AIMS:To compare up-to-date efficacy and safety data of sodium-glucose cotransporter-2 inhibitors (SGLT-2is) versus other metformin-containing oral dual-therapies (ODTs) in type 2 diabetes mellitus. METHODS:We updated a 2016 systematic literature review (SLR), searching MEDLINE, Embase, the Cochrane Database of Systematic Reviews, congress abstracts and SLR/meta-analysis (MA) bibliographies to identify randomised controlled trials. Two independent reviewers determined eligible studies, which were extracted and assessed using the Cochrane Risk of Bias tool. MA was conducted using random-effects pairwise models. RESULTS:We included 36 publications (23 unique studies). Mean differences (MD) indicated comparable change in HbA1c from baseline at Weeks 24 and 52 between SGLT-2i plus metformin and other metformin-containing ODTs. Patients on SGLT-2i plus metformin showed a significantly lower risk of hypoglycaemia (risk ratio [RR]: 0.27, 95% CI: 0.09, 0.84) and significantly greater weight reduction (MD: -2.59; 95% CI: -4.42, -0.77), but an elevated risk of genital infection (RR: 5.08; 95% CI: 3.49, 7.38) at Week 52 compared with other ODTs. Other safety outcomes (e.g., urinary tract infections) were comparable between SGLT-2i plus metformin and other ODTs. CONCLUSION:Compared with other ODTs, SGLT-2i plus metformin exhibited overall comparable efficacy and safety, with a lower risk of hypoglycaemia and greater weight reduction at Week 52.

BACKGROUND/AIMS:Metabolic dysfunction-associated steatotic liver disease (MASLD) lacks effective pharmacotherapy. Although AMP-activated protein kinase (AMPK) is a central metabolic regulator with hepatoprotective effects, the upstream mechanisms governing its degradation in MASLD remain poorly defined. Here, we identify potassium channel modulatory factor 1 (KCMF1) as a previously unrecognized E3 ubiquitin ligase targeting AMPKα and investigate its role in MASLD pathogenesis. METHODS:Protein interactions were characterized by co-immunoprecipitation and GST pull-down assays. Ubiquitin-linkage specificity and AMPKα stability were assessed biochemically. Hepatocyte-targeted gain-of-function and hepatocyte-specific KCMF1 ablation were evaluated across multiple mouse MASLD models (HFD, GAN, CDAHFD, and ob/ob), with AMPK dependency assessed by pharmacological modulation. An AI-guided virtual screen with biophysical validation was conducted to identify candidate KCMF1 inhibitors. RESULTS:KCMF1 expression was markedly upregulated in hepatocytes from murine and human MASLD livers. KCMF1 directly interacted with AMPKα and catalyzed its K48-linked polyubiquitination, promoting its degradation and suppressing hepatic AMPK signaling. Functionally, hepatic KCMF1 overexpression exacerbated steatosis, inflammation, and fibrosis, whereas its knockdown or hepatocyte-specific deletion conferred protection across MASLD models. Pharmacological modulation of AMPK in vivo and in primary hepatocytes demonstrated pathway dependency, as AMPK activation attenuated KCMF1-driven pathology. Furthermore, the flavonoid Rhoifolin was identified as a direct KCMF1 binder that stabilized AMPKα and ameliorated MASLD in mice. CONCLUSIONS:KCMF1 drives MASLD pathogenesis by promoting K48-linked ubiquitination and degradation of AMPKα. Targeting the KCMF1-AMPK axis restores hepatic metabolic homeostasis and represents a potential therapeutic strategy for MASLD.

