Obesity disrupts skeletal muscle metabolism through insulin resistance, oxidative stress, and ectopic fat deposition, yet transcriptomic findings across individual studies remain inconsistent. We performed a meta-analysis of four independent RNA sequencing (RNA-seq) studies of human vastus lateralis muscle, comparing 29 individuals with obesity (body mass index (BMI) ≥ 30 kg/m2) and 23 with normal weight. Differential expression was analyzed using DESeq2, with age and sex included as covariates in studies where individual-level data were available. Study-level results were integrated using the direction-aware inverse normal method (weighted Stouffer). Between-study heterogeneity was assessed by gene-level I2 statistics derived from random-effects meta-analysis of log2 fold changes. Functional annotation was performed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The weighted Stouffer method identified 2136 differentially expressed genes (DEGs) (adjusted p < 0.05), comprising 1028 upregulated and 1108 downregulated genes, of which 674 (31.6%) were detected only through the meta-analysis. Three genes-PHLDA3 (down), CNKSR2 (down), and SFRP4 (up)-were significant in every individual study and in the combined analysis. Downregulated DEGs were enriched in cytoplasmic translation, ribosomal structure, and oxidative phosphorylation, whereas upregulated DEGs were associated with extracellular matrix organization and the focal adhesion pathway. This RNA-seq meta-analysis of skeletal muscle in obesity identifies robust DEGs and dysregulated pathways, providing candidate targets for future mechanistic and translational research.

PURPOSE:This meta-analysis aims to summarize the effects of gut microbiome-targeted therapies (MTTs) on glucometabolic, inflammatory factors and gut microbiota in patients with type 2 diabetes mellitus (T2DM). METHODS:Four databases were searched for randomized controlled trials (RCTs) that included subjects with T2DM who received MTTs. All results were presented as standardized mean difference (SMD) or mean difference (MD) and 95% CIs. In addition, subgroup analyses were performed according to region, type of MTTs, number of probiotic strains, probiotics dose, prebiotics dose, duration of MTTs, mean age, and baseline body mass index. RESULTS:A total of 54 RCTs were included, encompassing 60 groups and 3390 subjects. Overall, MTTs intervention decreased fasting plasma glucose (MD = -7.97 mg/dL [95% CI = -10.82, -5.12]; P < .00001), 2-hour postprandial blood glucose (MD =  -43.30 mg/dL [95% CI = -75.83, -10.77]; P = .009), fasting insulin (MD = -1.73 uU/mL [95% CI = -2.63, -0.84]; P = .0001), HbA1c (MD = -0.28%, [95% CI = -0.39, -0.17]; P < .00001), and homeostatic model assessment of insulin resistance (MD =-0.53 [95% CI = -0.85, -0.20]; P = .0002). Furthermore, MTTs supplementation reduced high-sensitivity C-reactive protein, tumor necrosis factor alpha, and lipopolysaccharides. Meanwhile, the levels of interleukin-10 were increased. Moreover, the abundance of Actinobacteria, Lactobacillus, and Lactobacillus casei subgroup increased. CONCLUSION:MTTs modestly improved glucometabolic parameters, reduced pro-inflammatory cytokines, and enriched beneficial microbes (eg, Actinobacteria, Lactobacillus) in subjects with T2DM. However, heterogeneity and limited long-term data highlight the need for large-scale RCTs.

Among different age groups, middle-aged individuals are particularly susceptible to obesity, with a 22% higher risk of all-cause mortality. However, the underlying mechanisms remain unclear. In this study, we identify adipose progenitor cells (APCs) in the white adipose tissue (WAT) of middle-aged subjects as potential causes of midlife obesity. Specifically, the extracellular vesicles (EVs) derived from APCs display an impaired ability to mitigate the inflammaging of adipose tissue macrophages (ATMs) in middle-aged individuals. Mechanistically, these EVs, lacking miR-145-5p, fail to suppress the expression of L-selectin in ATMs, thereby facilitating their M1 program via the NF-κB signaling pathway. In contrast, EVs from young APCs effectively inhibit M1 macrophage polarization. Accordingly, targeted liposomes are designed to deliver miR-145-5p mimics to ATMs, which effectively prevent the obesity in middle-aged mice. Collectively, our findings highlight the role of APC-derived EVs in midlife obesity and propose miR-145-5pas a promising therapeutic target for clinical applications. Middle-aged individuals are more susceptible to obesity, but the mechanisms are unclear. Here, the authors show that extracellular vesicles from adipose progenitor cells in middle-aged individuals lack miR-145-5p, driving inflammation, and that restoring miR-145-5p could prevent midlife obesity.

