The gut microbiota exhibits robust circadian oscillations that synchronize with host metabolic cycles. Disruption of these microbial rhythms is increasingly recognized as a factor contributing to the pathogenesis of obesity. Clinical evidence supports that chrono-modulated interventions, including chrono-nutrition, temporal fecal microbiota transplantation (FMT), and engineered microbial systems, represent promising approaches in obesity management. This review synthesizes the features of gut microbiota circadian dynamics, the intrinsic and extrinsic factors regulating microbiota oscillations, and the precise microbial intervention measures targeting temporal patterns. Through the integration of insights into the microbiota-clock-metabolism axis, this review emphasizes the necessity of time-specific strategies in translating microbial circadian biology into effective, personalized obesity therapies.

BACKGROUND:Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease, yet its pathogenesis remains incompletely understood. Immune dysregulation, particularly intrahepatic T-cell responses, is implicated in disease progression; however, the specific roles of T-cell subsets and their regulatory mechanisms are not fully defined. METHODS:We performed single-cell RNA sequencing (scRNA-seq) on human liver tissues from patients with varying severities of metabolic dysfunction-associated steatotic liver disease (MASLD). To establish causality, we generated T cell-specific NAT10 knockout mice. The molecular mechanism was elucidated using acetylated RNA immunoprecipitation sequencing (acRIP-seq) and mRNA stability assays. RESULTS:scRNA-seq revealed a marked increase in NAT10 expression in intrahepatic effector CD8+ T cells from patients with severe MASLD. In mice, T cell-specific deletion of NAT10 significantly attenuated MASH progression, reducing hepatocyte injury, fibrosis, and intrahepatic CD8+ T cell accumulation. NAT10 deficiency suppressed CD8+ T cell cytotoxicity, evidenced by decreased production of IFN-γ, TNF-α, and GZMB. Mechanistically, NAT10 stabilizes Fhit mRNA through ac4C modification, enhancing its expression. CONCLUSIONS:Our study identifies NAT10 as a critical regulator of CD8+ T cell-mediated immunopathology in MASH. By stabilizing Fhit mRNA, NAT10 promotes the expression of inflammatory factors, shaping the pro-inflammatory hepatic microenvironment. Targeting NAT10 presents a promising therapeutic strategy to modulate intrahepatic immunity and arrest MASH progression.

Background:The global prevalence of obesity continues to rise, with gut microbiota implicated as a key environmental factor in its development. However, microbial heterogeneity across BMI categories and its potential as an early diagnostic marker remain poorly understood. Here, we systematically compared the gut microbiota of adults with normal weight, overweight, and obesity, and evaluated the diagnostic utility of integrated microbial and clinical indicators. Methods:In this study, a cohort of 214 participants was recruited and categorized into three groups based on BMI: normal weight (Nor, n = 85), overweight (Ow, n = 91), and obesity (Ob, n = 38). The gut microbiota was analyzed using 16S rRNA sequencing, which facilitated the assessment of α- and β-diversity, the identification of differentially abundant bacterial genera, and the evaluation of Spearman correlations with clinical indicators. Additionally, a diagnostic model was developed utilizing random forest, Least Absolute Shrinkage and Selection Operator (LASSO) regression and receiver operating characteristic (ROC) curve analysis. Results:Clinical data showed no significant age differences among groups (p > 0.05), but the Ob group had markedly higher weight, BMI, total cholesterol, triglycerides, and uric acid levels (p < 0.001). Microbial analysis revealed reduced alpha diversity (Shannon index) in the Ob group and distinct microbial community structures among groups (PCoA, p < 0.001). LEfSe analysis showed enrichment of Escherichia-Shigella, Lactobacillus, and Parabacteroides in the Ob group, while Faecalibacterium, Enterobacter, and Agathobacter were predominant in the Nor group. The Ow group exhibited intermediate or specific enrichment, particularly in Ruminococcus gnavus group, Morganella, and Clostridium innocuum group. Correlation analysis indicated that bacteria abundant in the Nor group negatively correlated with BMI, TG, LDL-C, and positively with HDL-C, whereas those enriched in the Ow and Ob groups showed opposite trends. Four genera differentiated Ob from Ow individuals (AUC = 0.684), eight distinguished Ob from Nor (AUC = 0.787), and five separated Ow from Nor (AUC = 0.721). Integrating microbial and clinical data notably improved classification, with AUCs increasing to 0.908, 0.969, and 0.995, respectively. Conclusion:Intestinal microecological profiles vary significantly across BMI categories, and a model combining microbiota with metabolic markers shows strong potential for early obesity detection.

