BackgroundUltra-processed food (UPF) consumption has been linked to cardiometabolic diseases, but the association with non-alcoholic fatty liver disease (NAFLD) remains unclear. Moreover, whether all UPFs confer similar risk is unknown.ObjectiveTo systematically review and meta-analyze the association between total UPF intake (strictly defined by NOVA classification) and selected UPF-related food-group exposures [red/processed meat and sugar-sweetened beverages (SSBs)] and NAFLD risk in adults.MethodsWe searched PubMed, Web of Science, and Cochrane Library up to March 31, 2026, for observational studies reporting adjusted effect estimates for total UPF intake or selected food-group exposures and NAFLD. Study quality was assessed using the Newcastle-Ottawa Scale (NOS) or AHRQ criteria. Random-effects models pooled odds ratios (ORs) comparing highest vs. lowest intake categories. Subgroup and sensitivity analyses explored heterogeneity.ResultsTwenty-four studies were included in the systematic review. Of these, nine studies (5 prospective cohorts, 4 cross-sectional) comprising 250,349 participants were included for total UPF intake. Higher total UPF consumption was associated with a 26% increased NAFLD risk (pooled OR = 1.26; 95% CI: 1.16–1.37; I2 = 53%; P < 0.001). Red/processed meat consumption (6 studies) showed a stronger association (pooled OR = 1.70; 95% CI: 1.29–2.24; I2 = 76%; P < 0.001). SSB consumption (3 studies) was associated with a 50% increased risk (pooled OR = 1.50; 95% CI: 1.23–1.84; I2 = 0%; P < 0.001). Sensitivity analyses confirmed robustness.ConclusionTotal UPF intake is associated with a moderate increase in NAFLD risk. Red/processed meat and sugar-sweetened beverages show stronger associations, suggesting that dietary recommendations may prioritize these high-risk food groups, although blanket avoidance of all UPFs is not directly supported by the current data.

Introduction and Objective: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by liver steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. Mazdutide, an agonist of glucagon-like protein-1 receptor (GLP-1R) and glucagon receptor (GCGR), has been demonstrated to alleviate MASH and liver fibrosis in animal models. However, its underlying mechanism and exact target cells in liver fibrosis remain unclear. Herein, we explored its effect on hepatocytes and the crosstalk between Hepatocytes and Hepatic Stellate Cells (HSCs) in vitro and in vivo. Methods: C57BL/6J mice were provided with a diet that was high in fat, fructose, and cholesterol(AMLN). After 32 weeks, the mice were randomly assigned to receive either vehicle or Mazdutide by subcutaneous injection every 2 days for 6 weeks. Immunohistochemistry and biochemical assays were conducted to evaluate the drug effects on inflammation and liver fibrosis. Liver samples were subjected to transcriptome analysis and single cell sequencing analysis. Hepatocytes were treated with palmitic acid and Mazdutide and their effect on HSCs was further explored via condition medium and coculture model. Results: Mazdutide alleviated liver fat accumulation, inflammation and liver fibrosis. It could reprogram hepatic cholesterol metabolism and homeostasis and stimulate complement and coagulation cascades activation through GCGR on Hepatocytes. Mazdutide decreased Hepatocytes lipid deposition and decrease cholesterol content, and thereby interrupting Hepatocytes-induced HSCs activation and reducing collagen secretion. Conclusion: Mazdutide alleviates liver fibrosis in MASH mice via regulating Hepatocytes lipid metabolism and inhibiting HSCs activation through indirect effect, which provides a novel therapeutic avenue for MASH and liver fibrosis. Disclosure L. Zhang: None. H. Wang: None. L. Li: None. H. Jiang: None. Funding National Natural Science Foundation of China (82020108029, 82073398, 823023677, 82473867, 82370424)