ABSTRACTPurposePrevious studies have shown higher cardiovascular mortality risk with higher monocyte–lymphocyte ratio levels in general population. However, the levels of oxidative stress in individuals with type 2 diabetes are higher than those in the general population, which may affect the link between monocyte‐to‐lymphocyte ratio and cardiovascular disease deaths. And the association between the monocyte‐to‐lymphocyte ratio and mortality risk in people with type 2 diabetes still be unknown. This study aimed to investigate the prognostic significance of monocyte‐to‐lymphocyte ratio in type 2 diabetes.MethodsThis analysis involved 2,954 individuals with type 2 diabetes from the National Health and Nutrition Examination Survey 1999–2010. The National Death Index records through December 31, 2019, was used to determine all‐cause and cardiovascular mortality. The prognostic roles were determined using Cox regression models, restricted cubic spline analysis, and time‐dependent receiver operating characteristic curve analysis.ResultsDuring an average follow‐up period of 12.4 years, a total of 1,007 deaths occurred, while 252 were due to cardiovascular disease. An elevated monocyte‐to‐lymphocyte ratio level exhibited a significant dose–response relationship with an increased risk of all‐cause mortality (1.34 [95% CI 1.12, 1.60] for all‐cause mortality [P trend = 0.001]). The multivariable‐adjusted HR was 1.81 (95% CI 1.25, 2.63) (P trend = 0.001) for cardiovascular mortality indicating a U‐shaped relationship (P nonlinear = 0.013).ConclusionsThe results of this study indicate a U‐shaped relationship between the monocyte‐to‐lymphocyte ratio and cardiovascular mortality in individuals with diabetes. Both very low and high monocyte‐to‐lymphocyte ratio monocyte‐to‐lymphocyte ratio values were found to be associated with increased cardiovascular mortality risk.

Introduction:The association between aldehyde dehydrogenase-2 (ALDH2) rs671 and diabetes remains controversial, with uncertainty about whether alcohol consumption or other factors mediate or modify this relationship. This study aimed to examine the ALDH2-diabetes association using standardized clinical criteria while systematically investigating potential confounding, mediating, and interacting factors in a community-based cohort. Method:We analyzed baseline data from 4,535 participants in the China Cardiometabolic Disease and Cancer Cohort Study (4C study). Diabetes was diagnosed based on standardized clinical criteria, including fasting plasma glucose, 2-h postprandial glucose, glycosylated hemoglobin A1c (HbA1c), or documented prior diagnosis. We evaluated the association between ALDH2 rs671 and diabetes risk using both logistic and Cox regression models, with age as the time scale and adjustment for potential confounders. Comprehensive mediation and interaction analyses were performed to elucidate the underlying mechanisms. Result:Among male participants, the ALDH2 rs671 GA/AA genotype was associated with a lower diabetes risk compared to the GG genotype after adjusting for alcohol consumption and other potential confounders (OR = 0.751, 95% CI: 0.567-0.995). Subgroup analyses revealed that this protective effect was most pronounced in individuals with BMI < 24 (OR = 0.651, 95% CI: 0.448-0.947), with significant interaction p-values of 0.024. In mediation analysis, abdominal adiposity accounted for 30.4% (95% CI: 10.0%-127.0%) of the ALDH2-diabetes association and BMI mediated 18.9% (95% CI: 4.8%-75.4%) of this relationship, while alcohol consumption showed no significant mediating effect (p = 0.56). Conclusion:Our findings revealed that East Asian men with the ALDH2 GG genotype had an increased risk of diabetes compared to those with the GA/AA genotype, particularly among individuals with a BMI < 24. Interestingly, increased adiposity, especially abdominal fat, emerged as a potential mediator rather than alcohol consumption. Thus, individuals with the GG genotype, even with a relatively normal BMI, may benefit from regular moderate-intensity exercise and dietary interventions aimed at managing waist circumference.

