AIMS:To determine whether recovery of fasting C-peptide (ΔFCP) reduces deterioration in sudomotor small-fibre function, whether a threshold exists, and whether associations are complication-specific. METHODS:Retrospective real-world cohort of 288 hospitalised adults with diabetes with repeated fasting C-peptide and Sudoscan electrochemical skin conductance (ESC). Deterioration in sudomotor small-fibre function was defined as worsening foot ESC. Large-fibre neuropathy (LFN) and diabetic kidney disease (DKD) progression were assessed by nerve conduction and kidney outcomes. Cox models, restricted cubic splines, maximally selected rank statistics, and subgroup/landmark/sensitivity analyses were performed. RESULTS:Over a median 2.2 years, higher ΔFCP was independently associated with lower risk of deterioration in sudomotor small-fibre function, but not with LFN or DKD progression. Highest versus lowest ΔFCP tertile: adjusted HR 0.31 (95% CI 0.14-0.69; p < 0.001). An optimal ΔFCP cutoff of 126.8 pmol/L was identified; ΔFCP ≥ 126.8 pmol/L was associated with a 66% lower risk of sudomotor deterioration (HR 0.34, 95% CI 0.17-0.69; p < 0.001), remaining robust in landmark and sensitivity analyses. Baseline C-peptide mediated little of the association. CONCLUSIONS:Endogenous fasting C-peptide recovery is linked to a clinically meaningful, threshold-dependent reduction in the progression of sudomotor small-fibre dysfunction, supporting β-cell preservation/recovery as targets in early diabetic neuropathy.

IntroductionAutosomal dominant hypocalcemia type 1 (ADH1) is a rare inherited disorder caused by gain-of-function mutations in the calcium-sensing receptor (CASR) gene, with clinical manifestations ranging from asymptomatic hypocalcemia to recurrent seizures.MethodsClinical evaluation and genetic testing were performed. Through activation of the MAPK signaling pathway,cellular functional validation was conducted to confirm the pathogenicity of this variant.ResultsWe report a two-generation family in which the proband presented with lifelong recurrent convulsive episodes and was misdiagnosed with epilepsy for decades, resulting in persistent symptoms despite antiepileptic therapy. His son exhibited similar manifestations. A whole-exome sequencing (WES) analysis was identified a previously unreported heterozygous CASR mutation, c.2452T>C (p.Trp818Arg). Functional cellular analyses confirmed that it caused a novel gain-of-function CASR mutant.ConclusionThis case highlights the critical role of genetic testing in the diagnosis of ADH1, particularly in patients with recurrent seizures or neonatal hypocalcemia with hyperphosphatemia and normal renal function. Once the diagnosis is established, treatment options for symptomatic patients include calcium supplementation and calcitriol, aiming to maintain serum calcium at the lower end of the reference range and relieve symptoms.