GLP-1 receptor agonists (GLP-1 RAs) effectively reduce weight in obesity, although significant weight regain typically follows discontinuation. Here, in a randomized clinical trial (ChiCTR2200066014), we found that GLP-1 RA (semaglutide) and a high-fibre diet achieved similar 12-week weight reduction, but semaglutide recipients exhibited significantly higher weight rebound at the 14th week after intervention cessation. Shotgun metagenomic sequencing revealed that semaglutide aggravated the proinflammatory signature in the gut microbiome, which contrasted with high-fibre diet intervention. The microbiota transplanted from semaglutide-treated subjects to germ-free mice induced gut barrier dysfunction, systemic inflammation and an increase in the bacterial antigen load in the liver and adipose tissue, which activated the NF-κB pathway to drive lipid accumulation. Using a diet-induced obesity mouse model, we found that semaglutide exacerbated gut microbiome dysbiosis by weakening host immune surveillance of the gut microbiota through downregulating IFN-γ to reduce antimicrobial peptides expression and delaying gut transit time to shift microbial metabolism from saccharolysis towards proteolysis. Crucially, combining semaglutide with dietary fibre in mice mitigated microbiome dysbiosis and attenuated weight regain post-cessation. These findings suggest that GLP-1 RA-exacerbated gut microbiome dysbiosis in obesity as a key mediator of post-treatment weight rebound and propose adjunctive fibre supplementation as a strategy to sustain weight loss. ### Competing Interest Statement Chenhong Zhang is the co-founder of Adfontes (Ningbo) Co., Ltd. The remaining authors declare no conflict of interest. ### Clinical Trial The trial was registered in the Chinese Clinical Trial Registry: ChiCTR2200066014 (https://www.chictr.org.cn/). ### Funding Statement This work was supported by the National Key Research and Development Project (No. 2022YFF1100103), the National Natural Science Foundation of China (81870594) and the Clinical Research Plan of Shanghai Hospital Development Center (No. SHDC2020CR1016B). This work was also supported by Adfontes (Ningbo) Co., Ltd. The sponsor was not in the study design, data collection, analysis, writing of the manuscript, or the decision to submit the article for publication. ### 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 semaglutide or high-fibre diet intervention study is an open-label, multicenter clinical trial for overweight and obese subjects. Its protocol was approved by the Shanghai General Hospital Ethics Committee (ID: [2022]188), conducted with the Declaration of Helsinki. All subjects provided written informed consent. 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 To protect participant privacy, access to and use of deidentified individual-level clinical data should be requested from the corresponding authors. Generally, all requests for access to data will be responded to within 1 month. The clinical data can only be used for non-commercial scientific research purposes. The raw sequence data have been deposited in the Genome Sequence Archive (GSA) database in the National Genomics Data Center (NGDC) (https://ngdc.cncb.ac.cn/gsa), and the accession numbers of the clinical study, the FMT animal trial, and the semaglutide and dietary fibre interventions animal trial are CRA033354, CRA033365, and CRA033219, respectively. Source Data are provided with this paper. No custom code was used in this paper. All publicly available codes and tools used to analyse the data are reported and referenced in the Methods.

Metabolic dysfunction-associated fatty liver disease ((MASLD) affects over 25

Diabetes, a leading global chronic disease, poses a significant health threat, with physical inactivity being a major risk factor for its development and progression. This guideline, developed by the Chinese Society of Endocrinology, synthesizes the latest evidence and expert insights to provide evidence-based recommendations for physical activity and exercise therapy in adults with type 2 diabetes (T2D). It is generally recommended that all adult patients with T2D engage in at least 150-300 min of moderate-intensity aerobic exercise per week, or a minimum of 75-150 min of vigorous-intensity exercise, or an equivalent combination of moderate- and vigorous-intensity exercise (with a total exercise volume of at least 450 metabolic equivalent-min per week). For patients with T2D who are capable, moderate over-exercise and a combination of different forms of exercise (aerobic, resistance, flexibility, and/or balance training) are encouraged. The guideline also underscores the necessity of targeting specific subgroups of patients with T2D, including the elderly, individuals with obesity or pre-obesity, cardiovascular disease, hypertension, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease, and/or diabetic foot and its high-risk populations. The guideline provides a scientific basis for clinicians to develop personalized exercise guidance and recommendations, with the goal of improving the disease prognosis of the relevant population.

