The gut constantly interacts with both pathogens and dietary signals, but how it balances immune and metabolic responses remains unclear. Here we show that intestinal cGAS, a key DNA sensor, acts as a regulator linking gut immunity to whole-body metabolism. We show that cGAS signalling is activated in the intestines of humans and male mice with obesity, leading to increased type I interferon production and heightened immune activity in intestinal cells. Strikingly, deleting cGAS specifically in intestinal epithelial cells enhances energy expenditure, protects against diet-induced obesity and improves metabolic health. These effects depend on the gut microbiota, particularly Lactobacillus murinus and its metabolite indole-3-acetic acid (IAA), which promotes adipose thermogenesis. Our findings position intestinal cGAS as a key driver of obesity through gut-to-fat signalling and suggest that targeting the intestinal cGAS-microbiota IAA axis could offer promising strategies to combat obesity and related metabolic diseases.

Type 2 diabetes (T2DM), a chronic metabolic disorder characterized by pancreatic β-cell dysfunction and insulin resistance, is closely associated with oxidative stress. Interferon-stimulated gene 15 (ISG15), a ubiquitin-like modifier, has been implicated in redox regulation; however, its mechanistic role in T2DM progression remains unclear. To identify novel bio-factors contributing to T2DM, peripheral blood mononuclear cells (PBMCs) and serum samples were collected from T2DM patients and age-/BMI-matched healthy controls to quantify ISG15 expression. Complementary studies utilized a T2DM mouse model to assess β-cell-specific ISG15 expression within pancreatic islets. In parallel, MIN6 pancreatic β-cells were exposed to pathophysiological stressors, including hyperglycemic/hyperlipidemic (HG/PG) conditions and hydrogen peroxide (H2O2)-induced oxidative stress, to mimic the diabetic microenvironment. Protein-protein interactions were evaluated, and functional analyses were conducted following ISG15 genetic ablation. The results demonstrated that ISG15 expression was significantly elevated in PBMCs and serum from T2DM patients compared to healthy controls. Similarly, T2DM mouse models exhibited marked upregulation of ISG15 in islet β-cells. In vitro, exposure to HG/PG or H2O2 increased ISG15 levels, reduced MIN6 cell viability, and heightened reactive oxygen species (ROS) accumulation. Mechanistic studies revealed that ISG15 directly interacts with the PI3K regulatory subunit PIK3R2, suppressing its activity and thereby disrupting the PI3K/AKT/Nrf2 antioxidant signaling axis. This disruption led to exacerbated oxidative stress. Collectively, these findings indicate that ISG15 acts as a novel mediator of oxidative stress in T2DM by targeting and inhibiting the PIK3R2-dependent PI3K/AKT/Nrf2 pathway. These results uncover a previously unrecognized molecular mechanism driving β-cell dysfunction and identify ISG15 as a potential therapeutic target for mitigating oxidative damage in diabetes.

Innate antibacterial defense in Drosophila relies on the IMD pathway to induce antimicrobial peptides (AMPs), but the auxiliary transcriptional networks that amplify or fine-tune this response remain poorly defined. Here, we identify the Fork head (Fkh) transcription factor, a FoxA-family protein classically linked to development and metabolism, as a critical amplifier of humoral immunity. Our results show that bacterial infection rapidly induces Fkh expression, and enhances host survival, as well as promotes robust induction of AMPs including Diptericin (Dpt), Attacin-A, and Cecropin-A1. Mechanistically, Fkh directly binds the Dpt promoter and synergizes with the NF-κB factor Relish, ensuring strong promoter activation. In parallel, Fkh activates miR-34 transcription to repress the negative regulator p38b, thereby relieving inhibitory pressure on IMD signaling. Disruption of either Fkh-binding motifs or the miR-34 seed site abolishes these effects. Together, our findings uncover a dual regulatory strategy in which Fkh simultaneously acts as a promoter-bound transcription factor and as an upstream activator of an immune-enhancing miRNA. This integrated Fkh-miR-34-p38b axis establishes a feed-forward mechanism that ensures rapid and high-amplitude antibacterial defense, providing a new paradigm for transcription factor-miRNA cooperation in innate immunity.