AIM:To investigate whether the antidiabetic agent glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can exert anti-inflammatory effects while lowering blood glucose, we performed a meta-analysis and systematic review. METHODS:We searched 4 online databases (Medline, Embase, Cochrane Library and the Web of Science) for randomised controlled trials (RCTs) that examined changes after GLP-1RAs intervention in commonly accepted biomarkers of inflammation: C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), monocyte chemotactic protein-1(MCP-1) and advanced glycation end products (AGEs). RESULTS:This meta-analysis included 52 eligible RCTs (n = 4734) with a median follow-up of 24 weeks, a mean age of 54.13 years, 44.46% females, body mass index (BMI) 29.80 kg/m2, glycated haemoglobin (HbA1c) 8.28% and diabetes duration 7.27 years. GLP-1 RAs treatment, compared to placebo or conventional diabetes therapies (including oral medicine and insulin), resulted in significant reductions in CRP, TNF-α, IL-6, IL-1β and leptin (standard mean difference [SMD] -0.63 [-1.03, -0.23]; SMD -0.92 [-1.57, -0.27]; SMD -0.76 [-1.32, -0.20], SMD -3.89 [-6.56, -1.22], SMD -0.67 [-1.09, -0.26], respectively), as well as significant increases in adiponectin (SMD 0.69 [0.19, 1.19]). CONCLUSIONS:Our meta-analysis demonstrates that GLP-1 RAs exert significant anti-inflammatory effects in patients with T2DM. Our findings provide important insights that may guide the therapeutic application of GLP-1 RAs and inform the development of related therapies.

Several studies have suggested that the gut microbiota (GM) may be associated with type 2 diabetes mellitus (T2DM). However, the causal relationship between GM and T2DM and whether inflammatory cytokines act as mediators remain unclear. To investigate the association between GM and T2DM and the proportion of this association that is mediated through inflammatory cytokines. We conducted a bidirectional and mediation Mendelian randomization (MR) study utilizing data from the genome-wide association studies (GWAS) of four sources of GM taxa (MiBioGen consortium, n = 18,340; Dutch Microbiome Project, n = 7,738; German biobanks, n = 8,956; FINRISK 2002, n = 5,959), a meta-analysis of inflammatory proteins (n = 14,824), and European-ancestry T2DM (n = 1,528,967). The inverse variance weighted method was applied as the primary method. And two-step MR was employed to identify potential mediating inflammatory cytokines. We found evidence for 28 positive and 20 negative causal effects between multiple sources of GM and T2DM using at least two MR methods. And there were 2 positive and 5 negative causal relationships between cytokines and T2DM using at least two MR methods. The mediation MR analysis found that interferon-gamma (IFN-γ) mediated the causal effects of species Kandleria vitulina on T2DM (proportion mediated = 22.5

Skeletal muscle is a critical organ in maintaining homoeostasis against metabolic stress, and histone post-translational modifications are pivotal in those processes. However, the intricate nature of histone methylation in skeletal muscle and its impact on metabolic homoeostasis have yet to be elucidated. Here, we report that mitochondria-rich slow-twitch myofibers are characterized by significantly higher levels of H3K36me2 along with repressed expression of Kdm2a, an enzyme that specifically catalyses H3K36me2 demethylation. Deletion or inhibition of Kdm2a shifts fuel use from glucose under cold challenge to lipids under obese conditions by increasing the proportion of mitochondria-rich slow-twitch myofibers. This protects mice against cold insults and high-fat-diet-induced obesity and insulin resistance. Mechanistically, Kdm2a deficiency leads to a marked increase in H3K36me2 levels, which then promotes the recruitment of Mrg15 to the Esrrg locus to process its precursor messenger RNA splicing, thereby reshaping skeletal muscle metabolic profiles to induce slow-twitch myofiber transition. Collectively, our data support the role of Kdm2a as a viable target against metabolic stress. Kdm2a demethylates H3K36me2 to mediate fast-to-slow-twitch myofiber transition and reshape skeletal muscle metabolic flexibility under metabolic stress conditions.