Introduction and Objective: Metabolic dysfunction-associated steatohepatitis (MASH) is highly prevalent among individuals with type 2 diabetes (T2D) and significantly increases the risk of liver-related events. Individuals with at-risk MASH (MASH+F2-4) are the main target for emerging therapies. We aimed to develop and validate a non-invasive model to identify at-risk MASH in adults with T2D. Methods: A multicenter derivation cohort undergoing liver biopsy (n=525) was used for model development. External validation was conducted in three transient elastography-based cohorts: a Chinese cohort (n=3,711), a Singapore cohort (n=422), and a US NHANES cohort (n=1,674). At-risk MASH was defined histologically in the derivation cohort and by the FibroScan-aspartate aminotransferase (FAST) score in validation cohorts. Performance was compared with the Fibrosis-4 index (FIB-4), non-alcoholic fatty liver disease fibrosis score (NFS), and AST/alanine aminotransferase (ALT) ratio (AAR). Results: The DiabetesMASH Index (DMI), which incorporates age, waist circumference, ALT, and hemoglobin A1c, showed satisfactory discrimination in the derivation cohort (AUROC 0.79; 95% CI 0.75 - 0.83) and validation cohorts (AUROC 0.91 [95% CI 0.89 - 0.94], 0.88 [0.80 - 0.96], and 0.90 [0.86 - 0.94]), outperforming the FIB-4, NFS, and AAR. Calibration analyses showed agreement between predicted and observed risks. Rule-out and rule-in thresholds were 0.184 (sensitivity 0.85; negative predictive value [NPV] 0.92) and 0.452 (specificity 0.90; PPV 0.57). The indeterminate zone accounted for 35.8% of patients in the derivation cohort and 19.9%, 24.8%, and 19.1% in validation cohorts. Conclusion: DMI is a validated, affordable, and accessible non-invasive tool for identifying at-risk MASH in T2D. Disclosure Y. Chen: None. B. Dong: None. C. Liu: None. Z. Li: None. M. Zheng: None. K. Chen: None. G. Goh: None. B. Ye: None. X. Liang: None. A. Hu: None. Y. Li: None. Q. Zeng: None. Y. Sun: None. W. Gou: None. H. Bian: None. J. Lv: None. J. Shen: None. X. Liang: None. X. Zhou: None. M. Huang: None. Q. Zhang: None. Y. Wang: None. X. Xiao: None. Y. Wang: None. Y. Qi: None. Y. Zhou: None. J. He: None. Z. Dai: None. X. Qi: None. Funding The Key Research and Development Program of Jiangsu Province (BE2023767a), the Health Research Program of Anhui (AHWJ2023A30169), and the Natural Science Foundation of Anhui Province (2508085QH314)