AIMS:We examined whether phenotypic age (PhenoAge) acceleration was associated with the incidence and progression of diabetic retinopathy (DR) and diabetic kidney disease (DKD). METHODS:In 8,194 adults with T2DM, PhenoAge was calculated from nine routine biomarkers at baseline and follow-up. DR was deep-learning graded and DKD met Kidney Disease: Improving Global Outcomes criteria. Associations of PhenoAge acceleration and longitudinal change with incident DR/DKD, concurrent DR-DKD, and progression were estimated using modified Poisson models adjusted for conventional risk factors. RESULTS:Compared with participants in the lowest tertile, those in the highest tertile of baseline PhenoAge acceleration had higher risks of incident DR (RR 1.56, 95% CI 1.10-2.23), DKD (RR 1.30, 1.10-1.54), and concurrent DR and DKD (RR 3.24, 1.56-6.76). Among participants with baseline DR or DKD, respectively, those in the highest tertile of PhenoAge acceleration had an increased risk of DKD progression (RR 2.04, 1.60-2.59), but not DR progression. Longitudinal increases in PhenoAge acceleration were associated with incident DKD (RR 1.36, 1.14-1.62), while decreases in PhenoAge acceleration were associated with lower DKD progression risk (RR 0.59, 0.41-0.85). CONCLUSIONS:PhenoAge acceleration, a routine biomarker-based measure of biological aging, was associated with microvascular complications in T2DM.

Objective: The role of ubiquitin-specific protease 13 (USP13) in metabolic dysfunction-associated steatohepatitis (MASH) remains unclear. This study aimed to elucidate the role of USP13 in MASH progression. Methods: THLE-2 cells were subjected to palmitate acid (PA) to generate an in vitro model of lipid accumulation and inflammation. Two in vivo models of MASH were established by feeding mice with a high-fat, high-fructose and high-cholesterol (HFFC) diet for 16 weeks and a methionine/choline-deficient diet (MCD) for 4 weeks, respectively. Usp13 overexpression and knockout (KO) techniques were employed to investigate its role in MASH. Results: USP13 expression was significantly downregulated in the livers of MASH mice and in the in vitro model of lipid accumulation and inflammation. Hepatic overexpression of Usp13 markedly alleviated liver steatosis, inflammation and fibrosis, while knockout of Usp13 exacerbated the MASH phenotype. Mechanistically, USP13 directly bound to phosphatase and tensin homolog (PTEN) and deubiquitinated it, thereby elevating the PTEN expression and improving the MASH phenotype. Notably, Pten overexpression in Usp13 knockout mice reversed the exacerbation of MASH brought from Usp13 deficiency. Conclusions: Our findings revealed that USP13 alleviates MASH by directly binding to and deubiquitinating PTEN. The USP13-PTEN axis may represent a promising molecular target for MASH treatment.

AIM:To evaluate the efficacy of chiglitazar, a novel pan-PPAR agonist, on metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with type 2 diabetes (T2D) in a real-world clinical setting. MATERIALS AND METHODS:This prospective cohort study included T2D patients with MASLD who received either chiglitazar or other glucose-lowering medications over a 24-week period. To minimize selection bias, 1:1 propensity score matching (PSM) was implemented. The primary outcomes were changes in controlled attenuation parameter (CAP, measuring hepatic steatosis) and liver stiffness measurement (LSM, assessing fibrosis). Secondary outcomes included glycemic parameters and liver enzymes. RESULTS:A total of 235 T2D patients were enrolled (40 chiglitazar users, 195 non-chiglitazar users), and 31 matched pairs were derived after 1:1 PSM. The adjusted mean reduction in CAP from baseline to 24 weeks was significantly greater in the chiglitazar group (-28.38 dB/m [95 % CI:36.11;-20.65]) compared to the non-chiglitazar group (-16.74 dB/m [-24.47;-9.01]), with a between-group difference of -11.64 dB/m (-22.38;-0.90, P = 0.038). LSM changes were similar between groups (difference in LS mean:0.11 [-1.04;0.82], P = 0.813). Subgroup analyses indicated that the beneficial effect of chiglitazar was consistent across variables such as sex, age, body mass index, and concomitant use of SGLT-2 inhibitors or GLP-1 receptor agonists (all P for interaction > 0.05). CONCLUSIONS:Chiglitazar administration is associated with a significant reduction in CAP values in T2D patients with MASLD, suggesting its potential as a dual therapeutic approach for both conditions.