Stem cell-based therapies exhibit considerable promise in the treatment of diabetes and its complications. Extensive research has been dedicated to elucidate the characteristics and potential applications of adipose-derived stromal/stem cells (ASCs). Three-dimensional (3D) culture, characterized by rapid advancements, holds promise for efficacious treatment of diabetes and its complications. Notably, 3D cultured ASCs manifest enhanced cellular properties and functions compared to traditional monolayer-culture. In this review, the factors influencing the biological functions of ASCs during culture are summarized. Additionally, the effects of 3D cultured techniques on cellular properties compared to two-dimensional culture is described. Furthermore, the therapeutic potential of 3D cultured ASCs in diabetes and its complications are discussed to provide insights for future research.

Introduction & Objective: This study aimed to examine the associations of system inflammation index, including system inflammation response index (SIRI) and system immune-inflammation index (SII), with cardiovascular mortality in adults with type 2 diabetes (T2D). Methods: This analysis included 2,954 individuals from the National Health and Nutrition Examination Survey (NHANES) 1999-2010. Cardiovascular mortality was ascertained by linkage to National Death Index (NDI) records through 31 December 2019. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During an average of 12.4 years of follow-up, 248 cardiovascular disease (CVD) deaths occurred. After multivariate adjustment, per one-unit increment in SIRI was significantly associated with a 16% higher risk of cardiovascular mortality (P <0.0001) in a dose-response manner (P non-linear = 0.26). However, the association between SII and CVD deaths exhibits a J-shaped relationship (P non-linear = 0.03) and When extreme level of SII was compared, the multivariate-adjusted HR was 1.81 (95% CI 1.11, 2.95) for CVD deaths (P trend = 0.017). Conclusion: Higher SIRI and very high SII were linearly associated with elevated risk of cardiovascular mortality among individuals with T2D. Disclosure H. Li: None. W. Guo: None. Y. Li: None. T. Zeng: None. W. Kong: None. Funding National Natural Science Foundation of China (Grant No. 81974107); Bethune-Merck Diabetes Research Foundation (Grant No. G-X-2019-056);

PurposePrevious observational studies about the link between dietary factors and diabetic microvascular complications (DMCs) is controversial. Thus, we systemically assessed the potential causal relationship between diet and DMCs risk using Mendelian randomization (MR) methods.MethodsWe used genome-wide association studies (GWAS) statistics to estimate the causal effects of 17 dietary patterns on three common DMCs in European. Summary statistics on dietary intakes were obtained from the UK biobank, and data on DMCs [diabetic retinopathy (DR), diabetic nephropathy (DN), and diabetic neuropathy (DNP)] were obtained from the FinnGen Consortium. A two-sample MR (TSMR) was conducted to explore the causal relationships of dietary habits with DMCs. In addition, multivariable MR analysis (MVMR) was performed to adjust for traditional risk factors for eating habits, and evaluated the direct or indirect effects of diet on DMCs.ResultsTSMR analysis revealed that salad/raw vegetable intake (odd ratio [OR]: 2.830; 95% confidence interval [CI]: 1.102–7.267; p = 0.0306) and fresh fruit intake (OR: 2.735; 95% CI: 1.622–4.611; p = 0.0002; false discovery rate [FDR] = 0.0082) increased the risk of DR, whereas cheese intake (OR: 0.742; 95% CI: 0.563–0.978; p = 0.0339) and cereal intake (OR: 0.658; 95% CI: 0.444–0.976; p = 0.0374) decreased the risk of DR. Salad/raw vegetable (OR: 6.540; 95% CI: 1.061–40.300; p = 0.0430) and fresh fruit consumption (OR: 3.573; 95% CI: 1.263–10.107; p = 0.0164) are risk factors for DN, while cereal consumption (OR: 0.380; 95% CI: 0.174–0.833; p = 0.0156) is the opposite. And genetically predicted higher pork intake increased the risk of DNP (OR: 160.971; 95% CI: 8.832–2933.974; p = 0.0006; FDR = 0.0153). The MVMR analysis revealed that cheese intake may act as an independent protective factor for DR development. Moreover, fresh fruit intake, salad/raw vegetable intake and pork intake may be independent risk factors for DR, DN and DNP, respectively. Other causal associations between dietary habits and DMCs risk may be mediated by intermediate factors.ConclusionThis causal relationship study supports that specific dietary interventions may reduce the risk of DMCs.