Objectives This study aimed to investigate the relationship between serum regenerating protein Iα (REG Iα) levels and estimated glomerular filtration rate (eGFR) and to evaluate the diagnostic efficiency of REG Iα in chronic kidney disease (CKD).Design This is a cross-sectional study.Setting The study was conducted in eastern China between August 2022 and August 2023.Participants A total of 880 participants aged over 18 years were enrolled, with 220 non-CKD participants (111 males, 50.45%) and 660 patients with CKD (366 males, 55.45%). CKD was diagnosed based on the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines. Exclusion criteria included participation in other trials, acute kidney injury, end-stage kidney disease undergoing renal replacement therapy, pregnancy, active infections, gastrointestinal or pancreatic inflammation, history of gastrointestinal or pancreatic resections, cancer and mental disorders.Results Serum REG Iα was significantly higher in the CKD group (125.54 (60.28–303.39) ng/mL) compared with those in the non-CKD group (24.62 (14.09–37.32) ng/mL, p<0.001). Positive correlations were observed between serum REG Iα and serum creatinine, cystatin C (Cys-C), and kidney injury molecule 1 (KIM-1), while a negative correlation was identified with eGFR. After adjusting for sex, diabetes, hypertension and fasting blood glucose, the multivariate regression analysis demonstrated a significant association between serum REG Iα and eGFR (OR=1.737 (1.263–2.388), p=0.001). Furthermore, serum REG Iα levels increased progressively with declining kidney function categorised by eGFR (p<0.001). In CKD screening, serum REG Iα demonstrated strong diagnostic performance, with an area under the receiver operating characteristic curves (AUC) of 0.860 (0.813–0.899), providing a sensitivity of 71.63%, a specificity of 86.89%, a positive predictive value of 94.30% and a negative predictive value of 46.85%. Additionally, serum REG Iα exhibited an AUC of 0.769 (0.712–0.819) for identifying high- and very-high-risk CKD based on KDIGO risk stratification. Its sensitivity significantly outperformed serum Cys-C and KIM-1 (82.80% vs 75.16% and 36.94%, respectively).Conclusions This study provided compelling evidence that serum REG Iα levels were notably elevated in patients with CKD and closely associated with kidney function. REG Iα may serve as a promising biomarker for CKD detection and risk stratification.Clinical trial registration The study was approved by the Ethics Committee of Zhongda Hospital (approval number: 2022ZDSYLL204-P01) and conducted in compliance with the Helsinki Declaration. The clinical trial was registered under ChiCTR2300072247.

Background:Patients with type 2 diabetes mellitus (T2DM) exhibit an elevated risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD). The uric acid to high-density lipoprotein cholesterol ratio (UHR) has emerged as a novel metabolic biomarker implicated in MASLD pathogenesis. This study aimed to evaluate the association between UHR and MASLD in a T2DM population. Methods:In this cross-sectional study, we analyzed clinical data from 1081 T2DM patients (464 without MASLD, 617 with MASLD). Physiological and biochemical parameters were collected and analyzed. UHR was calculated as [uric acid (mg/dL)/HDL-C (mg/dL)] × 100%. Univariate and multivariate logistic regression analyses were performed to examine the association between UHR and MASLD. Results:T2DM patients with MASLD had significantly higher UHR levels than those without MASLD (12.12[9.06-16.83] vs 10.36[7.65-14.08], p<0.001). UHR showed a strong positive correlation with TG/HDL (r =0.673, p < 0.001), moderate correlations with TG (r = 0.516, p < 0.001) and TC/HDL (r =0.548, p < 0.001), weak but significant associations with BMI (r = 0.330), WHR (r = 0.289), HOMA-IR (r = 0.121), ALT (r = 0.123), and GGT (r = 0.267) (all p < 0.05). Multivariate logistic regression showed that elevated UHR levels were significantly associated with increased MASLD risk (adjusted OR = 1.057, 95% CI: 1.016-1.100, p = 0.006), after adjusting for age, diabetes duration, BMI, blood pressure, and biochemical confounders. Conclusion:Elevated UHR is independently associated with MASLD in T2DM patients, suggesting its clinical relevance in MASLD screening among this high-risk population.