Background::Substantial metabolic heterogeneity exists prior to the development of diabetes, creating opportunities for earlier and more precise intervention. This study aimed to analyze common clinical indicators in a diabetes-free population using innovative clustering methods to identify characteristic subgroups and evaluate their utility in stratified prediction of diabetes risk and related complications.Methods::This analysis included 13,829 adults without diabetes from the Kunshan Aging Research with E-health (KARE) cohort, a population-based longitudinal cohort of 51,400 community-dwelling residents from both urban and rural areas of Kunshan City, China, who have received annual health examinations between January 2014 and December 2023. A novel subtype classification method based on complication clustering and weighted naive Bayes classification was applied to select the most informative variables and categorize individuals into distinct diabetes subtypes. We then assessed 3-year risks of diabetes and complications, including cardiovascular disease (CVD), fatty liver disease (FLD), and stroke. To evaluate the influence of genetic factors, polygenic risk scores (PRS) were compared across all participants. External validation was performed using data from 6209 diabetes-free individuals in a cohort of 22,630 people who have been followed since 2014 at Beijing Jiuhua Hospital.Results::Thirteen clinically relevant variables were identified: sex, age, body mass index (BMI), waist circumference, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), alanine aminotransferase (ALT), uric acid (UA), blood urea nitrogen (BUN), fasting blood glucose (FBG), systolic blood pressure (SBP), and heart rate. Three clusters were identified in the Kunshan cohort. Cluster 1 ( n = 6751) had favorable indicators and the lowest risks of diabetes (2.04%, 138/6751) and complications, including CVD (4.52%, 305/6751), FLD (15.30%, 1033/6751), and stroke (9.07%, 612/6751). Cluster 2 ( n = 4622) had the poorest glucose and lipid control, with the highest 3-year cumulative incidence of diabetes (9.95%, 460/4622) and FLD (52.14%, 2410/4622). Cluster 3 ( n = 2456) was characterized by the oldest age, highest SBP, BMI, and waist circumference, with intermediate diabetes risk (3.05%, 75/2456) and the highest risks of CVD (8.47%, 208/2456) and stroke (14.13%, 347/2456). In Cox survival analysis for FLD (adjusted), using Cluster 1 as reference, the hazard ratio (HR) was 2.357 (95% confidence interval [CI]: 2.161-2.571, P <0.001) for Cluster 2, and was 1.903 (95% CI: 1.718-2.108, P <0.001) for Cluster 3. In Cox survival analysis for CVD, HRs were 1.193 (95% CI: 0.975-1.459, P = 0.087) for Cluster 2 and 1.295 (95% CI: 1.041-1.611, P = 0.02) for Cluster 3. In stroke analysis, HRs were 1.058 (95% CI: 0.911-1.23, P = 0.46) for Cluster 2 and 1.212 (95% CI: 1.029-1.428, P = 0.021) for Cluster 3. The risks of diabetes and CVD predicted by PRS were consistent with those identified by clinical clustering. The findings were independently confirmed in the Beijing Jiuhua Hospital cohort. Conclusions::Phenotypes derived from clinical characteristic analysis using the new clustering method effectively identify and stratify the risk of diabetes and related complications, such as CVD, FLD, and stroke, in two large cohorts of diabetes-free Chinese adults, supporting the development of more precise and individualized prevention strategies.

Background: Chronic inflammation plays a central role in the pathogenesis of diabetes mellitus (DM). Aims: This study delineated two-time-point inflammatory status patterns and examined their relationship with incident DM risk using data from the China Health and Retirement Longitudinal Study (CHARLS). Methods: The temporal changes in the inflammatory score between Wave 1 (2011) and Wave 3 (2015), which was calculated as the sum of Z-scores for C-reactive protein (CRP) and white blood cell (WBC) counts, were specified as the exposure. Incident DM was assessed at Wave 3 (2015) and Wave 4 (2018). Associations between inflammatory status patterns and incident DM was analyzed using a longitudinal targeted maximum likelihood estimation (LTMLE) framework in a cohort study. Results: A total of 4305 participants were included, 2404 (55.84%) of whom were female, with a median baseline age of 58 years. During a 7-year follow-up period, 730 individuals (17.0%) developed incident DM. Four distinct inflammatory status patterns were identified: low-stable, high-stable, increasing, and decreasing. After adjusting for multiple covariates, LTMLE analyses showed that the high-stable pattern was significantly associated with an increased risk of DM compared with the low-stable reference group (risk ratio [RR] = 1.430, 95% confidence interval [CI]: 1.204-1.698), with an E-value 2.21. In a landmark analysis of incident DM at Wave 4 (n = 150), the estimates for the high-stable pattern remained directionally positive across the adjusted models but were imprecise and compatible with no association. Exploratory subgroup analyses showed no statistical evidence of effect modification, as neither multiplicative nor additive interaction tests were statistically significant. Conclusions: A persistently elevated inflammatory score is significantly associated with a heightened risk of incident DM.