Gut microbiota contributes to prediabetes progression, however, whether microbiota features can guide targeted prevention and treatment for diabetes requires validation through large-scale clinical trials. Here, in a randomized, open-label trial, we randomly assigned 802 prediabetic subjects to a usual care control group (patient education and dietary recommendations, n = 393) or a dietary fiber intervention group (n = 409) for 6 months. The primary outcome was the percentage change in whole-blood HbA1c, and secondary outcomes were the changes in other glucose, insulin, lipid, liver and kidney function, and anthropometric parameters. There were no statistically significant differences in the primary and secondary outcomes between groups. In post-hoc analysis, we reclassified subjects into four clusters using a multivariate clustering model based on age, BMI, HbA1c, HOMA2-IR and HOMA2-B. These clusters differed in metabolic status, risks of diabetes and its complications, gut microbiome and serum metabolites. Notably, dietary fiber improved glycemic control in Clusters 3 and 4, but not in Clusters 1 and 2, consistent with observed gut microbiota alleviations. By using a LightGBM machine learning model, we calculated a microbiome-based clinical decision score to predict personalized fiber intervention responses and identified individuals who can get glycemic benefits. In conclusion, our study suggests that the gut microbiota response influences the effectiveness of dietary fiber intervention and provides a clinically applicable model to guide microbiome-targeted personalized medicine for prediabetes. Clinical Trial Registry: ChiCTR1900027663. Here, in a large-scale clinical trial, the authors associate gut microbiota composition and metabolic status with effectiveness of dietary fiber intervention in prediabetes, and provide a clinically applicable model to guide microbiome-targeted personalized medicine.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly, leading to an Omicron outbreak in Shanghai in mid-December after adjustments to the Coronavirus Disease 2019 (COVID-19) control strategy. To investigate the impact of COVID-19 infection among hypothyroid patients, we gathered data on the hypothyroid outpatients with COVID-19 infection during this time at the Thyroid Disease Center (TDC) of Shanghai Central Hospital. Patients were divided into two groups based on whether their hypothyroidism was caused by Hashimoto’s Thyroiditis (HT): the HT and the non-HT group. We assessed the differences between pre-infection and clinical follow-up at one month (day (D) 30) and three months (D90) after COVID-19 infection. In HT group, thyroid-stimulating hormone (TSH) levels decreased significantly compared to pre-infection levels (p = 0.013), while free triiodothyronine (FT3) levels increased at D90 compared to both D30 post-infection and pre-infection levels (p < 0.001 and p = 0.005). Hemoglobin levels also increased after COVID-19 infection (p = 0.033). For non-HT patients, FT3 levels increased at D30 compared to pre-infection levels (p = 0.017). Moreover, inactivated SARS-CoV-2 vaccination can preserve thyroid function stability in patients with hypothyroidism.

Nickel, a transition metal, is ubiquitous in the environment due to both natural processes and anthropogenic activities. While exposure to nickel has been linked to various adverse health outcomes—including genomic damage, allergic reactions, renal disorders, pulmonary fibrosis, carcinomas of the lung and nasal cavities—its cardiovascular toxicity and metabolic implications remain comparatively underexplored. Recently, a series of cross-sectional analyses utilizing data from the National Health and Nutrition Examination Survey (NHANES) have emerged, providing valuable insights into this issue. Based on the literature from PubMed, this review aims to comprehensively, but narratively summarize clinical observations and database analyses derived from human survey datasets, alongside experimental studies conducted on animal models exposed to varying doses of nickel. Current literature suggests a potential association between nickel exposure, primarily indicated by urinary nickel levels, and cardiovascular as well as metabolic disease variables; however, at low doses, inconclusive findings remain even using the same databases, mainly due to the clinical variables differently used in different studies. Experimental research has demonstrated significant toxic effects of exposure to nickel across multiple organs, including the heart and liver, which seemed significantly associated with oxidative stress and damage. Consequently, this review underscores the urgent need for further investigation utilizing both human data and experimental animal models, particularly focusing on low-level nickel exposure, to elucidate the cardiovascular and metabolic consequences of nickel exposure in humans.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, and the effects of chlorogenic acid (CA) on it are unclear. This study investigated CA's therapeutic effects and mechanisms on a dehydroepiandrosterone (DHEA)-induced PCOS rat model and KGN granulosa cells, hypothesizing that CA ameliorates hormonal imbalance, inflammation, and oxidative stress in PCOS by regulating the NF - κB signaling pathway and ferroptosis - related proteins. The methods included in - vivo experiments on rats with different treatments and in - vitro experiments on KGN cells. Results showed that CA restored the estrous cycle and ovulation, alleviated hyperandrogenism, reduced inflammation and oxidative stress markers, improved follicular development, and decreased ferroptosis in PCOS rats. It upregulated GPX4 and SLC7A11 expression, decreased ROS levels, and bound strongly with NF - κB p65, downregulating NF - κB pathway activation markers. In KGN cells, CA improved proliferation, reduced ferroptosis, oxidative stress, and mitochondrial damage, similar to Fer - 1. The combined use of an NF - κB inhibitor and CA restored the cellular oxidative state. In conclusion, CA improves hormonal balance, alleviates inflammation and oxidative stress by regulating the NF - κB pathway and ferroptosis - related proteins, showing potential as a PCOS therapeutic agent, and further studies are needed for confirmation and clinical application exploration.