BackgroundLipoprotein lipase (LPL) is essential for plasma triglyceride (TG) hydrolysis, and biallelic LPL loss-of-function variants cause familial chylomicronemia syndrome. However, the clinical and functional significance of heterozygous LPL variants remains incompletely characterized. We investigated two heterozygous LPL missense variants, c.1187A>T (p.Glu396Val) and the novel c.1251G>C (p.Trp417Cys), in patients with severe hypertriglyceridemia (HTG).MethodsTwo probands underwent comprehensive clinical, biochemical, and imaging assessments. Genetic analysis involved whole-exome sequencing and Sanger confirmation. Variant interpretation incorporated in silico prediction, evolutionary conservation, AlphaFold-based residue mapping, LPL-GPIHBP1 structural-context analysis, and NetCGlyc prediction. Functional effects were assessed in HEK293T cells transfected with wild-type or mutant LPL plasmids, measuring mRNA/protein expression and enzymatic activity.ResultsClinically, Proband 1 exhibited recurrent pancreatitis with moderate hyperglycemia, whereas Proband 2 had extreme HTG without pancreatitis but with severe insulin resistance, reflecting variable expressivity. Two LPL missense variants, c.1187A>T (p.Glu396Val) and the novel c.1251G>C (p.Trp417Cys), both located in exon 8. Both affected residues were highly conserved and localized to the C-terminal domain by AlphaFold-based mapping. NetCGlyc predicted Trp417 as a potential C-mannosylation-related residue. Mutant LPL mRNA and protein expression were comparable to wild-type, whereas enzymatic activity was significantly reduced in cell lysates and culture medium.ConclusionsThese findings provide functional evidence that p.Glu396Val and the novel p.Trp417Cys impair LPL enzymatic activity despite preserved protein abundance, supporting a qualitative functional defect. Our findings highlight the value of functional validation and metabolic assessment in interpreting heterozygous LPL variants in HTG.

Introduction and Objective: The American Diabetes Association (ADA) consensus report recommends risk stratification for liver fibrosis in individuals with Type 2 diabetes mellitus (T2DM). This multicenter study aimed to evaluate the performance of the DiabetesLiver score versus the fibrosis-4 index (FIB-4) for screening clinically significant fibrosis in T2DM. Methods: This multicenter study prospectively recruited individuals with T2DM from primary care, specialist clinics, including an independent Singaporean cohort. Clinically significant fibrosis was defined as liver stiffness measurement (LSM) ≥8 kPa by vibration controlled transient elastography (VCTE). Following the ADA recommended pathway of FIB-4 combined with VCTE, we assessed its diagnostic performance and then replaced FIB-4 with the DiabetesLiver score to establish a DiabetesLiver VCTE pathway. Diagnostic accuracy and missed diagnosis rates were compared across all cohorts. Results: A total of 2,540 T2DM patients were included. The DiabetesLiver score showed significantly higher discriminative accuracy than FIB-4 (AUC 0.79 vs. 0.53) and markedly lower missed diagnosis rates overall (5.6% vs. 17.4%). Notably, in clinics settings, DiabetesLiver score further reduced missed diagnosis rate compared with FIB-4 (11.1% vs. 26.6%, P < 0.001). In the Singapore validation cohort, the DiabetesLiver score consistently outperformed FIB-4 (AUC 0.808 vs 0.478; missed diagnosis 5.2% vs. 18.5%; P < 0.001). Consistent benefits were observed in both primary care- and clinics-based subgroups. Conclusion: The DiabetesLiver score, combined with VCTE, achieves superior accuracy and fewer missed cases of clinically significant fibrosis than the standard FIB-4-based strategy in Chinese and Singaporean individuals with T2DM. These findings support the DiabetesLiver score as a first-line, non-invasive screening tool for liver fibrosis in diabetes care. Disclosure X. Wang: None. C. Liu: None. S. Liu: None. Y. Chen: None. D. Yu: None. Z. Dai: None. Y. Zhang: None. H. Shi: None. K. Chen: None. J. Song: None. H. Xin: None. Y. Tang: None. Z. Meng: None. P. Liu: None. X. Liang: None. H. Fan: None. C. Gu: None. Z. Dai: None. F. Xu: None. X. Li: None. J. Zhang: None. J. Miao: None. Y. Liao: None. Y. Shen: None. X. Ma: None. H. Wang: None. M. Zheng: None. X. Zhou: None. X. Qi: None. Funding The Key Research and Development Program of Jiangsu Province (BE2023767a)