Chronic pancreatitis (CP) is a long-standing progressive fibrosis and has long been considered incurable, which remains a heavy health burden worldwide. Mesenchymal stem cells (MSCs) with anti-fibrosis properties are currently used in the treatment of fibroinflammatory diseases. However, its therapeutic effect is limited mainly due to two main types of pathological barriers in CP: 1) Fibrotic collagen hinders cell delivery, and 2) Malignant microenvironment attacks cell inactivation. Here, a MSCs-based exogenous nitric oxide (NO) delivery system (MSCs-Lip@RNO) is constructed. In the MSCs-Lip@RNO, NO not only can be a cell booster to regulate collagen fibers, relieve the vascular compression and enhance the accumulation of MSCs in the whole pancreas, but also can form a protective gas layer on the cell surface, which enhances the therapeutic effect of MSCs. In the CP rat model, the pancreatic injury and fibrosis are reduced with 7 days after a single dose administration of this long-acting MSCs. Collectively, this study offers a promising strategy for enhancing the delivery and therapeutic efficacy of MSCs to break pathological barriers in CP treatment.

Introduction and Objective: Islet encapsulation is an effective method to achieve immune isolation for islet transplantation. The injectable property of the self-healing hydrogel enables minimally invasive transplantation of hydrogel-encapsulated pancreatic islets. Methods: We prepared hydrogel short fiber scaffolds for wrapping islet cells using a microfluidic approach in this experiment. Oxidized sodium alginate and carboxymethyl chitosan were synthesized to form self-healing hydrogels to wrap vascularized components. A mixture of the two hydrogels was injected subcutaneously into diabetic mice and continuously monitored the blood glucose. The mice were sacrificed on the 100th day of the experiment, and tissue sections were stained to observe the condition of the grafts. Results: The composite hydrogel was demonstrated to have good biocompatibility, injectability, permeability and adhesion. The inclusion of vascularized components also improved islet function. In vivo glycemic control was achieved by transplanting the islet-encapsulated hydrogel for 100 days, and immunofluorescence staining showed that the grafts had insulin and glucagon expression. Conclusion: In conclusion, hierarchically structured vascularized hydrogels provide a new strategy for cell therapy of diabetes, as well as new ideas for tissue engineering, and regenerative medicine development. Z. Huan: None. J. Li: None. L. Li: None.

The efficacy of growth factor delivery-based therapies for bone tissue regeneration is frequently undermined by oxidative stress, especially under inflammatory conditions, which results in structure damage and function inactivation of growth factors. Herein, a straightforward and universal protective delivery strategy is proposed by employing the multiple physical interactions between epigallocatechin-3-gallate (EGCG) and growth factors (e.g., neuregulin-1/NRG-1) to efficiently form self-assembled particles (NE APs). NE APs provide sustained release of NRG-1 while protecting it from oxidative damage, preserving its biological functions of cell recruitment, migration, and angiogenesis. Additionally, NE APs leverage EGCG's ability to scavenge reactive oxygen species and maintain mitochondrial homeostasis, while synergistically enhancing TNF/NF-κB/JAK-STAT signaling pathways to support immune responses and osteogenic differentiation. In vivo experiments demonstrated that NE APs create a favorable microenvironment for bone regeneration through stem cell recruitment, angiogenesis, and immune modulation, effectively promoting the repair of inflammatory bone defects. This versatile protective delivery strategy, based on polyphenol and growth factor self-assembly, offers the potential to advance the application of growth factors in regenerative medicine.

Aging is the risk factor for chronic pancreatitis and severity determinant for its acute attack, yet the underlying cause is unclear. Here, we demonstrate that senescent β-cells of endocrine pancreas decide the onset and severity of chronic and acute pancreatitis. During physiological aging, senescent β-cells increase the expression of miR-503-322 which is secreted as small extracellular vesicles to enter exocrine acinar cells, driving a causal and reversible role on aging-associated pancreatitis. Mechanistically, miR-503-322 targets MKNK1 to inhibit acinar-cell secretion leading to autodigestion and repress proliferation causing repair damage of exocrine pancreas. In the elderly population, serum miR-503 concentration is negatively correlated with amylase, prone to chronic pancreatitis due to increased miR-503 and decreased MKNK1 in the elderly pancreas. Our findings highlight the miR-503-322–MKNK1 axis mediating the endocrine-exocrine regulatory pathway specifically in aged mice and humans. Modulating this axis may provide potential preventive and therapeutic strategies for aging-associated pancreatitis. Aging is the risk factor for chronic pancreatitis and its acute attack. Here, the authors show that exocrine acinar cells received endocrine β-cell-derived miR-503-322 and caused pancreas autodigestion and anti-proliferation by repressing MKNK1 thereby promoting pancreatitis in the elderly