Metabolic-associated fatty liver disease (MAFLD), a highly prevalent global liver disorder, requires early diagnosis and treatment to delay progression, yet lacks simple diagnostic tools. We aimed to evaluate the validity of the triglyceride-glucose index (TyG) and its related indexes in predicting MAFLD and pre-MAFLD among Chinese individuals. This cross-sectional study enrolled 9,627 Chinese participants (mean age 46.53 ± 11.87 years; 62.1

Aim:The aim of this study was to compare the efficacy and safety of fixed-dose combination (FDC) of pioglitazone and metformin supplemented with dapagliflozin (test group) with those of basal insulin supplemented with metformin (control group) in patients with inadequately controlled type 2 diabetes mellitus (T2DM). Methods:This 16-week, prospective, randomized, open-label study enrolled patients aged 18-75 years with glycated hemoglobin (HbA1c) levels between ≥ 8% and ≤ 11%. The primary endpoint was the proportion of patients who achieved HbA1c < 7% at week 16 without hypoglycemia or weight gain. The secondary endpoints included blood glucose, lipid profile, body weight, body mass index, inflammatory markers, bone Gla-protein, liver enzymes, and patient satisfaction. Results:Among the full analysis set of 147 participants, no significant difference was observed in the primary endpoint between the test group and the control group. However, the test group had a higher percentage of patients who achieved HbA1c <7% at week 16 without hypoglycemia and experienced a weight loss of ≥3% (31.51% vs 13.51%, P=0.009). Patients in the test group whose BMI≥24 kg/m2 also achieved a substantial achievement rate (36.73% vs 15.79%, P=0.014). The test group also exhibited a greater reduction in body weight and improvements in 2-hour postprandial glucose level, systolic blood pressure, and lipid profile. Notably, combination therapy did not increase the risk of hypoglycemia or weight gain. Patients in the test group were more satisfied than those in the control group with continuing to accept pioglitazone/metformin FDC combined with dapagliflozin. Conclusion:In the absence of contraindications, pioglitazone/metformin FDC supplemented with dapagliflozin may serve as a safe and effective alternative to basal insulin combined with metformin for rectifying inadequate glucose control, as the former enables metabolic improvements without compromising safety. Chinese Clinical Trial Registry Number:CHiCTR2000036076. https://www.chictr.org.cn/showproj.html?proj=58825.