BackgroundMaturity-onset diabetes of the young (MODY) is an autosomal dominant monogenic diabetes, with HNF1A-MODY (MODY3) being a common subtype. Standard genetic testing for MODY often focuses on sequencing, which can lead to the misdiagnosis of cases caused by HNF1A copy number variants (CNVs). This study investigates the diagnosis of a Chinese family with a HNF1A(NM_000545.8):ex1_10del.MethodsWe evaluated a Chinese family with a clinical diagnosis of maturity-onset diabetes of the young (MODY). Clinical data and peripheral blood samples were collected from family members. A heterozygous HNF1A(NM_000545.8):ex1_10del was suspected by next-generation sequencing (NGS) using a hereditary diabetes gene panel.This finding was validated using multiplex ligation-dependent probe amplification (MLPA). We also conducted a literature review of previously reported HNF1A-MODY cases associated with heterozygous exon deletions.ResultsA heterozygous HNF1A(NM_000545.8):ex1_10del was identified by MLPA in the pedigree after next-generation sequencing (NGS) detected no pathogenic single-nucleotide variants (SNVs) or small insertions/deletions (indels). The deletion was classified as pathogenic according to ACMG/AMP and ClinGen guidelines. The family’s clinical phenotype aligned with previously reported HNF1A-MODY cases caused by whole-gene or exon deletions, showing similarities to phenotypes associated with SNVs and small indels. Following genetic diagnosis, the proband was transitioned from insulin to glimepiride, achieving optimal glycemic control.ConclusionsThis study identifies a HNF1A whole-gene deletion in a Chinese family with MODY, confirming the effectiveness of sulfonylureas for HNF1A-MODY management. Large HNF1A deletions, undetectable by standard sequencing, can cause MODY and necessitate copy number variant (CNV) analysis. MLPA is essential for definitive MODY diagnosis, particularly in cases with strong clinical suspicion but negative sequencing results. These findings broaden the known spectrum of HNF1A mutations and highlight the critical role of CNV detection in MODY genetic testing.

OBJECTIVE:To evaluate the efficacy and safety of tubeless hybrid closed-loop (HCL) systems in type 1 diabetes (T1D). METHODS:We searched Web of Science, PubMed, Scopus, and Embase from inception to April 1st, 2026 for randomized controlled trials (RCTs) comparing tubeless HCL systems with standard care (SC; sensor-augmented pumps [SAP] or multiple daily injections [MDI] + continuous glucose monitoring [CGM]). Primary efficacy outcomes were time in range of 3.9-10.0 mmol/L (TIR) and glycated haemoglobin (HbA1c). Secondary efficacy outcomes included time above range (TAR10.0, TAR13.9), time below range (TBR3.9, TBR3.0), and coefficient of variability (CV). Safety outcomes included severe hypoglycaemia (SH) and diabetic ketoacidosis (DKA) risks. Random- or fixed-effects models were used as appropriate. RESULTS:Four RCTs involving 514 participants were included. The mean age was 32.3 ± 15.7 years, with a mean T1D duration of 14.7 ± 11.1 years, and with mean baseline HbA1c 8.0% ± 1.0%. Three studies compared tubeless HCL with SAP, and one with MDI + CGM. Compared with SC, tubeless HCL improved TIR (MD = 15.31%, 95% CI [7.67%, 22.95%], I 2 = 95%, p < 0.001) and HbA1c (MD = -0.46%, 95% CI [-0.79%, -0.14%], I 2 = 91%, p = 0.005). Lower levels of TAR (TAR10.0, TAR13.9), TBR3.9 and CV were also observed (all p < 0.001) in tubeless HCL group. No significant differences were observed in TBR3.0 (MD = -0.06%, 95% CI [-0.17%, 0.06%], I 2 = 71%, p = 0.35) and insulin dose. DKA and SH events were rare in both groups. CONCLUSIONS:The available evidence suggests that tubeless HCL systems may improve glycaemic control without increasing insulin dose or short-term safety risks. Head-to-head trials using identical algorithms are needed to isolate form-factor-specific effects.