We were intrigued by the recent name change from NAFLD (non-alcoholic fatty liver disease) to MASLD (metabolic dysfunction-associated steatotic liver disease).1 This transition has garnered significant attention in metabolic research and clinical practice. It is not a mere name change but a choice made after a comprehensive understanding of the disease. As endocrinologists and researchers, we recognize the importance of accurate nomenclature in clinical settings and strive to enhance our understanding of the underlying pathophysiology.

A multisociety Delphi consensus statement on new fatty liver disease nomenclatureJournal of HepatologyVol. 79Issue 6PreviewThe principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. Full-Text PDF Open Access The definition of MASLD (metabolic dysfunction-associated steatotic liver disease) incorporates five cardiometabolic criteria that emphasize the impact of metabolic disorders.[1]Rinella M.E. Lazarus J.V. Ratziu V. et al.A multisociety Delphi consensus statement on new fatty liver disease nomenclature.J Hepatol. 2023; 79: 1542-1556Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar These criteria revolve around hypertension, hyperglycemia, and hyperlipidemia. However, we realize that hyperuricemia (HUA), known as the "fourth hyper",[2]Huang J. Ma Z.F. Zhang Y. et al.Geographical distribution of hyperuricemia in mainland China: a comprehensive systematic review and meta-analysis.Glob Health Res Pol. 2020; 5: 52Crossref PubMed Scopus (50) Google Scholar is not currently included. In today's society, the incidence of hyperuricemia is rapidly increasing due to high-purine diets and sugary beverages,[3]Dehlin M. Jacobsson L. Roddy E. Global epidemiology of gout: prevalence, incidence, treatment patterns and risk factors.Nat Rev Rheumatol. 2020; 16: 380-390Crossref PubMed Scopus (485) Google Scholar and a correlation between HUA and fatty liver has been reported.[4]Sun Q. Zhang T. Manji L. et al.Association between serum uric acid and non-alcoholic fatty liver disease: an updated systematic review and meta-analysis.Clin Epidemiol. 2023; 15: 683-693Crossref PubMed Scopus (3) Google Scholar In addition, serum uric acid levels can be easily obtained through routine checkups, unlike HOMA-IR (homeostasis model assessment of insulin resistance) and high-sensitivity C-reactive protein, which were required in the previous MAFLD (metabolic dysfunction-associated fatty liver disease) definition.[5]Eslam M. Newsome P.N. Sarin S.K. et al.A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement.J Hepatol. 2020; 73: 202-209Abstract Full Text Full Text PDF PubMed Scopus (2065) Google Scholar Regrettably, the new statement does not consider hyperuricemia as one of the cardiometabolic criteria for MASLD, and it remains unclear whether patients with HUA are covered by the MD (metabolic dysfunction with at least one of the cardiometabolic criteria for MASLD) category. Therefore, we conducted a study to investigate the feasibility of including HUA in the diagnosis of MASLD. This longitudinal study involved 16,152 patients who underwent a physical examination at a Chinese hospital from 2010 to 2014. All participants received a liver ultrasound to confirm the absence of fatty liver.[6]Sun D.Q. Wu S.J. Liu W.Y. et al.Association of low-density lipoprotein cholesterol within the normal range and NAFLD in the non-obese Chinese population: a cross-sectional and longitudinal study.BMJ Open. 2016; 6e013781Crossref Scopus (43) Google Scholar The mean age of the participants was 43.2 years. Those with excessive alcohol consumption (>140 g/week for men and >70 g/week for women), a history of viral hepatitis, autoimmune hepatitis, or other known causes of chronic liver disease, a BMI of ≥25 kg/m2, an LDL-c of >3.12 mmol/L, and those taking specific agents were excluded. Fatty liver was screened using liver ultrasound during follow-up periods. Within this cohort, the prevalence of the five cardiometabolic criteria that comprise MASLD were as follows: overweight (25.2%), hypertension (29.2%), hyperglycemia (13.9%), high triglyceride (TG, 19%), and low HDL-C (21.4%). The prevalence