Introduction and Objective: Pancreatic fat infiltration plays a significant role in the progression of diabetic microvascular complications (DMCs). Methods: Data were derived from a type 2 diabetes cohort study, including 666 patients from China, aged 70.9±7.7 years. Abdominal CT scans were used to assess organ-specific fat infiltration and volume, and a 3D U-Net convolutional neural network was applied for visceral segmentation. Continuous glucose monitoring (CGM) was used to measure glycemic fluctuations. Results: Our 3D U-Net model demonstrated high segmentation accuracy with dice similarity coefficients (DSC) of 0.96 for the liver, 0.78 for the pancreas, 0.95 for the kidneys, and 0.71 for the adrenal glands. Pancreatic fat infiltration was significantly associated with diabetic kidney disease (OR = 1.05, P = 0.02) and diabetic foot (OR = 1.04, P = 0.03). These associations were mediated by insulin resistance, with mediation effects of 29.8% and 5.3%, respectively. Excessive pancreatic fat was association with increased time of hypoglycemia, as measured by CGM. GWAS identified 9 significant SNPs associated with pancreatic fat deposition, including loci in MORC1, SDK1, and EYA1, which are involved in fat metabolism and vascular dysfunction. Conclusion: Pancreatic fat infiltration was associated with diabetic kidney disease, diabetic foot and time of hypoglycemia. Genetic loci associated with pancreatic fat provide new insights into the molecular mechanisms. Disclosure Y. Lu: None. Funding National Natural Science Foundation of China (82170870, 82470901)

AIMS:To evaluate the association of frailty with mortality and incident extrahepatic diseases in individuals with metabolic dysfunction-associated steatotic liver disease and the interaction between frailty and cardiovascular health. METHODS:This prospective cohort study included 107,867 participants with metabolic dysfunction-associated steatotic liver disease from the UK Biobank. Metabolic dysfunction-associated steatotic liver disease is defined as hepatic steatosis plus cardiometabolic abnormality. Frailty was assessed as physical frailty based on five components (weight loss, exhaustion, physical activity, gait speed, and grip strength) and the Rockwood frailty index, while cardiovascular health was evaluated using the Life's Essential 8 score. RESULTS:Frailty was associated with increased risks of all-cause mortality (physical frailty: HR 2.01, 95% CI 1.87-2.16; frailty index: HR 1.63, 95% CI 1.54-1.74) and incident extrahepatic diseases with the exception of cancer (physical frailty: HRs ranged from 1.62 to 3.35; frailty index: HRs ranged from 1.34 to 8.07). Among the five components of physical frailty, slow gait speed exhibited the strongest associations with most adverse outcomes. There were significant multiplicative and additive interactions between frailty and cardiovascular health on respiratory disease mortality, heart failure, and peripheral arterial disease. Compared with participants with no frailty and good cardiovascular health, those with both frailty and poor cardiovascular health had the highest risks of all adverse outcomes. CONCLUSION:Frailty was associated with increased risks of mortality and extrahepatic complications in metabolic dysfunction-associated steatotic liver disease, particularly in those with suboptimal cardiovascular health. Early detection and interventions for frailty are needed alongside cardiovascular health promotion to enhance the prognosis of metabolic dysfunction-associated steatotic liver disease.

Microplastics (MPs) are emerging environmental contaminants with potential hepatotoxicity, yet direct epidemiological evidence linking internal MP exposure to liver injury is scarce, particularly in individuals with type 2 diabetes (T2D). In this cross-sectional study nested within the METAL2 cohort, we aimed to characterize blood microplastic profiles in patients with T2D and to determine whether specific MP polymers are associated with hepatic steatosis and fibrosis risk, with experimental validation of the identified polymer. In patients with T2D, multiple MP polymers were detectable in blood, with polyvinyl chloride (PVC), polyamide 66 (PA66), and polystyrene (PS) being the most prevalent. Although PVC constituted the largest proportion of total MP burden, PS showed the most consistent nominal positive liver-related signal in the human analyses, including higher levels in participants with elevated fibrosis risk and higher FIB-4 and ALT in the highest exposure quartile. Experimental validation in diabetic mice demonstrated that PS microplastics markedly exacerbated hepatic steatosis, inflammation, and collagen deposition, leading to overt liver fibrosis. Mechanistically, PS-MPs exposure disrupted hepatic lipid homeostasis and concurrently activated the NLRP3 inflammasome and the TGF-β1/Smad signaling pathway, promoting inflammatory amplification and hepatic stellate cell activation. This integrated human and experimental study provides preliminary evidence that circulating PS-associated signals are linked to liver-related indices in T2D, while experimental findings support the biological plausibility that PS exposure may aggravate hepatic injury under diabetic conditions.