Background Dysbiosis of gut microbiota plays a key role in type 1 diabetes mellitus (T1DM). Fecal microbiota transplantation represents a novel therapeutic avenue. We hypothesize that youth-derived fecal microbiota transplantation (yFMT) can remodel the gut microecosystem and improve clinical outcomes. This study aims to investigate the efficacy and safety of orally administered yFMT capsules in adults with T1DM. Methods and analysis This single-center, randomized, double-blind, placebo-controlled pilot study will enroll adults with T1DM who have suboptimal glycemic outcomes (glycated hemoglobin[HbA1c] of 7-14% and time in range [TIR] <70%). Following a 17-day run-in period for insulin optimization, continuous glucose monitoring(CGM) wearing, baseline assessments and bowel preparation, participants will be randomly allocated (1:1) to take yFMT or placebo capsules for consecutive 6 days, alongside their standard insulin therapy, and then complete a 12-week follow-up. The primary efficacy endpoint is the change from baseline in the rate of achieving the composite target of TIR>70% and time below range<4% at 4 and 12 weeks post-randomization. Secondary efficacy endpoints comprise changes from baseline at weeks 4 and 12 in other glycemic metrics (including HbA1c, fasting glucose, 2-hour postprandial glucose, and additional CGM metrics), C-peptide, immune responses, infection markers, and gut microbiota composition. Changes from baseline at week 12 in serum metabolomic profiles will also be assessed, encompassing bile acids, short-chain fatty acids, and other related metabolites. Safety endpoints include the incidence of adverse events and serious adverse events. Discussion Our findings will offer new insight into the feasibility and effects of oral yFMT in adult with T1DM and provide the necessary evidence to power a subsequent multicenter large-scale study. Exploratory biomarker analyses conducted within this study may further pave the way for future individualized microbiome?based therapeutics. Trial registration Chinese Clinical Trial Registry identifier: ChiCTR2500111955 (November 2015). ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ChiCTR2500111955 ### Funding Statement Yes ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study has been approved by the Medical Ethics Committee, Zhongnan Hospital of Wuhan University [2025302]. All participants will provide written informed consent before enrollment. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data obtained during the course of this study will not be publicly available due to ethical and legal restrictions. De-identified data may be made available upon reasonable request to the corresponding author, subject to approval by the institutional ethics committee.

BackgroundIgG4-related autoimmune pancreatitis (IgG4-AIP) is a rare autoimmune pancreatic disorder with non-specific clinical manifestations that is often misdiagnosed as acute pancreatitis (AP). Its coexistence with type 2 diabetes mellitus (T2DM) may further complicate recognition of the underlying pancreatic disease.Case presentationA 60-year-old male with a 4-year history of T2DM was admitted for diabetic complications manifesting as blurred vision and lower limb numbness. During hospitalization, he developed recurrent epigastric pain associated with elevated pancreatic enzymes and was initially diagnosed with AP. Conventional treatment for AP did not lead to sustained improvement, and amylase and lipase remained persistently elevated. Serum IgG4 was markedly elevated at 13.8 g/L. Imaging findings were unremarkable. Endoscopic ultrasound-guided fine-needle aspiration revealed chronic inflammatory changes. The diagnosis of IgG4-AIP was ultimately established based on the markedly elevated serum IgG4 level, supportive (though atypical) imaging findings, histopathological features, and a favorable response to glucocorticoid therapy. The patient’s symptoms improved, accompanied by an overall decrease in serum IgG4 and pancreatic enzyme levels.ConclusionIn T2DM patients with recurrent abdominal pain and persistently elevated pancreatic enzymes unresponsive to routine AP treatment, IgG4-AIP should be considered. Timely measurement of serum IgG4 and careful integration of imaging, histopathology, and treatment response are important for early diagnosis. Early recognition may prevent misdiagnosis and enable timely initiation of glucocorticoid therapy.