Obesity in older adults has become a prominent public health issue. Owing to age-related physiological changes and multimorbidity, obesity in this population is associated with complex clinical manifestations and markedly increased difficulty in management. Based on this, a multidisciplinary panel of obesity experts from Beijing Hospital, National Center for Gerontology, formulated this consensus after rigorous evaluation and iterative revision. The consensus emphasizes that management of obesity in older adults requires comprehensive assessment according to age and overall health status and should adopt a patient-centered, individualized, and stratified strategy. By adhering to the principles of safety first, functional improvement, and steady progress, the goals are to reduce visceral fat accumulation, maintain or increase muscle mass, protect bone health, and improve physical function and overall health. Special attention should be paid to sarcopenia in older adults. Adequate intake of high-quality protein, combined with an individualized resistance exercise program, is an effective strategy for maintaining muscle mass. Selection of weight-loss medication should be guided by evidence supporting its benefit for obesity-related complications or comorbidities, with close monitoring of adverse reactions.

AIMS:Although growing evidence suggests that obesity/central adiposity predisposes to the development and exacerbation of heart failure with preserved ejection fraction (HFpEF), it remains to be clarified whether there is a causal relationship between adiposity and HFpEF pathogenesis. METHODS AND RESULTS:HFpEF was induced in male C57BL/6N mice using a high-fat diet + Nω-nitro-l-arginine methyl ester. Resection or transplantation of visceral adipose tissue (VAT) blunted or exacerbated HFpEF phenotypes, respectively, in mice. VAT from HFpEF mice displayed greater weight and secreted more small extracellular vesicles (sEVs) than those from chow-fed mice. Either systemic inhibition of sEV secretion or VAT-specific knockdown of Rab27b (an indispensable GTPase for sEV secretion) protected against HFpEF. Discovery-driven experiments identified miR-295-3p within sEVs as a possible mediator of the VAT-heart axis, which impaired cardiac autophagy by binding to Ulk1 mRNA. MiR-295-3p antagomir treatment mitigated HFpEF phenotypes. Additionally, neonatal mouse cardiomyocytes (NMCMs) manifested blunted autophagic flux after treatment with plasma sEVs from HFpEF mice. Notably, HFpEF patients displayed downregulated cardiac Ulk1 and autophagy compared with healthy individuals. Restoration of cardiac autophagy with rapamycin or ULK1 overexpression via AAV-9 attenuated the HFpEF phenotype in mice. CONCLUSION:The present work unveils a mechanism whereby obesity promotes HFpEF progression, emphasizing the role of VAT-heart crosstalk. Specifically, VAT-derived sEVs, miR-295-3p, and the resultant disruption of cardiac autophagy contribute significantly to the pathogenesis of HFpEF.

ObjectiveTongxinluo (TXL), a traditional Chinese medicine, has demonstrated cardioprotective effects in acute myocardial infarction (AMI), yet its impact on myocardial protein profiles remains largely unexplored. This study aimed to elucidate the proteomic mechanisms underlying the therapeutic effects of TXL in AMI.MethodsAMI was induced via left anterior descending artery ligation in C57BL/6J mice. TXL was administered by oral gavage during the acute phase. Myocardial tissues and serum were subjected to 4D label-free quantitative proteomics, Western blotting, ELISA, immunofluorescence, TUNEL staining, and molecular docking analyses. Cardiac function was evaluated by echocardiography and fibrosis was quantified by Sirius red staining.ResultsProteomic analysis identified 1,061 differentially expressed proteins between TXL- and vehicle-treated AMI mice, with KEGG enrichment highlighting significant downregulation of complement and coagulation cascades. Key complement components C1qa and C1s were markedly upregulated post-AMI but significantly suppressed by TXL. Molecular docking suggested potential interactions between multiple TXL bioactive compounds and C1qa/C1s. TXL treatment reduced complement activation (serum C3a), inhibited cardiomyocyte apoptosis (Bax/Bcl-2, TUNEL), improved left ventricular ejection fraction, and attenuated fibrosis. Notably, TXL monotherapy outperformed C1 inhibitor (C1i) alone, while combining C1i with TXL conferred no additional benefit, indicating that C1 complement inhibition is an intrinsic component of TXL’s mechanism.ConclusionModulation of C1-associated complement activation may be one of the mechanisms through which TXL protects against AMI, providing novel proteomic-level insights into the cardioprotective actions of this traditional Chinese medicine.

