglutide and Semaglutide were the highest. For Semaglutide, the higher the dose, the more likely it is to drive GI AEs. Meanwhile, the risk of these GI AEs is independent of the different formulations of the drug. All these findings can effectively guide individualized treatment.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022359346, identifier CRD42022359346.

ObjectiveWe aimed to explore the value of Huobahuagen tablet (HBT) in improving decreased renal function for patients with diabetic kidney disease (DKD) over time.MethodsThis was a single-center, retrospective, real-world study on eligible 122 DKD patients who continued to use HBT + Huangkui capsule (HKC) therapy or HKC therapy without interruption or alteration in Jiangsu Province Hospital of Chinese Medicine from July 2016 to March 2022. The primary observation outcomes included estimated glomerular filtration rate (eGFR) at baseline and 1-, 3-, 6-, 9-, and 12-month follow-up visits and changes in eGFR from baseline (ΔeGFR). Propensity score (PS) and inverse probability treatment weighting (IPTW) were used to control for confounders.ResultseGFR was significantly higher in the HBT + HKC group than in the HKC alone group at the 6-, 9-, and 12-month follow-up visits (p = 0.0448, 0.0002, and 0.0037, respectively), indicating the superiority of HBT + HKC over HBT alone. Furthermore, the ΔeGFR of the HBT + HKC group was significantly higher than that of the HKC alone group at the 6- and 12-month follow-up visits (p = 0.0369 and 0.0267, respectively). In the DKD G4 patients, eGFR was higher in the HBT + HKC group at the 1-, 3-, 6-, 9-, and 12-month follow-up visits compared with baseline, with statistically significant differences at the 1-, 3-, and 6- month follow-up visits (p = 0.0256, 0.0069, and 0.0252, respectively). The fluctuations in ΔeGFR ranged from 2.54 ± 4.34 to 5.01 ± 5.55 ml/min/1.73 m2. Change in the urinary albumin/creatinine ratio from baseline did not exhibit a significant difference between the two groups at any of the follow-up visits (p > 0.05 for all). Adverse event incidence was low in both groups.ConclusionThe findings of this study based on real-world clinical practice indicate that HBT + HKC therapy exhibited better efficacy in improving and protecting renal function with a favorable safety profile than HKC therapy alone. However, further large-scale prospective randomized controlled trials are warranted to confirm these results.

Abstract Aims/Introduction In this paper, we focused on exploring the diagnostic and predictive clinical utility of ankle‐brachial index (ABI) in combination with feet electrochemical skin conductance (FESC) for peripheral artery disease (PAD) in Chinese patients with type 2 diabetes mellitus (T2DM). Materials and Methods Overall, 183 Chinese T2DM patients were enrolled in this study. The patients were classified into three groups: Group 1 comprised of uncomplicated type 2 diabetics (n = 36), Group 2 consisted of patients with diabetic peripheral neuropathy (n = 103) whereas Group 3 patients displayed peripheral artery disease (n = 44). All patients underwent Sudoscan test using a Sudoscan (Paris, France) and ABI assessment. Results Multivariate logistic regression models revealed that FESC was an independent risk factor of developing PAD in patients with type 2 diabetes. The AUC for diagnostic, positive predictive and negative predictive value of ABI in combination with FESC for PAD were 0.907, 0.733 and 0.920, respectively. The specificity and sensitivity of ABI in combination with FESC for PAD were 0.914 and 0.750, respectively. Conclusions Ankle‐brachial index in combination with FESC can accurately be used in early diagnosis of PAD.

ObjectiveClinical trials have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2i) are closely associated with hepatic fibrosis and steatosis by FibroScan. This paper aimed at evaluating the effects of SGLT2i on hepatic fibrosis and steatosis, which are presented as liver stiffness measurement (LSM) and controlled attenuation parameter (CAP).MethodsPubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure Database, China Science and Technology Journal Database, and Wanfang Database were searched for randomized clinical trials from database establishment to 30 November 2022 with no language restrictions. The risk of bias was evaluated by Collaboration Handbook. Software Stata 17 and Review Manager (version 5.3) were used for meta-analysis.ResultsA total of eight articles including 686 patients were included. Compared with the control group, our results showed that SGLT2i could lower levels of LSM [MD = −0.82, 95%CI (−1.38, −0.25), p = 0.005] and CAP [MD = −12.80, 95%CI (−20.57, −5.03), p = 0.001]. Further subgroup analyses indicated that SGLT2i presented more advantages on longer treatment duration and more serious steatosis in decreasing LSM. For CAP, SGLT2i exhibited a clear advantage in subgroup analyses of longer treatment duration, younger people, dapagliflozin, worse fibrosis, and steatosis.ConclusionSGLT2i could reduce LSM and CAP in contrast to other antihyperglycemic drugs. However, the included studies are not definitive, and well-designed, more multi-centered, blinded randomized clinical trials are warranted to definitively establish reliable evidence.