BACKGROUND:Osteoporosis is a chronic disease of bone metabolism with high incidence rates. Recently, exosome therapy has emerged as a promising avenue for the treatment of osteoporosis. However, the role of autophagy-induced osteoblast-derived exosomes (Auto-exo) in osteoporosis has yet to be elucidated. METHODS:The effect of Auto-exo on bone formation was assessed in vivo. The composition of gut microbiota was determined through 16S rDNA sequencing, and metabolite profiles were analyzed using liquid chromatography-mass spectrometry (LC-MS). Cell experiments were conducted to explore the role of bilirubin in bone formation. RESULTS:Auto-exo were successfully isolated and identified. Auto-exo promoted bone formation and alleviated osteoporosis progression in a mouse model of osteoporosis. 16S rDNA sequencing revealed that Auto-exo changed diversity and composition of gut microbiota in osteoporotic mice, with a notable increase in Lactobacillus and a decrease in Dubosiella and Faecalibaculum. LC-MS analysis indicated that Auto-exo treatment reduced the elevated levels of bilirubin in osteoporotic mice. Cell experiments uncovered that bilirubin remarkably inhibited osteoblast differentiation. Furthermore, Auto-exo promoted osteoblast differentiation via inhibiting bilirubin production. CONCLUSIONS:Our findings demonstrated that Auto-exo promoted bone formation by modulating the gut microbiota-metabolite bilirubin axis, thereby alleviating osteoporosis progression. This discovery provides a novel perspective on the mechanism underlying the therapeutic effects of Auto-exo on osteoporosis.

AIM:We investigated the relationship between the complexity of the glucose time series index (CGI) during pregnancy and adverse pregnancy outcomes in women with gestational diabetes mellitus (GDM). MATERIALS AND METHODS:In this retrospective cohort study, 388 singleton pregnant women with GDM underwent continuous glucose monitoring (CGM) at a median of 26.86 gestational weeks. CGI was calculated using refined composite multiscale entropy based on CGM data. The participants were categorized into tertiles according to their baseline CGI (CGI <2.32, 2.32-3.10, ≥3.10). Logistic regression was used to assess the association between CGI and composite adverse outcomes or large for gestational age (LGA). The discrimination performance of CGI was estimated using receiver operating characteristic analysis. RESULTS:Of the 388 participants, 71 (18.3%) had LGA infants and 63 (16.2%) had composite adverse outcomes. After adjustments were made for confounders, compared with those with a high CGI (CGI ≥3.10), participants with a low CGI (CGI <2.32) had a higher risk of composite adverse outcomes (odds ratio: 12.10, 95% confidence interval: 4.41-33.18) and LGA (odds ratio: 12.68, 95% confidence interval: 4.04-39.75). According to the receiver operating characteristic analysis, CGI was significantly better than glycated haemoglobin and conventional CGM indicators for the prediction of adverse pregnancy outcomes (all p < .05). CONCLUSION:A lower CGI during pregnancy was associated with composite adverse outcomes and LGA. CGI, a novel glucose homeostasis predictor, seems to be superior to conventional glucose indicators for the prediction of adverse pregnancy outcomes in women with GDM.

Background As the primary source of glucose during fasting, hepatic gluconeogenesis is rigorously regulated to maintain euglycemia. Abnormal gluconeogenesis in the liver can lead to hyperglycemia, a key diagnostic marker and the primary pathological contributor to type 2 diabetes (T2D) and metabolic disorders. Hepatic nuclear factor-4 (HNF4α) is an important regulator of gluconeogenesis. In this study, we identify leupaxin (LPXN) as a novel coactivator for HNF4α. Although previous studies have shown that LPXN is highly correlated with cancer types such as B-cell differentiation and hepatocellular carcinoma progression, the role of LPXN in gluconeogenesis remains unknown. Methods We initially used protein pull-down assays, mass spectrometry and luciferase assays to identify the coactivator that interacts with HNF4α in gluconeogenesis. We further leveraged cell cultures and mouse models to validate the functional importance of molecular pathway during gluconeogenesis by using adenovirus-mediated overexpression and adeno-associated virus shRNA–mediated knockdown both in vivo and ex vivo, such as in ob/db/DIO mice, HepG2 and primary hepatocytes. Following, we used CUT&Tag and chip qPCR to identify the LPXN-mediated mechanisms underlying the observed abnormal gluconeogenesis. Additionally, we assessed the translational relevance of our findings using human liver tissues from both healthy donors and patients with obesity/type 2 diabetes. Results We found that LPXN interacts with HNF4α to participate in gluconeogenesis. Knockdown of LPXN expression in the liver effectively enhanced glucose metabolism, while its overexpression in the liver effectively inhibited it. Mechanistically, LPXN could translocate into the nucleus and was essential for regulating gluconeogenesis by binding to the PEPCK promoter, which controlled the expression of an enzyme involved in gluconeogenesis, mainly through the Gcg-cAMP-PKA pathway. Additionally, LPXN expression was found to be increased in the livers of patients with steatosis and diabetes, supporting a pathological role of LPXN. Conclusions Taken together, our study provides evidence that LPXN plays a critical role in modulating hepatic gluconeogenesis, thereby reinforcing the fact that targeting LPXN may be a potential approach for the treatment of diabetes and metabolic disorders.