Horizontal gene transfer (HGT) is the important driver for biological evolution. To date, most of the studies on HGT have focused on prokaryotes, and the HGTs involving eukaryotes are less investigated, especially for HGTs occurring in chordates. In this study, we firstly identify eleven horizontally transferred genes (HTGs) in cephalochordate amphioxus, including eight HTGs from eubacteria, one HTG from fungus, one HTG from virus, and one HTG from Trichoplax. Secondly, our results demonstrate that the HTGs with high GC content are more likely to be horizontally transferred into amphioxus. Thirdly, our analyses indicate that these HTGs are conserved with the donor genes in different degree and may generate some novel functions. Finally, our results suggest that these HTGs contribute to the functional optimization of the notochord during amphioxus evolution. Collectively, our work provides the evidences for the existence of HGT events in chordates and has important theoretical implications for further elucidating the mechanisms and functions of HGTs in the adaptive evolution of chordates.

AIM:This study aimed to evaluate its safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy in Chinese adults with T2DM and to preliminarily compare its efficacy and safety with semaglutide through multiple subcutaneous injections. MATERIALS AND METHODS:In this multicentre, randomised, placebo-controlled and semaglutide-positive-controlled trial, 64 Chinese adults with T2DM were randomly assigned to BGM0504 5 mg (n = 12), 10 mg (n = 12), 15 mg (n = 12), placebo (n = 12) or semaglutide 1 mg (n = 16). All participants received their assigned dose once weekly for 12 weeks. The primary endpoint was the change in HbA1c from baseline, and secondary endpoints included fasting plasma glucose (FPG), 2-h plasma glucose (2 h PG) and body weight. Safety was assessed through adverse events, laboratory tests and vital signs. RESULTS:At Week 12, the mean changes in HbA1c from baseline were -1.72% for the 5 mg dose, -1.94% for the 10 mg dose, -2.48% for the 15 mg dose, -1.43% for 1 mg semaglutide and 0.28% for placebo, with the treatment differences versus placebo (LSM) ranging from -1.82% to -2.56% (all p < 0.05). The proportion of participants achieving HbA1c < 6.5% or < 7.0% increased in a dose-dependent manner. BGM0504 also shows a signal for lowering FPG, 2 h PG and body weight (all p < 0.05), with the 15 mg dose showing superior weight reduction to semaglutide. Pharmacokinetics analysis confirmed a linear exposure-response relationship. All doses were well tolerated, with mostly mild adverse events. CONCLUSION:BGM0504 shows a signal reduction for HbA1c, FPG, 2 h PG and body weight in Chinese adults with T2DM. The 12-week treatment with BGM0504 was safe and well-tolerated, with the 15 mg dose showing the most substantial effects.

Rosai-Dorfman disease(RDD)is a rare form of non-Langerhans cell histiocytosis.In August 2024,a 38-year-old man was admitted to the Department of Endocrinology,The Third Xiangya Hospital of Central South University.He initially presented with diabetes insipidus,and his condition gradually progressed over a 15-year disease course,eventually leading to panhypopituitarism.Imaging examinations revealed marked thickening of the pituitary stalk,2 meningioma-like dural nodules,multiple osteolytic lesions,mild interstitial pneumonia,and urinary system involvement.RDD was confirmed by a pituitary stalk biopsy,and a BRAF V600E mutation was identified.The patient subsequently received targeted therapy with the BRAF inhibitor dabrafenib in combination with pituitary hormone replacement therapy.Follow-up brain magnetic resonance imaging after 8 months of treatment demonstrated a reduction in pituitary stalk thickening and complete disappearance of the 2 meningioma-like dural nodules.The patient's quality of life also improved substantially.This retrospective analysis of the case may assist clinicians in determining the etiology and differential diagnosis of pituitary stalk thickening and enhance awareness of RDD as a rare disease.

The innate immune response requires precise spatiotemporal regulation for organisms to ensure effective pathogen clearance while avoiding detrimental overactivation. Although the core components of the Drosophila Toll pathway are well-established, the post-transcriptional regulatory networks, particularly those involving non-coding RNAs (ncRNAs), remain incompletely understood to date. Here, we elucidate a novel tripartite feedback loop comprising the long noncoding RNA (lncRNA) CR42715, the microRNA (miRNA) miR-965-3p, and the transcription factor (TF) Dif that dynamically modulates Drosophila Toll signaling. Firstly, our results demonstrate that upon Gram-positive bacterial challenge, Dif activates CR42715 expression, which acts as a competitive endogenous RNA (ceRNA) by sponging miR-965-3p to alleviate miR-965-3p-mediated repression of Dif and enhance Dif protein synthesis, thus facilitating Toll signaling immune responses. Secondly, disruption of this feedback loop via genetic manipulation of CR42715 or miR-965-3p leads to dysregulated AMP expression and compromised host survival. Thirdly, the temporal expression analysis reveals that CR42715 is rapidly induced early in infection to boost immunity, while miR-965-3p expression increases later, ensuring timely signal attenuation, which suggests that this dynamic Dif/CR42715/miR-965-3p feedback loop can ensure robust early-phase antimicrobial peptide production while preventing excessive late-phase immunity. Collectively, we unveil a novel TF-lncRNA-miRNA feedback loop that acts as a rheostat to ensure an effective immune response.