Background: Diabetic nephropathy (DN) is one of the most serious chronic micro-vascular complications of diabetes and the leading cause of end-stage kidney disease (ESRD) worldwide, with reduced expectancy and quality of life and colossal financial and social burden worldwide. In spite of emerging treatments on DN, effective therapy on delaying the progression of DN is still lacking. In clinical practice, there are many studies focusing on Abelmoschus moschatus (AM) capsules together with Tripterygium glycoside (TG) tablets in the treatment of DN, and excellent results have been obtained.Objective: The study aimed to evaluate the efficacy and safety of AM combined with TG in the treatment of DN.Methods: Databases including PubMed, Web of Science, Cochrane Library, Embase, CNKI, WF, and VIP were searched from their inception to 1 March 2022. The “risk of bias” evaluation tool produced by the Cochrane Collaboration Handbook was used for evaluating the quality of the included studies. Revman 5.3 software was used for meta-analysis.Results: Here, 11 studies with a total of 1,072 participants were included for this meta-analysis. Our results showed that AM combined with TG plus basic treatment could lower levels of 24 h-UP [MD = -0.18; 95% CI: (-0.21, -0.14); p < 0.00001], Scr [MD = -15.29; 95% CI: (-28.69, -1.88); p = 0.03], and BUN [MD = -1.18; 95% CI: (-1.69, -0.68); p < 0.00001]. Meanwhile, the adverse reaction rate increased in the combination group [RR = 1.88; 95% CI (1.26, 2.82); p = 0.002].Conclusion: Current evidence suggests that AM combined with TG may be more effective in the treatment of DN, which will be highly beneficial to further theoretical discussion and practical clinical applications. However, the safety cannot be ignored because of nearly increasing 2-fold adverse events, although they can be mitigated through systematic treatment. Meanwhile, due to low quality of the included studies, great possibility of publication bias, and large heterogeneity among different studies, the results of our review should be evaluated with more prudence and high-quality RCTs are warranted to confirm this in the future.Systematic review Registration:www.crd.york.ac.uk, identifier CRD42022344359.

Diabetic nephropathy is a serious complication of diabetes. Hyperoside has been widely reported to ameliorate diabetes-associated disease. The current study is designed to explore the mechanism of hyperoside in diabetic nephropathy. In the present study, high glucose was used to treat podocytes. Diabetic nephropathy mice models were established by high-fat feeding followed by multiple low dose injections of streptozocin. Western blot analysis was conducted for detection of extracellular matrix accumulation, inflammatory response and cell apoptosis. We found out that hyperoside improved high glucose-induced cell injury. Additionally, hyperoside prevented mice with diabetic nephropathy from diabetic symptoms and renal dysfunction. Mechanistically, hyperoside inhibited the mRNA and protein expression of APC. MiR-499–5p was found to be an upstream negative mediator of APC, and hyperoside induced the upregulation of miR-499–5p. MiR-499–5p bound with the 3’ untranslated region of APC to inhibit its expression. Finally, rescue assays revealed that the suppressive effects of miR-499–5p overexpression on renal dysfunction were rescued by upregulation of APC in mice with diabetic nephropathy. In conclusion, these findings indicated that hyperoside ameliorates diabetic nephropathy via targeting the miR-499–5p/APC axis, suggesting that hyperoside may offer a potential tactic for diabetic nephropathy treatment.

Abstract Background The balance between T helper 17 (Th17) cells and regulatory T cells (Tregs) is involved in immunological tolerance. Destruction of immunological tolerance by dendritic cell (DC)-mediated T cells is involved in the pathogenesis of ulcerative colitis (UC). Qingchang Huashi granule (QCHS) has been confirmed in the treatment of UC involved by inhibiting the activation of DCs. The aim of this study was to investigate the mechanism through which QCHS restores the Th17/Treg balance by modulating DCs in the treatment of UC. Methods The effects of QCHS on Th17 cells, Tregs and DCs were detected in a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis model. Furthermore, we injected QCHS-treated DCs into colitis model to test whether QCHS modulates the Th17/Treg balance via DCs. Tregs and Th17 cells were analyzed by FACS. IL-10, IL-17, and Foxp3 were measured by ELISA, Western blot and qRT-PCR. Results Both QCHS and QCHS-treated DCs improved colonic histopathology, diminished Th17 cell differentiation and inhibited IL-17 production while promoting CD4+CD25+Foxp3+ Treg differentiation and augmenting IL-10 and Foxp3 expression in colitis mice. Additionally, QCHS reduced CD86 and MHC-II expression on DCs, decreased IL-12 production ex vivo and restored the Th17/Treg ratio in the colitis model. Conclusion The findings of this study indicate that QCHS ameliorates TNBS-induced colitis by restoring the DC-mediated Th17/Treg balance.