of HUA was 10.9%, with the majority (86.7%) having a comorbid MD, while a proportion (13.3%) did not have MD (Fig. S1A). During a mean follow-up period of 2.8±1.1 years, a total of 2,321 individuals developed fatty liver. Overweight, hypertension, hyperglycemia, high TG, low HDL-C, and hyperuricemia all increased the risk of non-alcoholic fatty liver disease (NAFLD). The incidence of NAFLD in the HUA group without MD (8.2%) was much higher than in the group without HUA/MD (2.9%, Fig. S1B). To eliminate the interactions between metabolic factors, the population was subdivided into the Only overweight group, Only hypertension group, Only hyperglycemia group, Only high TG group, Only low HDL-C group, and Only HUA group. Compared with the group without HUA/MD, the hazard ratio (HR) for the Only HUA group and NAFLD was 2.168 (95% CI 1.349, 3.485), which was higher than that for the Only hyperglycemia group and the Only low HDL-C group (Table 1). However, this study cannot guarantee that the Only HUA group will remain Only HUA or not develop other metabolic abnormalities during the follow-up period. Therefore, more studies are needed in the future to focus on the impact of dynamic changes in this status on outcomes.Table 1Relationship between cardiometabolic risk factors and fatty liver.HR (95% CI)aAdjusted age and sex.p valueHR (95% CI)bAdjusted for age, sex, alanine aminotransferase, aspartate aminotransferase, total bilirubin, serum creatinine, and blood urea nitrogen.p valueHUA2.158 (1.951, 2.387)<0.0011.527 (1.374, 1.696)<0.001Cardiometabolic criteria Overweight5.253 (4.832, 5.711)<0.0014.058 (3.728, 4.417)<0.001 Hypertension2.190 (2.017, 2.378)<0.0011.719 (1.579, 1.871)<0.001 Hyperglycemia2.292 (2.084, 2.519)<0.0011.778 (1.613, 1.959)<0.001 High TG4.059 (3.740, 4.405)<0.0013.113 (2.864, 3.383)<0.001 Low HDL-C1.861 (1.694, 2.044)<0.0011.655 (1.506, 1.819)<0.001MD6.945 (6.004, 8.034)<0.0015.516 (4.761, 6.391)Without HUA/MDReferencesReferencesOnly overweight8.168 (6.711, 9.943)<0.0016.645 (5.455, 8.096)<0.001Only hypertension2.442 (1.902, 3.135)<0.0012.240 (1.744, 2.878)<0.001Only hyperglycemia2.296 (1.522, 3.464)<0.0012.130 (1.410, 3.215)<0.001Only high TG5.833 (4.523, 7.523)<0.0014.940 (3.829, 6.375)<0.001Only HDL-C1.207 (0.871, 1.673)0.2581.501 (1.083, 2.081)0.015Only HUA2.593 (1.615, 4.161)<0.0012.168 (1.349, 3.485)<0.001Without HUA/MDReferencesReferencesHUA/MD overlap10.597 (8.915, 12.598)<0.0016.925 (5.797, 8.273)<0.001Only MD6.821 (5.847, 7.958)<0.0015.623 (4.814, 6.569)<0.001HUA and/or MD7.269 (6.241, 8.466)<0.0015.731 (4.912, 6.686)<0.001CI, confidence interval; HR, hazard ratio; HUA, hyperuricemia; TG, triglyceride; MD, metabolic dysfunction with at least one of the cardiometabolic criteria for MASLD.The results were obtained by Cox regression.a Adjusted age and sex.b Adjusted for age, sex, alanine aminotransferase, aspartate aminotransferase, total bilirubin, serum creatinine, and blood urea nitrogen. Open table in a new tab CI, confidence interval; HR, hazard ratio; HUA, hyperuricemia; TG, triglyceride; MD, metabolic dysfunction with at least one of the cardiometabolic criteria for MASLD. The results were obtained by Cox regression. The available literature confirms that serum uric acid increases insulin resistance through multiple pathways, and in turn insulin resistance increases uric acid synthesis and inhibits its excretion, exacerbating the vicious cycle.[4]Sun Q. Zhang T. Manji L. et al.Association between serum uric acid and non-alcoholic fatty liver disease: an updated systematic review and meta-analysis.Clin Epidemiol. 2023; 15: 683-693Crossref PubMed Scopus (3) Google Scholar Our research also revealed that 86.7% of patients with HUA had comorbid MD. However, it is important to note that uric acid can directly induce hepatic steatosis through NLRP3-mediated inflammation,[7]Wan X. Xu C. Lin Y. et al.Uric acid regulates hepatic steatosis and insulin resistance through the NLRP3 inflammasome-dependent mechanism.J Hepatol. 2016; 64: 925-932Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar and oxidative stress can impair energy metabolism in liver cells, leading to lipid accumulation.