Figure S1, related to Fig 1

Mazdutide is a once-weekly glucagon and glucagon-like peptide 1 receptor dual agonist developed for the treatment of type 2 diabetes (T2D)1. Here we report on a randomized phase III trial assessing the efficacy and safety of mazdutide, compared with dulaglutide, in participants with T2D who were also treated with background oral anti-diabetic drugs. In this study, 731 participants with T2D were randomized 1:1:1 to receive 4 mg mazdutide, 6 mg mazdutide or 1.5 mg dulaglutide for 28 weeks. Both doses of mazdutide showed non-inferiority and superiority to the 1.5-mg dose of dulaglutide in terms of the mean change in the diagnostic marker glycated haemoglobin A1c (HbA1c) from baseline to week 28, with a least-squares mean treatment difference of -0.24% (P = 0.0032) for 4 mg mazdutide and -0.30% (P = 0.0003) for 6 mg mazdutide, relative to 1.5 mg dulaglutide. Significantly greater reductions in body weight were achieved with mazdutide than with dulaglutide, with a least-squares mean treatment difference of -3.78% for 4 mg mazdutide and -5.76% for 6 mg mazdutide (both P < 0.0001), relative to dulaglutide. Moreover, significantly more participants who received mazdutide 4 mg or 6 mg reached the composite end point of HbA1c < 7.0% with a body-weight reduction of at least 5% at week 28 (both P < 0.0001), compared with those who received dulaglutide. The most common treatment-emergent adverse events were diarrhoea, nausea and vomiting. In summary, we found that in Chinese participants with T2D, 28 weeks of treatment with mazdutide (4 mg and 6 mg) provided reductions in HbA1c and body weight that were superior to those attained with 1.5 mg dulaglutide. Mazdutide was generally safe, although the incidence of gastrointestinal adverse events was higher for mazdutide than for dulaglutide.

Benzophenone-1 (BP-1), a widely used benzophenone-type UV filter in personal care products, has garnered global attention owing to its ubiquitous environmental occurrence and multiple adverse effects. However, its early molecular responses associated with molecular initiating events (MIEs) remain poorly understood. In this study, a dose-dependent yeast functional genomics approach (DYFGA) was employed to explore disturbed biological pathways, which were prioritized based on their point of departure (POD) induced by BP-1 at environmentally relevant concentrations, with these results further validated in HepG2 cell lines. Our results demonstrated that the BP-1-induced pathway-level POD (PODPATH: 3.152 μg/L) was more sensitive than the gene-level POD (PODDRG: 10.646 μg/L), both of which were much more sensitive than apical endpoint, as determined by the half-inhibitory concentration (IC50: 49.47 mg/L). Quantitative POD calculation based on KEGG pathway showed that the most sensitive altered pathway was lipid metabolism, followed by DNA replication, DNA damage and repair, cell cycle, and oxidative phosphorylation. Subsequently, we determined that the phenotypic-based no observed effect concentrations (NOECs) perturbed by BP-1 were 0.625 mg/L (lipid metabolism), 2.5 mg/L (DNA replication, DNA damage, and cell cycle), and 5 mg/L (oxidative stress) by human cell lines. A significant positive correlation was observed between these NOEC values and the DYFGA-derived POD. Overall, this study not only validated the DYFGA as a robust and effective tool for identifying early-sensitive biological pathways perturbed by chemicals, but also pinpointed lipid metabolism as the conserved primary molecular response induced by BP-1, providing critical insights for the environmental risk assessment of BP-1 and its structural analogues.