AIMS:To estimate the prevalence and incidence of hypoglycaemia and the variations in Chinese type 2 diabetes (T2D) patients. MATERIALS AND METHODS:A multi-centre, non-interventional study was conducted across 103 hospitals in 20 provinces in China between 18 March 2022 and 5 December 2023. The study adopted an integrated 12-week prospective cohort study design, enrolling 15 437 adults with T2D. Hypoglycaemic events were captured through a structured questionnaire and patient diary, including laboratory-confirmed, symptomatic, any, severe and nocturnal hypoglycaemia. Variations in hypoglycaemia burden were examined by socio-demographic factors, health status, treatment regimens, geographic region and hospital level. The endpoints were the prevalence of patients experiencing at least one hypoglycaemic event and the corresponding incidence during the study period. RESULTS:The 15 437 participants who completed the follow-up at Week 12 were included in this study. During this period, 9.0% [95% CI: 8.6, 9.5] of the participants experienced at least one hypoglycaemic event, corresponding to an incidence rate of 79.8 [76.9, 82.8] events per 100 person-years. Hypoglycaemia burden differed markedly according to treatment background. The 12-week prevalence of any hypoglycaemia was 5.5%, 9.7% and 12.2% among participants receiving neither insulin nor secretagogues, secretagogues without insulin and insulin, respectively, with corresponding incidence rates of 48.6, 105.0 and 104.3 events per 100 person-years. Similar treatment-related patterns were observed for laboratory-confirmed, symptomatic and nocturnal hypoglycaemia. Hypoglycaemia burden also varied substantially across age, diabetes duration, body mass index (BMI), HbA1c, geographic region and hospital level. Greater hypoglycaemia burden was generally observed among participants with longer diabetes duration and lower BMI. The prevalence of any hypoglycaemia was highest in the eastern region and tertiary hospitals, whereas its incidence rate was highest in western regions and primary hospitals. CONCLUSIONS:Although the prevalence and incidence of hypoglycaemia among Chinese T2D patients were lower than previous studies, hypoglycaemia still remains a significant clinical concern. These findings highlight the importance of individualized strategies for glycaemic management to minimize hypoglycaemia risk in routine diabetes care. TRIAL REGISTRATION:Chinese Clinical Trial Registry: ChiCTR2100053847.

Pathological cardiac fibrosis arising from acute/chronic myocardial injury drives ventricular remodeling, functional impairment, and elevated mortality through mechanisms lacking effective therapies. Central to fibrogenesis, myofibroblast activation via TGFβ1-Smad3 signaling necessitates targeted therapeutic strategies. Anti-fibroblast activation protein (FAP)-functionalized nanoparticles (NPs-SIS3-Ab) were fabricated using PLGA@PDA cores to deliver a Smad3 inhibitor (SIS3). In vitro targeting was assessed through confocal microscopy in TGFβ1-stimulated myofibroblasts. Therapeutic efficacy was evaluated in murine acute myocardial infarction (AMI) and transverse aortic constriction (TAC) models using in vivo imaging system, confocal microscopy, histopathology, transthoracic echocardiography and Western blotting. The NPs-SIS3-Ab nanoparticles demonstrated efficient SIS3 loading, antibody conjugation density, and colloidal stability. Anti-FAP antibody modification enabled specific targeting ability to myofibroblasts both in vitro and in vivo. NPs-SIS3-Ab significantly suppressed TGFβ1-Smad3 pathway activation of myofibroblast in vitro and furthermore, systemic intravenous delivery of NPs-SIS3-Ab markedly inhibited Smad3 phosphorylation, decreased cardiac fibrosis area and more importantly, restored cardiac function both in AMI and TAC models without evident side effects. This FAP-targeted nanoplatform achieves precision Smad3 inhibition, demonstrating dual efficacy against acute ischemic and chronic pressure-overload fibrosis while preserving systemic safety. Our findings establish a clinically translatable strategy for modulating pathological fibroblast activity in heart failure.