BackgroundTo compare the efficacy of lipid accumulation product (LAP) and urine glucose excretion (UGE) in predicting diabetes and evaluate whether the combination of LAP and UGE would help to improve the efficacy of using LAP alone or UGE alone in identifying diabetes.MethodsData from 7485 individuals without prior history of diabetes who participated in a cross-sectional survey in Jiangsu, China, were analyzed. Each participant underwent an oral glucose-tolerance test. Operating characteristic curves (ROC) and logistic regression analyses were used to evaluate the performance of LAP and UGE in identification of newly diagnosed diabetes (NDM) and prediabetes (PDM).ResultsFor subjects with NDM, the area under the ROC curve was 0.72 for LAP and 0.85 for UGE, whereas for PDM, these values were 0.62 and 0.61, respectively. Furthermore, LAP exhibited a comparable sensitivity with UGE in detecting NDM (76.4% vs 76.2%, p = 0.31). In predicting PDM, LAP showed a higher sensitivity than UGE (66.4% vs 42.8%, p < 0.05). The combination of LAP and UGE demonstrated a significantly higher sensitivity than that of LAP alone and UGE alone for identification of NDM (93.6%) and PDM (80.1%). Moreover, individuals with both high LAP and high UGE had significantly increased risk of NDM and PDM than those with both low LAP and low UGE.ConclusionsThe combination of LAP and UGE substantially improved the efficacy of using LAP and using UGE alone in detecting diabetes, and may be a novel approach for mass screening in the general population.

Background: Diabetes mellitus is considered a common comorbidity of COVID-19, which has a wide spectrum of clinical manifestations ranging from asymptomatic infection to severe respiratory symptoms and even death. However, the impact of COVID-19 on blood glucose has not been fully understood. This meta-analysis aimed to summarize available data on the association between glycemic parameters and severity of COVID-19.Methods: PubMed, EMBASE, and Cochrane Library were searched from December 1, 2019 to May 15, 2020. Observational studies investigating blood glucose or glycated hemoglobin A1c (HbA1c) according to the severity of COVID-19 were considered for inclusion. Two independent researchers extracted data from eligible studies using a standardized data extraction sheet and then proceeded to cross check the results. Data were pooled using a fixed- or random-effects model to calculate the weighted mean differences (WMDs) and 95% confidence intervals (CIs).Results: Three studies reported blood glucose and HbA1c according to the severity of COVID-19 and were included in this meta-analysis. The combined results showed that severe COVID-19 was associated with higher blood glucose (WMD 2.21, 95% CI: 1.30–3.13, P < 0.001). In addition, HbA1c was slightly higher in patients with severe COVID-19 than those with mild COVID-19, yet this difference did not reach significance (WMD 0.29, 95% CI: −0.59 to 1.16, P = 0.52).Conclusions: This meta-analysis provides evidence that severe COVID-19 is associated with increased blood glucose. This highlights the need to effectively monitor blood glucose to improve prognosis in patients infected with COVID-19.

Currently, chronic kidney disease (CKD) is one of the most common diseases; it is also a serious threat to human health due to its high mortality, and its treatment is still a major clinical challenge. Mitochondrial dyshomeostasis plays an important role in the development of CKD. ZLN005 is a novel peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) activator from our laboratory. To explore whether ZLN005 can protect against CKD in vivo and in vitro, a unilateral ureteral obstruction (UUO) model and TGF-β1-treated renal tubular epithelial cells (TECs), respectively, were used in this study. We found that ZLN005-administrated UUO mice showed less kidney damages than control mice, as indicated by the reduced expression of fibrotic biomarkers in the kidney of UUO mice. ZLN005 treatment also alleviated the TGF-β1-induced fibrotic phenotype and lipid accumulation in TECs. Our study demonstrated ZLN005 treatment improved mitochondrial homeostasis at least partially via the activation of PGC-1α, thus maintaining mitochondria function and energy homeostasis. In summary, ZLN005 treatment ameliorates UUO-induced renal fibrosis, providing conceptional support for mitochondria-targeting therapies for chronic kidney disease.