AIMS:Insulin antibodies (IAs) are prevalent in insulin-treated patients with diabetes and may cause immunological dysglycemia, known as exogenous insulin antibody syndrome (EIAS). This study aims to elucidate the clinical, genetic, and proteomic characteristics of patients with concurrent type 2 diabetes (T2D) and EIAS. METHODS:This was a case-control study with 177 IA-positive and 177 IA-negative T2D patients receiving insulin therapy. Among the IA-positive group, 46 patients with hypoglycemia and aberrantly elevated molar ratio of insulin to C-peptide (ICPR > 1) were identified as EIAS cases, followed with human leukocyte antigen (HLA) genotyping and plasma proteomic analysis by Olink platform. RESULTS:Patients with EIAS exhibited greater glycemic variability than patients in other groups (IA-positive ICPR ≤ 1 or IA-negative). Higher ICPR was associated with increased glycemic variability in the IA-positive group. DRB1*0405-DQA1*03-DQB1*0401, DRB1*0803-DQA1*0103-DQB1*0601, and DRB1*1501-DQA1*0102-DQB1*0502 are the susceptible HLA haplotypes for EIAS. Additionally, nine differentially expressed proteins were identified in EIAS patients, with GALNT3, IL10, and CCL28 showing promising diagnostic performance. CONCLUSIONS:IA-positive patients with remarkably elevated ICPR are prone to glycemic variability and should be evaluated for the diagnosis of EIAS. In this pilot study with limited sample size, EIAS is associated with unique HLA-DR-DQ risk haplotypes and enhanced immunoinflammatory response.

Type 1 diabetes (T1D) is an autoimmune disease characterized by hyperglycemia caused by the destruction of insulin-producing β cells. Viral infection is an important environmental factor which is associated with the islet autoimmunity in genetically susceptible individuals. Loss of β-cells and triggering of insulitis following viral infection could result from several non-exclusive mechanisms. Despite a significant increase in ISG15 levels following viral infection, the specific role of ISG15 in the impairment of insulin-producing β-cells is unclear. To address this issue at the clinical level, we conducted this experimental work, and found elevated levels of ISG15 in the peripheral blood of T1D patients, suggesting a potential link between ISG15 and T1D. In the T1D animal model, we discovered that both ISG15 levels and cellular apoptosis were increased in pancreatic islet tissue. To investigate at the cellular level, we cultured MIN6 cells in the presence of supernatants derived from iBMDM cells transfected with poly(I:C) (PIC), a viral mimic. This exposure led to an upregulation of ISG15 expression in MIN6 cells, which was accompanied by the suppression of their functional capabilities and viability. Intriguingly, the direct transfection of MIN6 cells with PIC increased the expression of ISG15. We further found that elevated levels of ISG15 had a direct inhibitory effect on insulin secretion and it also contributed to β-cell apoptosis in a TNF-α-dependent manner. In conclusion, our study revealed a potential underlying mechanism through which ISG15 increases the apoptosis of β-cells, providing valuable insights that could facilitate the development of T1D treatment strategies.

The activator protein 1 (AP-1) family, a group of dimerized transcription factors ubiquitously expressed in mammalian cells, plays versatile roles in diverse cellular and physiological processes. However, the functional characteristics of AP-1 remains unexplored in amphioxus (Branchiostoma belcheri tsingtauense), an evolutionarily pivotal chordate model for studying the origins of vertebrate development and immunity. Here, we report the discovery and functional characterization of two novel AP-1 subunit homologs, designated as AmphiFos and AmphiJun, in amphioxus. Our findings demonstrate that both AmphiFos and AmphiJun are involved in the innate immune response to lipopolysaccharide (LPS) challenge. Furthermore, the AmphiFos/AmphiJun heterodimer binds specifically to the conserved AP-1 DNA motif and activates downstream cytokine expression. Intriguingly, we have identified bbe-miR-210 as a post-transcriptional regulator that directly targets the coding sequences of both AmphiFos and AmphiJun, thereby suppressing their expressions to balance immune responses. Collectively, this work not only reveals the evolutionary conservation of AP-1-mediated immune regulation in basal chordates but also uncovers a mechanism by which microRNA fine-tunes AP-1 activity in amphioxus.