Glucagon-like peptide-1 receptor (GLP1R) agonists and dual glucose-dependent insulinotropic polypeptide receptor/glucagon-like peptide-1 receptor (GIPR/GLP1R) agonists are established treatments for diabetes and obesity, but their potential effects on biological aging remain uncertain. In this drug target Mendelian randomization study, we assessed the associations of genetically proxied modulation of GLP1R, GIPR, and dual GIPR/GLP1R pathways with four aging phenotypes, including frailty index, phenotypic age (PhenoAge) acceleration, telomere length, and longevity. Glycated hemoglobin (HbA1c) lowering via GIPR, modeling the glucose-lowering effect of variants in GIPR loci, was consistently associated with a lower frailty index (primary dataset: β = − 0.10 [95

OBJECTIVE:To evaluate the association between gestational diabetes mellitus (GDM) and accelerated biological aging in middle-aged and elderly women. RESEARCH DESIGN AND METHODS:We included parous women with a baseline survey on history of GDM and biological aging biomarkers from the UK Biobank. Information regarding prior GDM was collected via a touchscreen questionnaire and linkage to hospital admission records. Biological aging was evaluated using validated phenotypic age (PhenoAge) based on chronological age and nine biomarkers measured at baseline (2006-2010). Biological aging acceleration was determined as the residual by regressing PhenoAge estimates on chronological age. All-cause mortality and incident cardiometabolic disease during follow-up were also assessed. RESULTS:Among the 178,363 women (mean age, 57.0 [SD 7.9] years), 1,141 had a history of GDM. In a multivariable-adjusted model, a history of GDM was associated with an increase in PhenoAge acceleration by 2.34 (95% CI 2.02, 2.66) years. The association persisted regardless of the occurrence of type 2 diabetes and related comorbidities after GDM. Consistent results were observed across subgroups, while the GDM-related PhenoAge acceleration was more prominent among women with less physical activity and obesity (both Pinteraction < 0.01). The mediation analysis demonstrated that PhenoAge acceleration explained 57.0% (95% CI 21.0, 86.9), 12.4% (7.3, 20.4), and 21.9% (14.0, 32.5) of the positive associations between GDM and all-cause mortality, type 2 diabetes, and cardiovascular disease, respectively. CONCLUSIONS:Women with a history of GDM were biologically older than their non-GDM counterparts. The biological aging acceleration partially accounted for the associations between GDM and adverse health outcomes.

Immune checkpoint molecules (ICMs) are a class of surface proteins predominantly expressed on immune cells that play a key role in maintaining immune homeostasis by regulating the functions of T cells and other immune cells. Beyond their established immunoregulatory roles, emerging evidence indicates that ICMs are also involved in metabolic regulation. Within the tumor microenvironment (TME), tumour-derived ICMs have been shown to modulate glucose, amino acid, and lipid metabolism in infiltrating T cells, thereby influencing their metabolic reprogramming and functional states. Certain ICMs expressed on immune cells may directly regulate systemic metabolism through cell-intrinsic, immune-independent mechanisms. Moreover, specific ICMs are constitutively expressed in key metabolic tissues, such as pancreatic islets, liver, and adipose tissue, where they are thought to contribute to the maintenance of systemic metabolic homeostasis. Clinically, host metabolic status can affect the efficacy of immune checkpoint inhibitor (ICI) therapies. Conversely, ICI treatment can lead to metabolism-related adverse effects, such as ICI-associated diabetes (ICI-DM), which may extend beyond classic autoimmune insulin-dependent diabetes. Accumulating evidence suggests that ICMs can exert direct regulatory roles in metabolism independent of their canonical immune functions. Elucidating how ICMs regulate metabolism could, on the one hand, improve ICI therapy by maintaining metabolic homeostasis and preventing T cell exhaustion, and on the other hand, facilitate the development of novel therapeutic strategies for metabolic diseases that simultaneously target metabolic and inflammatory pathways. This review synthesises current knowledge on the metabolic roles and regulatory mechanisms of ICMs.