Introduction and Objective: MASH is characterized by hepatic steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis, which is a frequent comorbidity of T2DM. Mazdutide, an agonist of glucagon-like protein-1 receptor (GLP-1R) and glucagon receptor (GCGR), has been demonstrated to lower blood glucose and body weight. However, its effect and underlying mechanism on hepatic fibrosis remain unclear. Recognizing the crucial role of the liver-gut axis in the pathogenesis, we explored the therapeutic effect of Mazdutide in mice with MASH and fibrosis. Methods: C57BL/6J mice were provided with a diet that was high in fat, fructose, and cholesterol (AMLN). After 32 weeks, the mice were randomly assigned to receive either vehicle, GLP1R agonist, GCGR agonist, or Mazdutide by subcutaneous injection every 2 days for 6 weeks. The body weight was monitored, and insulin/glucose tolerance tests were carried out. Immunohistochemistry, quantitative PCR, immunoblot analysis, and biochemical assays were conducted to evaluate the drug effects on inflammation, hepatic fibrosis, cell death, and intestinal structures. Feces were gathered, and 16S rRNA gene sequencing and microbiome profiles were analyzed. Results: The mice presented NASH and fibrosis phenotypes. Mazdutide decreased body weight, liver weight, hepatic triglyceride levels, serum inflammatory factor levels (TNF-α, IL-1β, IL-6), and alleviated insulin resistance. Notably, Mazdutide also mitigated hepatic fat accumulation, inflammation, and hepatic fibrosis, compared with a single GLP1R or GCGR agonist. Mazdutide reconfigured MASH-induced gut microbiota dysbiosis and significantly raised the abundance of Alloprevotella. Conclusion: In conclusion, Mazdutide alleviates hepatic fibrosis in MASH mice and regulates lipid metabolism as well as the gut microbiota, which may contribute to providing a novel therapeutic method and therapeutic target for MASH. H. Wang: None. L. Li: None.

Organoid-on-a-chip technologies have been proven beneficial in establishing human vital organ models, while their integration of different kinds of human organoids remains challenging. Here, we present a human liver-islet coculture system using a microfluidic organoid-on-a-chip platform for creating metabolic dysfunction-associated steatotic liver disease/non-alcoholic fatty liver disease (MASLD/NAFLD) model, enabling tissue function reconstruction, interorgan communication, disease modeling, and drug screening. Two chambers in the microfluidic chip are designed for housing liver and islet organoids, forming their functional crosstalk. By simulating liver steatosis on the chip, we can recreate the conditions of MASLD through such interconnected system. This liver-islet-connected organoid system can reveal MASLD pathogenesis characterized by insulin resistance and hepatocellular injury. In addition, we have also demonstrated the efficacy of specific agents in treating MASLD by conducting drug screening experiments on the chip. Therefore, our work demonstrates the simulation of human liver-islet crosstalk on a microfluidic chip, showcasing its potential for investigating complex diseases and advancing drug discovery efforts in the context of MASLD and related disorders.

ABSTRACT The rise in pancreatic diseases, resulting from improved living quality and lifestyle habits changes, has imposed a serious social burden. To better understand the pancreatic functions during disease progression, constructing a bionic pancreas is vital yet challenging in tissue engineering. Herein, inspired by the physiological anatomy of the pancreas, we introduce core‐shell microfibers with pancreatic stellate cells (PSCs) in the shell and pancreatic β‐cells in the core. Compared to traditional plate culture, the β‐cells encapsulated in the microfiber exhibit enhanced glucose‐stimulated insulin secretion. Such microfibers also serve as a platform to study the progression of diabetes of the exocrine pancreas, where the PSCs are activated under conditions of pancreatic exocrine diseases such as chronic pancreatitis. The activated PSCs impede insulin synthesis and increase apoptosis in β‐cells, resulting in elevated blood glucose. This high‐glucose microenvironment further exacerbates the activation of PSCs, causing a vicious cycle of diabetes. Additionally, the bio‐inspired pancreas also demonstrates its potential in drug screening, as evidenced by testing the glucagon‐like peptide 1 receptor agonist, Exendin‐4. Building upon such features, it is convincing that these multi‐component microfibers hold promise for exploring the pancreatic exocrine and endocrine interactions, and showing potential in disease modeling, drug screening, and regenerative medicine.