Introduction and Objective: BGM0504 is a dual agonist targeting the glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR). This study aimed to evaluate the safety and efficacy of BGM0504 in Chinese adults with type 2 diabetes mellitus (T2DM) and compare its performance to Semaglutide through multiple subcutaneous injections. Methods: This multicenter, randomized, placebo-controlled, and Semaglutide positive-controlled trial included 64 Chinese adults with T2DM. Participants were randomized into five groups: BGM0504 5 mg (n=12), 10 mg (n=12), 15 mg (n=12), placebo (n=12), and Semaglutide 1.0 mg (n=16). The study consisted of a titration phase (2-6 weeks), 12 weeks of once-weekly treatment, and a 2-week follow-up. The trial was registered with the Chinese NMPA (CTR20232464). Results: Changes in HbA1c from baseline to week 12 relative to placebo were as follows (LSM, 95% CI): * 5 mg group: −1.82% (−2.83 to −0.81) * 10 mg group: −2.05% (−3.27 to −0.82) * 15 mg group: −2.56% (−3.58 to −1.54) * Semaglutide 1.0 mg: −1.86% (−2.83 to −0.90) The 15 mg dose was superior to Semaglutide (p=0.0327). Improvements in FPG and 2h-PPG relative to placebo ranged from −3.18 to −1.63 mmol/L and −6.16 to −4.76 mmol/L, respectively (p < 0.05). The percentage of participants achieving HbA1c <7.0% was: * 5 mg group: 76.9% * 10 mg group: 81.8% * 15 mg group: 91.7% * Semaglutide 1.0 mg: 75.0% * Placebo: 16.7% All BGM0504 doses were superior to placebo in achieving this target (p < 0.05). The 15 mg group also demonstrated significantly greater weight reduction compared to Semaglutide (p < 0.001). All doses of BGM0504 were well tolerated, with common adverse events. Conclusion: BGM0504 was safe and well-tolerated, with the 15 mg dose showing the most substantial effects. It is a promising treatment option for improving glycemic control and achieving weight reduction in patients with T2DM. J. Yuan: Employee; BrightGene Bio-Medical Technology Co., Ltd. Y. Huang: Employee; BrightGene Bio-Medical Technology Co., Ltd. H. Ding: Employee; BrightGene Bio-Medical Technology Co., Ltd. D. Xie: Employee; BrightGene Bio-Medical Technology Co., Ltd. X. Jiang: Consultant; BrightGene Bio-Medical Technology Co., Ltd. X. Yuan: None. Z. Cao: None. P. Jin: None. L. Ji: None.

Purpose:To investigate how lifestyle interventions alter fat distribution and organ-specific iron deposition in individuals with obesity, and whether these changes can serve as indicators of glycemic remission in obese patients with dysglycemia. Methods:This prospective study included individuals with obesity who participated in a 6-month lifestyle intervention, which comprised a caloric-restricted balanced diet and an exercise regimen. Ultimately, 104 participants completed the follow-up phase. Magnetic resonance imaging (MRI) was utilized to monitor the dynamics of fat mobilization and organ iron deposition at baseline and 6-month follow-up. Correlation analysis, logistic regression, and receiver operating characteristic (ROC) curve analysis were employed to examine the relationships between regional fat distribution, organ iron deposition, and glycemic improvement. Results:Initially, the 104 participants were divided into three categories: normal glucose regulation (NGR, n=41), prediabetes (n=23), and type 2 diabetes mellitus (T2DM, n=40). After a 6-month lifestyle change, the number of patients with T2DM and prediabetes decreased, and those with NGR increased. There were also notable decreases in liver and pancreatic fat, as well as visceral and subcutaneous fat, with the largest decrease in liver fat (-43.2%) among obese participants. There were also reductions in liver and pancreatic iron deposition after intervention. ROC curve analysis revealed that the change in liver fat was the best indicator of diabetes remission among obese participants, with an area under the curve of 0.819 (95% confidence interval [CI]: 0.681-0.957). Notably, liver fat reduction ≥38.8% predicted diabetes remission (OR=2.5, 95% CI:1.59-5.60) in individuals with obesity. Conclusion:Lifestyle intervention can effectively reduce ectopic fat and iron overload in individuals with obesity. The extent of hepatic fat mobilization has emerged as the most significant indicator of diabetes remission in individuals with obesity, potentially serving as a pivotal focus for future therapeutic interventions.