Context: Total flavones extracted from Abelmoschus manihot L. (Malvaceae) medic (TFA) have been proven clinically effective at improving renal inflammation and glomerular injury in chronic kidney disease (CKD). Objective: This study evaluated the function of TFA as an inhibitor of iRhom2/TACE (tumour necrosis factor-α converting enzyme) signalling and investigated its anti-DN (diabetic nephropathy) effects in a DN rat model. Materials and methods: In vitro, cells were treated with 200 μg/mL advanced glycation end products (AGEs), and then co-cultured with 20 μg/mL TFA for 24 h. Real time PCR, western blotting and co-immunoprecipitation assays were performed. In vivo, DN was induced in 8 week old male Sprague-Dawley rats via unilateral nephrectomy and intraperitoneal injection of streptozotocin, then TFA were administered to rats by gavage for 12 weeks at three different doses (300, 135 and 75 mg/kg/d). 4-Phenylbutanoic acid (2.5 mg/kg/d) was used as a positive control. Results: IC50 of TFA is 35.6 μM in HK2 and 39.6 μM in HRMC. TFA treatment (20 μM) inhibited the activation of iRhom2/TACE signalling in cultured cells induced by AGEs. LD50>26 g/kg and ED50=67 mg/kg of TFA in rat by gavage, TFA dose-dependently downregulated the expression of proinflammatory cytokines and exerted anti-inflammatory effects significantly though inhibiting the activation of iRhom2/TACE signalling. Discussion and conclusions: Our results show that TFA could dose-dependently ameliorate renal inflammation by inhibiting the activation of iRhom2/TACE signalling and attenuating ER stress. These results suggest that TFA has potential therapeutic value for the treatment of DN in humans.

Modern lifestyle-associated factors, such as high-calorie intake, high-fat diet (HFD), and excessive artificial light, are risk factors for glucose and lipid metabolism disturbances. Melatonin may be beneficial for managing obesity and diabetes; however, the underlying molecular mechanisms are not well elucidated. We aimed to assess whether melatonin has beneficial effects on constant artificial light-induced fat deposition, lipid metabolism, and insulin resistance. Guinea pigs were randomly divided into five experimental groups: control (C), HFD (H), 12 h light (12HL), 24 h light (24HL), and melatonin (M). The majority of indexes, including insulin resistance and obesity, were measured after 10 weeks. AMP-activated protein kinase α (AMPKα)/peroxisome proliferator-activated receptor-α (PPARα) pathway expression was analyzed by quantitative reverse transcription PCR and western blotting. Although insulin resistance and obesity indexes were higher in the 24HL group than in the 12HL group, they were significantly lower in the M group than in the 24HL group. Melatonin treatment markedly upregulated AMPKα, phosphorylated AMPKα (p-AMPKα), PPARα, and carnitine palmitoyl-CoA transferase 1 A (CPT1A) gene and protein expression. Melatonin may alleviate insulin resistance and obesity caused by persistent artificial light exposure in guinea pigs, likely via activation of the AMPKα/PPARα signaling pathway.

Purpose: We investigated the effects of Traditional Chinese Medicine (TCM) on the occurrence and progression of albuminuria in patients with type 2 diabetes.Methods: In this randomized, double-blind, multicenter, controlled trial, we enrolled 600 type 2 diabetes without diabetic nephropathy (DN) or with early-stage DN. Patients were randomly assigned (1:1) to receive Liuwei Dihuang Pills (LWDH) (1.5 g daily) and Ginkgo biloba Tablets (24 mg daily) orally or matching placebos for 24 months. The primary endpoint was the change in urinary albumin/creatinine ratio (UACR) from baseline to 24 months.Results: There were 431 patients having UACR data at baseline and 24 months following-up in both groups. Changes of UACR from baseline to follow-up were not affected in both groups: −1.61(−10.24, 7.17) mg/g in the TCM group and −0.73(−7.47, 6.75) mg/g in the control group. For patients with UACR ≥30 mg/g at baseline, LWDH and Ginkgo biloba significantly reduced the UACR value at 24 months [46.21(34.96, 58.96) vs. 20.78(9.62, 38.85), P < 0.05]. Moreover, the change of UACR from baseline to follow-up in the TCM group was significant higher than that in the control group [−25.50(−42.30, −9.56] vs. −20.61(−36.79, 4.31), P < 0.05].Conclusion: LWDH and Ginkgo biloba may attenuate deterioration of albuminuria in type 2 diabetes patients. These results suggest that TCM is a promising option of renoprotective agents for early stage of DN.Trial registration: The study was registered in the Chinese Clinical Trial Registry. (no. ChiCTR-TRC-07000037, chictr.org)