Adipose tissue serves as a crucial energy storage and metabolic organ in the human body. With the surging of elderly population in China comes significant challenges in preventing and managing age-associated diseases, while adipose tissue aging represents one of the pivotal initiating events for multi-organ senescence. To address these challenges, the Aging China Biomarkers Consortium (ABC) has established an expert consensus on biomarkers of adipose tissue aging by digesting literature and collecting insights from scientists and clinicians. This consensus provides a comprehensive evaluation of the key changes and characteristics, as well as biomarkers related to adipose tissue aging and proposes a systematic framework categorizing these biomarkers into functional, structural and humoral dimensions. Within each dimension, the ABC recommends clinically and empirically validated biomarkers and parameters for assessing both physiological and pathological changes in adipose tissue during aging, which aims to establish a foundation for future prediction, diagnosis, early warning and treatment for adipose tissue aging and its related diseases, with the ultimate goal of improving adipose tissue health and promoting healthy aging in elderly populations both in China and worldwide.

Introduction and Objective: The mechanisms driving hepatic fat deposition heterogeneity in obesity remain unclear. This study explores these mechanisms through proteomics and single-cell transcriptomics analyses of liver tissues from obese patients with varying degrees of fat deposition. Methods: A total of 110 bariatric surgery patients, categorized by MRI liver fat quantification (no, mild, moderate, and severe fatty liver), were included with ethical approval. Liver tissues (100 mg) were collected during surgery. Proteomics and lipidomics were performed on 91 patients, and 18 underwent single-cell and spatial transcriptomics analysis. Results: Proteomics revealed increased FABP4 expression with higher fat deposition, but expression decreased in diabetes cases with similar fat levels. Single-cell transcriptomics mapped 170,451 cells across 18 samples, identifying 11 cell types. FABP4 expression rose in hepatocytes and macrophages as fat increased, but only FABP4-high macrophages (MAC-FABP4) showed significant proportional growth. MAC-FABP4 displayed specific high expression of genes like LPL, APOC1, and PLA2G7, and interacted extensively with hepatocytes and neutrophils during fatty liver progression. In mouse models (high-fat diet and Ob/Ob mice), FABP4 expression in hepatic macrophages was elevated, and inhibiting FABP4 significantly delayed fatty liver progression. Conclusion: MAC-FABP4 plays a crucial role in the formation and progression of fatty liver, highlighting its potential as a therapeutic target. Z. Dai: None. H. Wang: None. Medical Sci-Tech innovation platform of Zhongnan Hospital, Wuhan University (PTXM2021016, PTXM2024015); Health Commission of Hubei Province (WJ2019M204)

Background Metabolic dysfunction-associated steatotic liver disease is linked to type 2 diabetes mellitus, but its relationship with a risk of prediabetes or type 2 diabetes in patients with obesity remains unclear. MRI-derived proton density fat fraction (PDFF) can accurately quantify liver fat. Purpose To define the precise dose-response relationship between liver MRI-derived PDFF and risk of prediabetes or type 2 diabetes in patients with obesity, and to explore the mediating role of liver enzymes. Materials and Methods This retrospective study included adult patients with obesity who underwent MRI to determine PDFF and who were administered a 75-g oral glucose tolerance test between September 2020 and December 2023. Based on oral glucose tolerance test results, patients were classified as having normal glucose tolerance, prediabetes, or type 2 diabetes. Steatosis severity was categorized by PDFF (<5%, 5% to <15%, 15% to <25%, or ≥25%). Multinomial logistic regression assessed the association between liver PDFF and prediabetes or type 2 diabetes. Mediation analysis evaluated the levels of alanine aminotransferase and aspartate aminotransferase. The findings were validated in an independent cohort. Results A dose-response relationship was found between liver PDFF and abnormal glucose metabolism in 683 patients (mean age, 33 years ± 6.5 [SD]; 121 male patients). Each 1% increase in PDFF was associated with higher odds of both prediabetes and type 2 diabetes (odds ratio [OR], 1.04; 95% CI: 1.02, 1.07; P < .001). Severe steatosis (PDFF ≥ 25%) was associated with higher odds of prediabetes (OR, 3.49; 95% CI: 1.35, 9.02; P = .01) and type 2 diabetes (OR, 3.45; 95% CI: 1.30, 9.13; P = .01). The association was partially mediated by aspartate aminotransferase (mediation proportion, 27.3%) and alanine aminotransferase (mediation proportion, 38.8%) (P < .001 for both). These findings were validated because patients with dysglycemia had higher mean liver PDFF than did patients with normoglycemia (19.7% vs 12.9%, respectively; P < .001). Conclusion In patients with obesity, the liver MRI-derived PDFF was strongly associated with the odds of prediabetes and type 2 diabetes, showing a dose-response relationship partially mediated by liver enzymes. © The Authors 2025. Published by the Radiological Society of North America under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Reeder and Starekova in this issue.