Introduction and Objective: Although schizophrenia is often accompanied by metabolic disorders, the biological mechanism is yet unknown. This study focused to examine the gene-gene interaction of rare mutations in Trace Amine-Associated Receptor 1 (TAAR1) and Glucagon-Like Peptide 1 Receptor (GLP1R) and their contribution to metabolic disturbances in schizophrenia individuals. Methods: 434 patients meeting DSM-5 criteria for schizophrenia with genotype and metabolic data were retained. Rare protein-truncating and deleterious missense variants were identified in TAAR1 and GLP1R, and gene-gene interaction analyses were performed for BMI, waist circumference, fasting glucose, lipid profiles, and HbA1c while controlling for demographic factors and antipsychotic exposure. Results: Significant gene-gene interaction effects between TAAR1 and GLP1R mutations were found for metabolic phenotypes. The TAAR1 exon2:c.A936G variant had interaction effects with several GLP1R mutations, leading to increased BMI, greater central adiposity, and elevated fasting glucose. Other such interactions involving TAAR1 exon2:c.A864G and TAAR1 exon2:c.T900A affected disturbed lipid profiles, indicating converging effects on pathways regulating energy balance and glucose-lipid homeostasis. Conclusion: TAAR1-GLP1R genetic interactions contribute to metabolic vulnerability especially glucose-lipid metabolic disease in schizophrenia patients. Disclosure Y. Lu: None. Funding National Natural Science Foundation of China (82170870, 82470901)

Mitochondrial redox imbalance and defective oxidative phosphorylation are central features of lipotoxic cardiac injury, but whether diet-related chemical exposures perturb cardiomyocyte mitochondrial gene-expression machinery remains unclear. Here, we investigated whether sucralose promotes cardiac redox-metabolic remodeling and lipid accumulation involving MRPL12-associated mitoribosomal impairment. Male C57BL/6J mice were exposed to sucralose in drinking water for 28 weeks; hiPSC-derived cardiomyocytes were used for mechanistic assays, and hiPSC-derived cardiomyocytes and H9c2 cardiomyoblast-like cells were used for lipid-accumulation assays under palmitic acid/oleic acid-induced lipid-loading conditions. Chronic sucralose exposure was associated with cardiac dysfunction, myocardial lipid accumulation, mitochondrial structural injury, ATP depletion, oxidative stress-associated signals, reduced glutathione redox buffering capacity, and reduced oxidative phosphorylation (OXPHOS) protein abundance. Quantitative cardiac proteomics identified mitochondrial ribosome- and oxidative phosphorylation-related changes, with MRPL12 emerging as a candidate mechanistic node. In cardiomyocytes, sucralose reduced MRPL12 abundance, altered the distribution of 39S/55S-enriched mitoribosomal fractions, suppressed residual nascent protein synthesis under cytosolic translation-suppressed conditions, reduced mitochondrially encoded OXPHOS proteins, impaired mitochondrial respiration, and aggravated lipid accumulation. Restoration of MRPL12 in cardiomyocytes or mouse hearts partially attenuated sucralose-associated redox-bioenergetic impairment, lipid deposition, and cardiac remodeling. Conversely, siRNA-mediated MRPL12 knockdown phenocopied key sucralose-associated abnormalities, including reduced abundance of mtDNA-encoded OXPHOS subunits, impaired respiration, increased mitochondrial superoxide-associated signal, and lipid accumulation. These findings support MRPL12-associated mitoribosomal impairment as a contributing mechanism linking sucralose exposure to mitochondrial redox-bioenergetic dysfunction and metabolic remodeling in the heart.

Atrial fibrillation (AF) should be recognized as a complication of diabetes, with a prevalence of up to 25% and increasing incidence rates in individuals with diabetes. Atrial fibrillation can develop in individuals with diabetes independent of hypertension, atherosclerotic cardiovascular disease, or heart failure. The pathogenesis linking diabetes to AF is multifactorial, involving atrial structural, electrical, electromechanical, and autonomic remodelling, as well as diabetes-related metabolic comorbidities. Given that the prevalence of diabetes (mainly Type 2 diabetes) is expected to increase further, the coexistent burden of AF on individuals, society, and healthcare systems will continue to increase. Thus, an integrated CARE-based management approach should be adopted to optimize care for diabetic patients across all stages of those at risk for AF and those with subclinical or clinical AF. This includes Comorbidity and risk factor management, Avoidance of stroke and thromboembolism, Reduction of symptoms by rate and rhythm control, and Evaluation and dynamic reassessment. This review outlines the intricate and close relationship between diabetes and AF, addressing the epidemiology, pathogenesis, and management strategies based on the CARE-based approach in diabetic patients. Such consideration may facilitate timely prevention, early detection, and effective intervention, ultimately improving the health outcomes of patients with AF and diabetes.