[8]Xu C. Hyperuricemia and non-alcoholic fatty liver disease: from bedside to bench and back.Hepatol Int. 2016; 10: 286-293Crossref PubMed Scopus (31) Google Scholar Individuals with HUA who do not have MD, comprising 13.3% of the population, are also at an increased risk of developing NAFLD, which supports this finding to some extent. This subgroup may not be individuals following a high-purine diet but those consuming sugary drinks. Fructose, found in sugary drinks, significantly contributes to uric acid synthesis and accumulation, thereby increasing the risk of NAFLD. Given the popularity of sugary drinks, this subgroup is expected to grow. It is worth noting that sugary beverages are trendy among younger individuals, and existing research suggests that being younger with NAFLD increases the risk of various diseases, including cancer.[9]Liu C. Liu T. Zhang Q. et al.New-onset age of non-alcoholic fatty liver disease and cancer risk.JAMA Netw Open. 2023; 6e2335511Crossref Scopus (1) Google Scholar Consequently, more attention needs to be paid to the effects of hyperuricemia on fatty liver disease. In conclusion, uric acid shows promise as the sixth cardiometabolic criterion for diagnosing MASLD. This additional criterion has the potential to enhance the accuracy and comprehensiveness of the identification of individuals at risk for MASLD and may facilitate the development of more effective diagnostic and management strategies. We anticipate that further studies can support the clinical application of this criterion. This study was supported by National Natural Science Foundation of China (Grant No. 82270909, No. 81974107). The authors declare no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details. Study concept and design: Tianshu Zeng, Wen Kong, and Linfeng He; Statistical analysis and interpretation: Linfeng He; Data acquisition and validation: Kangli Qiu, and Wenbin Zheng; All authors wrote and approved final manuscripts. The data used in this study are available in the "DATADRYAD" database (www.Datadryad.org). During the writing of this work, the authors used ChatGPT 3.5 in order to check grammar, spelling and optimize sentences to enhance the readability of the article. After using this tool/service, the authors reviewed and edited the content as necessary and take full responsibility for the content of the publication. 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Background Fluvoxamine is one of the selective serotonin reuptake inhibitors (SSRIs) that are regarded as the first-line drugs to manage mental disorders. It has been also recognized with the potential to treat inflammatory diseases and viral infection. However, the effect of fluvoxamine on autoimmune diseases, particularly type 1 diabetes (T1D) and the related cellular and molecular mechanisms, are yet to be addressed. Method Herein in this report, we treated NOD mice with fluvoxamine for 2 weeks starting from 10-week of age to dissect the impact of fluvoxamine on the prevention of type 1 diabetes. We compared the differences of immune cells between 12-week-old control and fluvoxamine-treated mice by flow cytometry analysis. To study the mechanism involved, we extensively examined the characteristics of CD4 + T cells with fluvoxamine stimulation using RNA-seq analysis, real-time PCR, Western blot, and seahorse assay. Furthermore, we investigated the relevance of our data to human autoimmune diabetes. Result Fluvoxamine not only delayed T1D onset, but also decreased T1D incidence. Moreover, fluvoxamine-treated NOD mice showed significantly attenuated insulitis coupled with well-preserved β cell function, and decreased Th1 and Th17 cells in the peripheral blood, pancreatic lymph nodes (PLNs), and spleen. Mechanistic studies revealed that fluvoxamine downregulated glycolytic process by inhibiting phosphatidylinositol 3-kinase (PI3K)-AKT signaling, by which it restrained effector T (Teff) cell differentiation and production of proinflammatory cytokines. Conclusion Collectively, our study supports that fluvoxamine could be a viable therapeutic drug against autoimmunity in T1D setting.