Introduction and Objective: The role transmembrane protein 258 (TMEM258) in hepatocytes remains unknown. This study aims to explore the role of this protein in the progression of MASLD. Methods: Human liver samples were obtained from patients with obesity, and proteomics analysis was performed on these samples. AAV8-injection by tail vein was used to establish Tmem258-knockdown (KD) mice, followed by a feeding with 60% high-fat diet (HFD). In AML12 cells, lentiviral transfection was used to construct liver cells with Tmem258-knockdown (KD-Tmem258). Results: In patients with obesity, TMEM258 protein expression levels increased with the accumulation of hepatic fat. Compared to the control mice (Con), Tmem258-KD mice exhibited significantly greater increases in body weight following HFD. In KD mice, liver tissue sections showed increased Oil-Red O staining positive areas, accompanied by elevated TG content. Transmission electron microscopy revealed significantly larger lipid droplets in hepatocytes of KD mice. Consistently, Tmem258 knockdown in AML12 cells also had similar results. RNA-seq analysis of Tmem258-KD cells revealed that differentially expressed genes were enriched in the fatty acid metabolism pathway and showed significant up-regulation of CD36 expression. Both in liver tissues and AML12 cells, CD36 protein expression was up-regulated when lacking Tmem258. Subsequently, after reversing the high expression of CD36 in KD-Tmem258 cells, fatty acid uptake capacity was decreased. Conclusion: In MASLD, the increased expression of TMEM258 may play a compensatory protective role. Reducing its expression exacerbates hepatic fat accumulation, the mechanism of which is closely related to increased CD36 expression. H. Wang: None. Z. Dai: None.

Background This meta-analysis was performed to obtain a comprehensive overview of the differences between once-weekly basal insulin (including icodec and basal insulin Fc) and once-daily basal insulin (including glargine and degludec) in patients with type 1 and type 2 diabetes mellitus. Methods PubMed, EMBASE, and Cochrane Library were systematically searched for eligible studies up to 2 January 2024. Results A total of 12 studies were included, comprising 5,895 patients, with 3,104 (52.7%) using once-weekly insulin and 2,791 (47.3%) using once-daily insulin. In the pooled data, glycated hemoglobin (HbA1c) change from baseline [mean difference (MD) -0.11%; 95% confidence interval (CI) -0.20 to -0.01%] and the odds of achieving an end-of-trial HbA1c <7% (OR 1.41, 95% CI 1.13, 1.77) demonstrated a significantly good glycemic control in the once-weekly insulin group, especially in insulin-na & iuml;ve type 2 diabetics or patients using icodec. Body weight increase for once-weekly insulin was 0.43 kg compared to controls (95% CI 0.09 to 0.76 kg). In addition, once-weekly insulin was correlated with a higher risk of level 1 hypoglycemia (OR 1.42, 95% CI 1.26 to 1.6). There was no significant difference in fasting plasma glucose (MD 2.46 mg/dL; 95% CI -2.60 to 7.52 mg/dL), time in range (MD 2.03%; 95% CI -0.50 to 4.56%), and level 2 or 3 hypoglycemic events (OR 1.19; 95% CI 0.93 to 1.53). Conclusions Once-weekly basal insulin is safe and effective in modestly reducing HbA1c with similar level 2 or 3 hypoglycemic events compared to once-daily insulin, although the risk of level 1 hypoglycemia and weight gain was slightly increased. Systematic review registration https://www.crd.york.ac.uk/PROSPERO, Identifier CRD42024496812.