The EAT-Lancet diet (ELD) and plant-based diets (PBDs) are recommended for their potential health and environmental benefits, but comparative analyses of these dietary patterns in relation to mortality risk remain limited. This study aimed to evaluate the associations of ELD and PBDs with mortality and life expectancy in two nationwide cohorts. Participants from the UK Biobank and the US National Health and Nutrition Examination Survey (NHANES) (2003–2018) were included. Dietary intake was assessed using 24-h dietary recalls. The ELD index (ELD-I), overall PBD index (PDI), healthful PBD index (hPDI), and unhealthful PBD index (uPDI) were calculated and categorized into tertiles. Primary outcomes were all-cause mortality, cause-specific mortality, and life expectancy. After full adjustment, the hazard ratio (HR) for all-cause mortality when comparing the highest versus lowest tertiles was 0.87 (95

Circulating Lp(a) is largely genetically determined, but repeated measurements indicate that Lp(a) concentrations may differ within individuals over time. It remains unclear whether self-reported use of common supplement categories is associated with differences between repeated Lp(a) measurements. We aimed to investigate associations between baseline self-reported supplement-category use and two-visit difference in Lp(a), and to explore whether these associations differed by Lp(a) genetic risk. We included 12,109 UK Biobank participants with Lp(a) measured at baseline and at the first repeat assessment. Self-reported use of common supplement categories (vitamins A, B, C, D, E, folate, and multi-vitamins) was assessed by questionnaire. The primary outcome was the continuous two-visit difference in log10[Lp(a)], defined as log10[repeat-assessment Lp(a)] minus log10[baseline Lp(a)]. The primary analysis used core behavioral/sociodemographic-adjusted multivariable linear regression. Threshold-category and genetic-risk analyses were secondary and exploratory. Among 12,109 participants with repeated Lp(a) measurements over a median 4.4 years, estimates in the primary core behavioral/sociodemographic-adjusted continuous log-scale model were small and centered near the null, ranging from β = -0.014 to 0.005 log10 units, corresponding to approximately − 3.18

Clonal haematopoiesis of indeterminate potential (CHIP) and low vitamin D are recognised as independent risk factors for type 2 diabetes mellitus (T2DM); however, their joint effects on T2DM incidence remain unclear. We hypothesised that CHIP mutations and vitamin D deficiency may be jointly associated with the risk of T2DM. This study included 405,095 participants from the UK Biobank without T2DM at baseline. CHIP was identified through whole-exome sequencing of peripheral blood samples, and vitamin D was categorised into quartiles. All the participants' variables were tested at baseline. Cox regression was used to evaluate the joint effects of CHIP and vitamin D on incident T2DM. The mean age of the participants was 56.4 ± 8.1 years, and 54.0% were female. After a median follow-up of 12.9 years, 24,724 (6.1%) participants developed T2DM. Multivariable analyses revealed that higher vitamin D quartiles were associated with a lower risk of incident T2DM (HR [95% CI]: 0.89 [0.86-0.92], 0.78 [0.75-0.81], and 0.70 [0.67-0.73] for the 2nd, 3rd, and 4th quartiles vs. Q1, respectively), with similar associations observed in participants with and without CHIP, and no evidence of interaction. In contrast, the presence of CHIP was not clearly associated with incident T2DM after adjustment (HR 1.03 [0.97-1.09]). These findings suggest that vitamin D is associated with type 2 diabetes risk, independent of clonal haematopoiesis, and may help to contextualise risk heterogeneity among individuals with and without CHIP.