BACKGROUND:Pharmacotherapy offers a potential solution for individuals with overweight and obesity to decrease their body weight. However, there is limited knowledge of the effects of antiobesity agents on the distribution of body fat. METHODS:The PubMed, Embase, and Cochrane Library databases were reviewed for randomized controlled trials (RCTs) of weight-lowering drugs between inception and May 23, 2023. The main results were visceral and subcutaneous adipose tissue (VAT and SAT). Secondary outcomes were altered body weights and waist circumferences. For the statistical analysis, STATA 14.0 was utilized, and the frequentist method was used for random-effect network meta-analyses. RESULTS:A total of 39 articles including 41 RCTs with 2741 patients were included. GLP-1 receptor agonists and SGLT-2 inhibitors were observed to lower VAT (-0.90 [-1.32 to -0.47] and -0.66 [-1.22 to -0.10]) after a mean of 29.4 weeks, whereas only GLP-1 receptor agonists reduced SAT (-1.01 [-1.58 to -0.43]). Naltrexone-bupropion, GLP-1 receptor agonists, SGLT-2 inhibitors, and metformin were found to reduce body weight (-5.60 [-8.64 to -2.56] kg, -4.73 [-5.58 to -3.88] kg, -3.20 [-4.69 to -1.72] kg, and -1.93 [-3.01 to -0.85] kg). Lastly, waist circumference was decreased by GLP-1 receptor agonists, metformin, SGLT-2 inhibitors, and naltrexone-bupropion. CONCLUSION:This analysis demonstrated that GLP-1 receptor agonists may have advantages over other antiobesity agents in reducing VAT and SAT. SGLT-2 inhibitors were more helpful to reduce VAT. The clinical significance relates to physicians being able to choose appropriate weight-loss agents in accordance with a patient's fat distribution.

Introduction and Objective: MAFLD is a prevalent chronic liver disorder with limited pharmacological options. Mazdutide is a dual agonist of the glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) approved for diabetes and obesity. This study aimed to evaluate the therapeutic effects and mechanisms of mazdutide in a diet-induced obese (DIO) mouse model of MAFLD. Methods: DIO mice were treated for eight weeks with mazdutide, semaglutide, or vehicle. A pair-fed group matched the food intake of the mazdutide group. Body weight, body composition, energy expenditure, glucose tolerance, and insulin sensitivity were assessed. Liver histology and serum and hepatic biochemical parameters were analyzed. Transcriptomic, proteomic, and metabolomic analyses were performed to investigate molecular mechanisms. Results: At only one-third the dose of semaglutide, mazdutide achieved comparable glucose-lowering effects and more pronounced weight loss. It significantly reduced systemic fat mass, remodeled energy metabolism, and improved systemic glucose tolerance and insulin sensitivity. Histological analysis revealed its ability to alleviate hepatic lipid deposition, oxidative stress, and inflammatory responses. Pair-feeding experiments indicated that these benefits were not solely attributable to reduced food intake. Multi-omics analysis demonstrated that mazdutide reprogrammed hepatic lipid metabolism by suppressing lipid uptake, de novo lipogenesis, and lipid droplet formation, primarily through modulation of the PPAR signaling pathway. Conclusion: The dual GLP-1R/GCGR agonist mazdutide improves systemic metabolic homeostasis and liver pathology in experimental MAFLD. These data suggest that dual receptor activation confers metabolic benefits beyond single GLP-1R agonism, highlighting its potential therapeutic value for MAFLD. Disclosure D. Gao: None. Q. Pan: None. L. Guo: Consultant; Current; Abbott Diabetes, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Dreisamtech, Dongbao, Eli Lilly and Company, Gan & Lee Pharmaceuticals, Hansoh, Hengrui, Hua Medicine, Huadong Medicine, Innovent, Johnson & Johnson, Novartis AG, Novo Nordisk, Merck & Co., Inc., Pfizer Inc., Sanofi, Synapsor, Takeda Pharmaceutical Company Limited, Zense, 3sbio. Research Support; Current; Abbott Diabetes, AstraZeneca, Bayer AG, Dreisamtech, Eli Lilly and Company, Hansoh, Hengrui, Hua Medicine, Huadong Medicine, Innovent, Meitekanger, Novo Nordisk, Salubris, Sanofi, Synapsor, Zense. Funding Capital’s Funds for Health Improvement and Research(2022-1-4051), Beijing Municipal Science & Technology Commission (No Z221100007422007)