Introduction and Objective: To investigate the HLA genotyping of immune checkpoint inhibitor-associated diabetes (ICI-DM). Methods: We enrolled 46 ICI-DM patients and 97 T1DM in our center, HLA-A, B, C and HLA-DRB1, DQA1, DQB1 genotyping was conducted. A literature review was conducted to compare the HLA class II genotypes of 100 Asian ICI-DM (55 cases from the literature) and 46 Caucasian ICI-DM patients. Results: Compared with T1DM patients, ICI-DM patients had significantly lower frequencies of the DR3 haplotype (3.33% vs 12.89%, p = 0.012), whereas the protective haplotypes DRB1*1101-DQA1*05-DQB1*0301 and DRB1*1202-DQA1*0601-DQB1*0301 were significantly increased in ICI-DM patients (11.11% vs 1.55%, p = 0.001; 13.33% vs 5.67%, p = 0.028). Compared with T1DM patients, ICI-DM patients presented significantly higher frequencies of HLA-A*26:01 (6.25% vs 0%, p = 0.042), HLA-B*46:01 (31.25% vs 11.61%, p = 0.003), HLA-B*55:02 (12.50% vs 2.68%, p = 0.036), HLA-C*01:02 (31.25% vs 16.96%, p = 0.043) and lower frequencies of HLA-A*24:02 (12.50% vs 26.79%, p = 0.047), HLA-B*40:01 (8.33% vs 24.11%, p = 0.021). Compared with Caucasian patients, the frequencies of HLA-DR9 and DRB1*0405-DQA1*03-DQB1*0401 in Asian ICI-DM patients were significantly higher ( 4.38% vs 35.00%, p<0.001; 0% vs 17.00%, p=0.002). Conversely, the frequencies of T1DM susceptibility haplotypes (DR3 and DR4) were significantly lower in Asian ICI-DM patients than those in Caucasian patients (4.00% vs 19.57%, p=0.006; 13.00% vs 43.48%, p<0.001). Conclusion: ICI-DM represents different HLA genotypes from classical T1DM. The HLA class II genotype varied among ICI-DM patients of different racial background. Y. Fu: None. L. Zhao: None. K. Chen: None. P. Jin: None.

Figure S2, related to Fig 2

We aimed to generate a population-specific type 1 diabetes genetic risk score (GRS) and assess whether it could improve discrimination between type 1 diabetes and type 2 diabetes in a Chinese population. We performed a genome-wide association analysis on 1303 individuals with type 1 diabetes and 2236 control individuals. An independent replication cohort of 501 individuals with type 1 diabetes and 853 control individuals was used to validate the top common variant associations. HLA typing data were used to identify tag SNPs for DQA1-DQB1 haplotypes. We integrated significant signals to construct a Chinese type 1 diabetes GRS (C-GRS). The accuracy of the C-GRS was tested in an independent validation cohort consisting of 262 individuals with type 1 diabetes, 1080 individuals with type 2 diabetes and 208 control individuals. We identified a variant, rs10232170, in BMPER as a possible novel type 1 diabetes locus (p=9.897×10−9). We identified tag SNPs for 13 DQA1-DQB1 haplotypes and 12 non-DQA1-DQB1 loci. Integrating 33 significant SNPs from HLA and non-HLA regions, C-GRS demonstrated high discriminative power for type 1 diabetes (AUC=0.876). It was tested in an independent validation cohort and showed high discrimination (AUC 0.871 for type 1 diabetes vs control group, 0.869 for type 1 diabetes vs type 2 diabetes). The C-GRS outperformed a European-derived GRS (0.871 vs 0.773, and 0.869 vs 0.793, respectively). A type 1 diabetes C-GRS comprising 33 SNPs was highly discriminative of type 1 diabetes risk in the Chinese population and could aid in discriminating between type 1 diabetes and type 2 diabetes. This study highlights the potential of genetic information in improving prediction and precision diagnosis of type 1 diabetes in the Chinese population. The raw sequencing data and summary statistics of genomic DNA derived from human samples have been deposited at the China National Center for Bioinformation ( https://ngdc.cncb.ac.cn/omix ) under accession number PRJCA023730.

Patients with type 2 diabetes mellitus (T2DM) who cannot achieve normal glycosylated hemoglobin (HbA1c) levels are sometimes given the combined therapeutic regimen of polyethylene glycol loxenatide (PEG-Loxe) + basal insulin. The aim of this study was to investigate the efficacy and safety of PEG-Loxe combined with basal insulin in patients with T2DM. This retrospective, real-world study included patients with T2DM aged ≥ 18 years for whom basal insulin therapy was ineffective, whose HbA1c levels were between 7.0