Schizophrenia (SCZ) is marked by profound biological and clinical heterogeneity, presenting major challenges for accurate diagnosis and personalized treatment. Traditional classifications based solely on clinical presentation are limited by inter-individual variability, overlapping symptom profiles, and low stability across disease stages and treatment states. Dysregulation of the excitation–inhibition (E–I) balance within neural circuits is thought to underpin diverse positive and negative symptoms. Classification based on neural excitability may therefore provide critical insights into disentangling this heterogeneity. We applied a cortical excitability (CE) mapping approach to spatially characterize E–I dysregulations in 77 drug-naïve first-episode SCZ (FES) patients and 76 healthy controls (HCs). CE abnormalities were identified using voxel-wise comparisons, and patients were subsequently clustered into subtypes based on the spatial patterns of CE alterations. Longitudinal analyses assessed the subgroups’ clinical trajectories over 12 months of antipsychotic treatment. Furthermore, CE maps were integrated with transcriptomic and neuroreceptor datasets to analyse potential molecular mechanisms underlying the observed CE abnormalities. Relative to HCs, FES patients exhibited CE abnormalities primarily in the bilateral frontal lobes, sensorimotor cortex, and right cuneus. Two subtypes were identified, differing in both the spatial extent of CE abnormalities and their clinical profiles: FES1 showed more widespread CE reductions across frontal and association cortices, associated with greater affective and cognitive burden, whereas FES2 demonstrated a comparatively preserved CE profile and milder symptom expression. Subsequent transcriptomic and receptor analyses revealed distinct biological underpinnings: FES1 was associated with synaptic dysfunction and neurodevelopmental disruption, while FES2 reflected multisystem involvement potentially accompanied by compensatory processes. CE-based subtyping captures clinically and biologically meaningful heterogeneity in FES. Moreover, this approach provides a promising framework for bridging neural circuit dysfunction with molecular signatures and may advance precision psychiatry in SCZ.

Importance:Thyroid eye disease (TED), a disfiguring and potentially sight-threatening condition with racial phenotypic variations, currently has limited effective treatments. Insulin-like growth factor 1 receptor (IGF-1R) inhibitors therapy has emerged as a promising treatment option, although it remains less accessible and lacks substantial evidence in Asian patients. Objective:To assess efficacy and safety of IBI311, an IGF-1R inhibitor with an identical amino acid sequence to teprotumumab but a different dosage form, in Chinese patients with active TED. Design, Setting, and Participants:This was a randomized, double-masked, placebo-controlled, multicenter, 24-week phase 3 trial with recruitment conducted across 20 tertiary hospitals in China from May to December 2023. Chinese participants with active (clinical activity score [CAS] ≥3) moderate to severe TED were included after excluding individuals with active TED onset over 270 days; sight-threatening TED; or history of steroid pulse therapy, radiotherapy, or surgery for TED. Interventions:Eighty-two participants were randomized 2:1 to receive intravenous infusions of either IBI311 or placebo once every 3 weeks for 21 weeks with follow-up through week 24. Main Outcomes and Measures:The primary outcome was the proptosis response rate (proptosis reduction ≥2 mm) in the study eye at week 24. Results:Participants (mean [SD] age, 39.6 [10.9] years; 56 [68.3%] women) were randomized to receive IBI311 (n = 54) or placebo (n = 28). At week 24, 45 of 52 participants receiving IBI311 (85.8%) and 1 of 26 receiving placebo (3.8%) had proptosis response (difference, 81.9 percentage points; 95% CI, 69.8 to 93.9; P < .001). The secondary outcomes included overall response (proptosis reduction ≥2 mm and CAS reduction ≥2, 80.2% vs 3.6%; difference, 76.3 percentage points; 95% CI, 63.3 to 89.4), CAS of 0 or 1 (83.5% vs 16.6%; difference, 67.1 percentage points; 95% CI, 49.4 to 84.8), least-squares mean (SE) change from baseline in proptosis (-2.85 [0.18] mm vs -0.02 [0.24] mm; difference, -2.83 mm; 95% CI, -3.39 mm to -2.27 mm) in the study eye (all P < .001), and diplopia response (diplopia reduction ≥1 grade, 66.0% vs 53.3%; P = .46). All adverse events of interest (infusion reaction, hearing impairment, hyperglycemia, muscle spasm, and nausea or diarrhea) were mild or moderate in severity. No serious adverse event or death occurred in the IBI311 group. Conclusions and Relevance:In this phase 3 randomized clinical trial, IBI311 demonstrated better and clinically relevant outcomes in proptosis and CAS than placebo with no new safety issues not identified in previous clinical trials. The results suggest that IBI311 represents a viable treatment option for Chinese patients with active TED. Trial Registration:ClinicalTrials.gov Identifier: NCT05795621.