Current research on islet transplantation is aimed at prolonging the survival time and enhancing the functionality of the transplantation system. Owing to the good biocompatibility of hydrogels and their ability to provide mechanical support and immunological isolation of islet cells, hydrogel encapsulation of islets offers an innovative solution for islet transplantation. In this work, inspired by the extracellular matrix structure of the pancreatic islets, an injectable self-healing hydrogel loaded with islet-integrated microfiber scaffolds was constructed for islet transplantation. The short microfiber was fabricated by introducing a gaseous phase into microfluidic spinning, causing the continuous microfibers to break into short segments due to bubble rupture. These short microfibers provide mechanical support for pancreatic islets and can be integrated into a self-healing matrix to form a vascularized hydrogel through Schiff base bonding of oxidized sodium alginate aldehyde groups with carboxymethyl chitosan amino groups. With the loading of human umbilical vein endothelial cells and vascular endothelial growth factor, this composite is both injectable and provides mechanical support for the grafts, extends islet survival time, and improves islet function. In vivo experiments further confirm that this bioinspired composite system minimizes implantation-associated trauma while promoting neovascularization at the graft site in diabetic rodents, thereby achieving prolonged glycemic control compared to non-vascularized systems. These findings demonstrate that this hierarchically structured multifunctional graft platform has substantial research value and extensive therapeutic potential in the fields of cell therapy and tissue engineering for the treatment of diabetes and related diseases.

Organ-on-a-chip is emerging as a vital platform for in vitro modeling of biological systems. However, its application in the gut–islets axis and assessing regulators of endocrine hormone secretion has yet to be explored. Here, we developed an organ-on-a-chip platform featuring a microfluidic chip with scaffolds of a closed-packed porous structure to recapitulate the characteristics of the gut–islets axis for bile acid (BA) evaluation. The scaffolds were fabricated by negative replication of assembled droplet templates, enabling intestinal L-cells and pancreatic β-cells to form uniform spheroids. The scaffolds were embedded within a well-designed cascading microfluidic chip capable of generating a concentration gradient. Through this, the assessment of different concentrations of BAs in promoting GLP-1 and insulin secretion was achieved, with results consistent with previous studies, indicating the high accuracy of our platform. This novel system holds promise for evaluating other drugs or signaling molecules involved in glucose homeostasis, offering a new avenue for metabolic drug discovery.

Introduction and Objective: Patients with type 1 and type 2 diabetes are subjected to insulin injection therapies. Repeated subcutaneous insulin administrations leads to physiological and psychological issues, such as low adherence, infections, subcutaneous nodules, scarring, and so on. Insulin microneedles enables minimally invasive delivery of insulin, reducing adverse effects of insulin therapy in patients. Herein, we designed a porous insulin microneedle that can release insulin in a controlled manner for diabetes treatment. Methods: Porous microneedles were constructed by gelatin methacrylamide loaded with insulin. We characterized the porous insulin microneedles via optical microscopy and scanning electron microscopy. Biocompatibility was evaluated by utilizing CCK8 assays. To observe penetration effects, agarose hydrogel was used for simulating human skin. The release of insulin from the microneedles was investigated by labeling insulin with FITC. Diabetic mouse models were established and treated with porous insulin microneedles, followed by continuous observation of blood glucose levels. Results: The porous microneedles were demonstrated homogeneous microneedle arrays under microscopy. Transversal section of the microneedles had porous structure, capable of loading macromolecules including insulin. It was shown good biocompatibility when culturing with cells. As minimally invasive patches, the fabricated porous insulin microneedles can penetrate through the skin model, which released insulin into the subcutaneous spaces rapidly. Diabetic mouse models were successfully established with high blood glucose levels. Treated with the porous insulin microneedles, the hyperglycemia was ameliorated in diabetic mice. Conclusion: The resultant porous insulin microneedles can delivery insulin efficiently in a minimally invasive manner, reducing high blood glucose levels of diabetic mice. It is innovative for diabetes treatment, drug delivery, and smart medicine. J. Li: None. Z. Huan: None. L. Li: None. National Natural Science Foundation Major International (Regional) Joint Research Program (82320108003); National Natural Science Foundation (82170845, 82000740, 81970717); Key Research & Developement Program (No.BE2022853); Medical Key Discipline (ZDXK202203) of Jiangsu Province; SEU Innovation Capability Enhancement Plan for Doctoral Students (CXJH_SEU 24223)