Obesity leads to a chronic inflammatory state throughout the body, with increased infiltration of immune cells and inflammatory factors in skeletal muscle tissue, and, at the same time, the level of intracellular mitochondrial oxidative stress rises. Meanwhile, obesity is closely related to the development of skeletal muscle fibrosis and can affect the metabolic function of skeletal muscle, triggering metabolic disorders such as insulin resistance (IR) and type 2 diabetes (T2D). However, whether there is a mutual regulatory effect between the two pathological states of inflammation and fibrosis in obese skeletal muscle and the specific molecular mechanisms have not been fully clarified. This review focuses on the pathological changes of skeletal muscle inflammation and fibrosis induced by obesity, covering the metabolic changes it causes, such as lipid deposition, mitochondrial dysfunction, and dysregulation of inflammatory factors, aiming to reveal the intricate connections between the two. In terms of intervention strategies, aerobic exercise, dietary modification, and pharmacotherapy can improve skeletal muscle inflammation and fibrosis. This article provides insight into the important roles of inflammation and fibrosis in the treatment of obesity and the management of skeletal muscle diseases, aiming to provide new ideas for the diagnosis and treatment of metabolic diseases such as obesity and IR.

Introduction & Objective: H2S is the third gaseous signaling molecule with a variety of biological effects.H2S may be involved in diabetes by modulating inflammation. The aim of this study was to determine the effects and mechanisms of H2S on high-fat diet-induced insulin resistance in skeletal muscle. Methods: Mice were injected intraperitoneally with NaHS (50 μmol/kg/d ), the Sirt2 inhibitor AGK2 (1 mg/kg/d), or disulfiram (50 mg/kg/d). Body weight, IPGTT, ITT, calculation of skeletal muscle/body weight ratio, skeletal muscle muscle fiber cross sectional area and adipose tissue were detected. The effects of NaHS-induced sirt2 changes and the NLRP3/caspase-1/GSDMD pathway were detected. Results: The SIRT2 inhibitor AGK2 accelerated blood glucose and body weight elevation and decreased skeletal muscle/body weight ratio in mice, and IPGTT and ITT indicated that AGK2 inhibited the recovery of blood glucose and exacerbated skeletal muscle atrophy and adiposity in mice.However, NaHS and disulfiram were effective in reversing the above changes. Conclusion: H2S regulates skeletal muscle satellite cell proliferation and differentiation by activating sirt2 and thereby inhibiting NLRP3/caspase-1/GSDMD pathway-mediated skeletal muscle scorpioning, resulting in increased skeletal muscle mass and thus alleviating IR resistance. Disclosure K. Qiu: None. W. Kong: None.

Albuminuria, or elevated urinary albumin-to-creatine ratio (UACR), is a biomarker for chronic kidney disease that is routinely monitored in patients with type 2 diabetes (T2D). Head-to-head comparisons of novel antidiabetic drugs on albuminuria outcomes remain limited. This systematic review qualitatively compared the efficacy of novel antidiabetic drugs on improving albuminuria outcomes in patients with T2D. We searched the MEDLINE database until December 2022 for Phase 3 or 4 randomized, placebo-controlled trials that evaluated the effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors on changes in UACR and albuminuria categories in patients with T2D. Among 211 records identified, 27 were included, which reported on 16 trials. SGLT2 inhibitors and GLP-1 RAs decreased UACR by 19–22