Thyroid eye disease (TED), a disfiguring and potentially sight-threatening condition with racial phenotypic variations, currently has limited effective treatments. Insulin-like growth factor 1 receptor (IGF-1R) inhibitors therapy has emerged as a promising treatment option, although it remains less accessible and lacks substantial evidence in Asian patients. To assess efficacy and safety of IBI311, an IGF-1R inhibitor with an identical amino acid sequence to teprotumumab but a different dosage form, in Chinese patients with active TED. This was a randomized, double-masked, placebo-controlled, multicenter, 24-week phase 3 trial with recruitment conducted across 20 tertiary hospitals in China from May to December 2023. Chinese participants with active (clinical activity score [CAS] ≥3) moderate to severe TED were included after excluding individuals with active TED onset over 270 days; sight-threatening TED; or history of steroid pulse therapy, radiotherapy, or surgery for TED. Eighty-two participants were randomized 2:1 to receive intravenous infusions of either IBI311 or placebo once every 3 weeks for 21 weeks with follow-up through week 24. The primary outcome was the proptosis response rate (proptosis reduction ≥2 mm) in the study eye at week 24. Participants (mean [SD] age, 39.6 [10.9] years; 56 [68.3%] women) were randomized to receive IBI311 (n = 54) or placebo (n = 28). At week 24, 45 of 52 participants receiving IBI311 (85.8%) and 1 of 26 receiving placebo (3.8%) had proptosis response (difference, 81.9 percentage points; 95% CI, 69.8 to 93.9; P < .001). The secondary outcomes included overall response (proptosis reduction ≥2 mm and CAS reduction ≥2, 80.2% vs 3.6%; difference, 76.3 percentage points; 95% CI, 63.3 to 89.4), CAS of 0 or 1 (83.5% vs 16.6%; difference, 67.1 percentage points; 95% CI, 49.4 to 84.8), least-squares mean (SE) change from baseline in proptosis (−2.85 [0.18] mm vs −0.02 [0.24] mm; difference, −2.83 mm; 95% CI, −3.39 mm to −2.27 mm) in the study eye (all P < .001), and diplopia response (diplopia reduction ≥1 grade, 66.0% vs 53.3%; P = .46). All adverse events of interest (infusion reaction, hearing impairment, hyperglycemia, muscle spasm, and nausea or diarrhea) were mild or moderate in severity. No serious adverse event or death occurred in the IBI311 group. In this phase 3 randomized clinical trial, IBI311 demonstrated better and clinically relevant outcomes in proptosis and CAS than placebo with no new safety issues not identified in previous clinical trials. The results suggest that IBI311 represents a viable treatment option for Chinese patients with active TED. ClinicalTrials.gov Identifier: NCT05795621

Objective: B7-H4 (B7S1, B7x, VTCN1) is an important immune checkpoint molecule that maintains immune homeostasis and is also expressed in pancreatic R cells. The polymorphism of B7-H4 influences the prevalence of Type 2 diabetes (T2D), suggesting a potential role of B7-H4 in the physiological function of pancreatic R cells and the pathogenesis of T2D. Methods: R-cell-specific B7-H4 knockout mice (B7-H4 cKO mice) and their wild-type littermates were used to investigate the in vivo effects of B7-H4 on pancreatic R-cell morphology and function. AAV2/8-ins2-B7H4 and a control virus were infused via the pancreatic intraduct into high- fat diet (HFD)-treated mice to elucidate the therapeutic effect of B7-H4. RNA sequencing was conducted on primary islets. A Luminex assay was used to quantify cytokine changes in B7-H4 cKO mice. Electron microscopy imaging was used to observe insulin secretory vesicles in pancreatic R cells. Results: Lesion of B7-H4 in R cells results in glucose intolerance due to reduced R-cell mass and deficient insulin secretion, whereas over- expression of B7-H4 in R cells ameliorates glucose intolerance in HFD-fed mice. Mechanistically, B7-H4 deficiency activates signal transducer and activator of transcription 5 (Stat5) signalling, which inhibits the expression of apolipoprotein F (Apof), leading to reduced cholesterol efflux and accumulated cholesterol in R cells, thereby impairing insulin processing and secretion. Overexpression of Apof in R cells or intraperitoneal injection of a Stat5 inhibitor reverses the metabolic phenotype and insulin secretion deficiency in B7-H4 cKO mice. Conclusion: Our study demonstrated that B7-H4 plays an important role in regulating R-cell mass and insulin secretion, which may shed new light on the development of novel strategies for T2D treatment. (c) 2024 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).