Background: Kisspeptin, a key regulator of the hypothalamic-pituitary-ovarian (HPO) axis through GnRH stimulation, is implicated in polycystic ovary syndrome (PCOS) pathogenesis via HPO axis dysregulation. Although follicular kisspeptin levels predict success in fresh IVF cycles, their prognostic value in PCOS patients undergoing frozen-thawed embryo transfer (FET) cycles remains unknown. This study investigated the correlation between serum kisspeptin levels on the day of embryo transfer and pregnancy outcomes in patients with PCOS undergoing FET cycles. Methods: 80 PCOS patients undergoing their first FET cycle were prospectively enrolled. Patients were divided into three groups based on the tertiles of serum kisspeptin levels on the day of embryo transfer. The relationship between serum kisspeptin levels and pregnancy outcomes was analyzed. Multivariate logistic regression analysis was conducted to adjust for potential confounders, and a restricted cubic spline model was employed to examine the dose-response relationship between kisspeptin levels and pregnancy outcomes. Results: There were no significant differences in baseline characteristics among the three groups, except for the basal follicle-stimulating hormone level (p < 0.001). Significant differences were observed among the three groups in terms of live birth rate, pregnancy rate, and clinical pregnancy rate. Multivariate logistic regression analysis revealed that the odds of live birth were significantly higher in the third tertile (T3) group (highest kisspeptin levels) than in the first tertile (T1) group (lowest kisspeptin levels). Restricted cubic spline analysis showed a significant dose-response relationship between serum kisspeptin levels and pregnancy outcomes. Additionally, serum kisspeptin levels were positively correlated with progesterone levels on the day of embryo transfer day, whereas no significant correlation was observed with estradiol levels. Conclusions: In PCOS patients undergoing frozen-thawed embryo transfer cycles, higher serum kisspeptin levels were associated with improved pregnancy outcomes, suggesting that kisspeptin may serve as a useful biomarker for predicting pregnancy success.

OBJECTIVES:To assess the performance of fibrosis-4 index (FIB-4), nonalcoholic fatty liver disease fibrosis score (NFS) and aspartate aminotransferase to platelet ratio index (APRI) for advanced fibrosis in metabolic dysfunction-associated fatty liver disease (MAFLD) subgroups categorized by concomitant liver conditions. METHODS:We conducted a multicentered study comprising inpatients with type 2 diabetes mellitus and MAFLD. Participants were categorized into 2 groups: MAFLD with pure metabolic etiologies (MAFLD-P) and MAFLD with mixed etiologies (MAFLD-M). Diagnostic performance of FIB-4, NFS, and APRI was assessed by area under the curve (AUC), sensitivity, and specificity. RESULTS:This study comprised a total of 1475 participants, with a mean (SD) age of 58.4 (13) years and 835 (56.6%) males. FIB-4 and APRI had higher AUCs for advanced fibrosis in the MAFLD-M group than in the MAFLD-P group (MAFLD-M vs MAFLD-P: FIB-4 0.680 vs 0.591, P = .0442; APRI 0.723 vs 0.631, P = .0363). No significant difference was observed in the AUC of NFS between the 2 subgroups (MAFLD-M 0.572 vs MAFLD-P 0.617; P = .3237). Besides, the sensitivity of FIB-4 (69.6% vs 54.0%; P = .019) and APRI (43.5% vs 26.1%; P = .005) was higher in the MAFLD-M group. However, no significant difference in sensitivity of NFS and specificity of FIB-4, NFS, and APRI was observed between subgroups. CONCLUSIONS:In this diagnostic study of the type 2 diabetes mellitus population, FIB-4 and APRI showed better performance for identifying advanced fibrosis in MAFLD with mixed etiologies.