Abstract Background The molecular mechanisms underlying nonalcoholic fatty liver disease (NAFLD) remain to be fully elucidated. Ubiquitin specific protease 13 (USP13) is a critical participant in inflammation-related signaling pathways, which are linked to NAFLD. Herein, the roles of USP13 in NAFLD and the underlying mechanisms were investigated. Methods L02 cells and mouse primary hepatocytes were subjected to free fatty acid (FFA) to establish an in vitro model reflective of NAFLD. To prepare in vivo model of NAFLD, mice fed a high-fat diet (HFD) for 16 weeks and leptin-deficient (ob/ob) mice were used. USP13 overexpression and knockout (KO) strategies were employed to study the function of USP13 in NAFLD in mice. Results The expression of USP13 was markedly decreased in both in vitro and in vivo models of NAFLD. USP13 overexpression evidently inhibited lipid accumulation and inflammation in FFA-treated L02 cells in vitro. Consistently, the in vivo experiments showed that USP13 overexpression ameliorated hepatic steatosis and metabolic disorders in HFD-fed mice, while its deficiency led to contrary outcomes. Additionally, inflammation was similarly attenuated by USP13 overexpression and aggravated by its deficiency in HFD-fed mice. Notably, overexpressing of USP13 also markedly alleviated hepatic steatosis and inflammation in ob/ob mice. Mechanistically, USP13 bound to transforming growth factor β-activated kinase 1 (TAK1) and inhibited K63 ubiquitination and phosphorylation of TAK1, thereby dampening downstream inflammatory pathways and promoting insulin signaling pathways. Inhibition of TAK1 activation reversed the exacerbation of NAFLD caused by USP13 deficiency in mice. Conclusions Our findings indicate the protective role of USP13 in NAFLD progression through its interaction with TAK1 and inhibition the ubiquitination and phosphorylation of TAK1. Targeting the USP13-TAK1 axis emerges as a promising therapeutic strategy for NAFLD treatment.

BACKGROUND:The aim of this study is to analyze the associations among fat distribution, left ventricular (LV) structure, and function in T2DM patients and further assess the sex differences among them. METHODS:Two thousand and one hundred seven T2DM patients were enrolled to this study. Patients' height, weight, BMI, visceral fat area (VFA), baPWV, parameters of cardiac structure and function, and clinical biochemical indicators were measured and collected. RESULTS:There were significant differences between male and female T2DM patients in age, duration of diabetes, complication ratio of hypertension and dyslipidemia, smoking history, visceral fat, baPWV, and ventricular structure and function (p < 0.05). Compared with the Q1 group, female patients in the highest quartile (Q4) of VFA had a decreased LVEF and significantly increased baPWV (p < 0.05), whereas no such changes were found in males. The correlation analysis showed that LVEF in male patients was negatively correlated with hypertension history, using of CCBs, GLP-1RA, lipid-lowering medications, BMI, WC, WHR, FPG, FC-P, HbA1c, GA, HOMA-IR, Cr, and baPWV, while the LVEF in female patients was negatively correlated with VFA, VSR, VFA/BMI, VFA/H2, VFA/weight in females (p < 0.05). LVMI was positively associated with diabetes duration, age, hypertension history, WC, WHR, VFA, SFA, VFA/BMI, VFA/H2, VFA/weight, and baPWV in both males and females. Multivariable-adjusted linear regression analysis showed that VFA was independently associated with LVEF (β = - 0.096, p = 0.010), LVMI (β = 0.083, p = 0.038), and baPWV (β = 0.120, p = 0.003) in females. CONCLUSIONS:Values of VFA were independently associated with LVEF, LVMI, and baPWV in women, but not in men, in patients with T2DM.