Objective Mitochondrial DNA copy number (mtDNA-CN) reflects mitochondrial function, but prior studies have reported inconsistent associations with type 2 diabetes risk, ranging from inverse to positive or null findings. We hypothesized that mtDNA-CN is nonlinearly associated with incident type 2 diabetes. Research Design and Methods We included 34,835 diabetes-free adults from the Kunshan Aging Research with E-health (KARE) cohort and 289,338 from the UK Biobank (UKB). Associations between blood mtDNA-CN and incident type 2 diabetes were evaluated using Cox proportional hazards and restricted cubic spline models stratified by age. Results A U-shaped association was observed in the KARE cohort (P < 0.001), where the hazard ratios (95% CIs) across increasing mtDNA-CN quartiles were 1.00 (reference), 0.94 (0.88–1.00), 0.85 (0.79–0.91), and 0.93 (0.87–1.00). In contrast, the UKB cohort exhibited a predominantly inverse linear trend. Age-stratified analyses revealed that this U-shaped association was particularly evident in younger participants (<65 years in KARE and <50 years in UKB), indicating elevated diabetes risk at both low and high mtDNA-CN levels. Additionally, mtDNA-CN declined with age in both cohorts, with an accelerated decrease beyond approximately 65 years in KARE and 50 years in UKB. Conclusions Blood mtDNA-CN showed a U-shaped association with incident type 2 diabetes in younger individuals.