Background:Hyperuricemia is highly prevalent among patients with type 2 diabetes mellitus (T2DM). Inflammation is associated with the process of hyperuricemia. However, it is unclear whether white blood cell (WBC) count, a convenient inflammatory marker, is associated with hyperuricemia in patients with T2DM. Thus, we aimed to explore the possible association between WBC count and hyperuricemia in patients with T2DM. Methods:A total of 1768 patients with T2DM were retrospectively included. Cumulative data were analyzed in patients with T2DM. Results:WBC count was significantly elevated in T2DM patients with hyperuricemia compared with those without hyperuricemia (6.80 [5.60, 8.02] vs 6.20 [5.27, 7.24] 109/L, p<0.001). There was a significant positive correlation between WBC count and serum UA levels in patients with T2DM (r=0.165, 95% CI: [0.118, 0.211], p<0.001). Multivariable logistic regression analysis revealed an independent association between WBC count and hyperuricemia in patients with T2DM (OR=1.185, 95% CI: [1.077, 1.303], p<0.001). Conclusion:Elevated WBC count, even within the normal range, is associated with hyperuricemia in patients with T2DM, suggesting that chronic inflammation, as indicated by a higher WBC count, may be related to the development of hyperuricemia in patients with T2DM and urate-lowering therapy may be helpful to ameliorate chronic inflammatory damage in T2DM patients with hyperuricemia.

Abstract Background The epidemic of metabolic dysfunction‐associated fatty liver disease linked to excessive high‐fat diet (HFD) consumption has sparked widespread public concern. Nuclear factor erythroid 2‐related factor 2 (NRF2) has been reported to improve glucose/lipid metabolism, liver lipid degeneration and alleviate HFD‐induced inflammation. However, its pathways and mechanisms of action are not fully understood. Methods To confirm the effect of NRF2 on glucose/lipid metabolism in the liver, Nrf2‐/‐ mice as well as liver‐specific Nrf2 knockout mice, and AAV‐TBG‐Nrf2 were employed. The hyperinsulinemic‐euglycemic clamp was utilized to determine the effect of NRF2 on glucose metabolism. To elucidate the effect of NRF2 on pyroptosis, we performed western blots, immunofluorescence, quantitative real‐time PCR, and Flow cytometry experiments. Finally, chromatin immunoprecipitation‐seq and dual‐luciferase reporter assay was used to underscore the transcriptional regulatory effect of NRF2 on Gsdmd. Results We found that overexpression of Nrf2 inhibited the expression of inflammatory cytokines and pyroptosis markers, including cle‐Caspase1, NLRP3 and the N‐terminus of gasdermin D (N‐GSDMD) both in vivo and in vitro, while Nrf2 deficiency was the opposite. Specifically, with NRF2 expression up‐regulated, GSDMD expression decreased and Gsdmd overexpression partially reversed the effect of Nrf2 overexpression on pro‐inflammatory phenotype. Mechanistically, we demonstrate that NRF2 binds to the Gsdmd promoter at the −2110 ‐ 1130 bp site, inhibiting the GSDMD expression and thereby improving glucose/lipid metabolism and liver steatosis. Conclusion Our data indicate that NRF2 is an effective inhibitor of pyroptosis and has a multi‐target effect in the treatment of obesity‐related metabolic diseases. Key points MAFLD is associated with increased hepatocytes NRF2 expression. NRF2 alleviates MAFLD by suppressing pyroptosis. NRF2 directly inhibits GSDMD expression to regulate pyroptosis. Targeting the NRF2–pyroptosis (GSDMD) axis offers a potential therapeutic strategy for MAFLD.