Introduction and Objective: In SUSTAIN 6 (NCT01720446), once-weekly subcutaneous semaglutide (0.5/1.0 mg) significantly reduced the risk of major adverse cardiovascular (CV) events (MACE) in people with type 2 diabetes (T2D) and established CV disease/high CV risk. This post hoc analysis assessed cardiorenal benefits of semaglutide across T2D phenotypic subtypes. Methods: The Discriminative Dimensionality Reduction Tree algorithm mapped 3251 SUSTAIN 6 participants to a non-linear 2-dimensional tree structure using 9 age- and sex-adjusted phenotypes. Correlations between phenotypes and cardiorenal outcomes from baseline to week 104 were visualized, and Cox proportional hazard models were used to determine semaglutide treatment efficacy on cardiorenal outcomes. Results: Four quadrants reflecting T2D subtypes were defined based on phenotype distribution (Figure A). Probability of 3-point MACE was lower with semaglutide vs placebo across subtypes (Figure B). Semaglutide reduced the risk of 3-point MACE, expanded composite CV outcomes, an additional composite outcome, and new or worsening nephropathy, across different T2D subtypes (Figure C). Conclusion: Semaglutide reduced the risk of cardiorenal outcomes across different T2D subtypes. Disclosure W. Wang: None. J. Zhang: None. B. Dong: Employee; Current; Novo Nordisk. P. Hu: Employee; Current; Novo Nordisk A/S. N. Marx: Other - Speaker - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; Abbott. Other - Consultant - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; Abbott. Other - Speaker - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; Amgen Inc. Other - Speaker - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; AstraZeneca. Other - Consultant - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; AstraZeneca. Other - Speaker - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; Bayer AG. Other - Consultant - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; Bayer AG. Other - Speaker - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; Boehringer Ingelheim International GmbH. Other - Consultant - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; Boehringer Ingelheim International GmbH. Other - Speaker - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; Daiichi Sankyo. Other - Consultant - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; F. Hoffmann-La Roche Ltd. Other - Speaker - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; Lilly. Other - Consultant - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; Lilly. Other - Speaker - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; Novo Nordisk. Other - Consultant - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; Novo Nordisk. Other - Speaker - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; Sanofi. Other - Consultant - Nikolaus Marx declines all personal compensation from pharma or device companies. All contracted fees and travel support are paid to the University Hospital RWTH Aachen. All contracts are between the University Hospital RWTH Aachen and the company.; Current; Sanofi. S.P. Prabhu: Employee; Current; Novo Nordisk A/S. Z. Shen: Employee; Current; Novo Nordisk. Stock/Shareholder; Current; Novo Nordisk. Q. Pan: None. L. Guo: Consultant; Current; Abbott Diabetes, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Dreisamtech, Dongbao, Eli Lilly and Company, Gan & Lee Pharmaceuticals, Hansoh, Hengrui, Hua Medicine, Huadong Medicine, Innovent, Johnson & Johnson, Novartis AG, Novo Nordisk, Merck & Co., Inc., Pfizer Inc., Sanofi, Synapsor, Takeda Pharmaceutical Company Limited, Zense, 3sbio. Research Support; Current; Abbott Diabetes, AstraZeneca, Bayer AG, Dreisamtech, Eli Lilly and Company, Hansoh, Hengrui, Hua Medicine, Huadong Medicine, Innovent, Meitekanger, Novo Nordisk, Salubris, Sanofi, Synapsor, Zense.

BACKGROUND Chronic kidney disease (CKD) is a major microvascular complication of diabetes and a leading cause of morbidity and mortality. Obesity and visceral fat accumulation contribute to renal dysfunction, but traditional measures such as body mass index may incompletely reflect metabolism-related harm from adipose tissue. Although numerous adiposity indices have been developed, comparative evidence on their associations with CKD in adults with diabetes remains limited. AIM To compare 10 adiposity indices and evaluate their associations and discriminative abilities for CKD among adults with diabetes. METHODS This retrospective cross-sectional study included 3526 adults with diabetes who underwent health examinations at a tertiary hospital. A total of 10 adiposity indices were calculated. CKD was classified as estimated glomerular filtration rate below 60 mL/min/1.73 m2 and/or an albumin-to-creatinine ratio >= 30 mg/g. Multivariable logistic regression estimated odds ratios per standard-deviation increase, with additional adjustment. Restricted cubic splines assessed dose-response patterns, and discrimination was evaluated using the area under the receiver operating characteristic curve. RESULTS Among the 3526 participants, 456 (12.9%) had CKD. The CKD group had a higher proportion of men (86.0% vs 80.7%, P = 0.007) and a higher prevalence of hypertension (62.7% vs 46.4%, P < 0.001) compared with the non-CKD group. In both the primary and the comorbidity-adjusted sensitivity models, all examined indices were positively associated with CKD (all P < 0.001). Restricted cubic splines analyses showed no evidence of nonlinearity for body mass index, Chinese visceral adiposity index (CVAI), body roundness index, conicity index, and waist-to-height ratio, whereas the other indices showed evidence of nonlinearity (P < 0.05). CVAI had the highest area under the curve (0.637), whereas a body shape index had the lowest (0.526). CONCLUSION In adults with diabetes, multiple adiposity indices are associated with CKD. CVAI shows the best discrimination and may aid CKD risk assessment.

Aging is the primary risk factor for most chronic diseases, yet substantial heterogeneity highlights a fundamental gap between chronological age and biological aging processes. Despite the high predictive accuracy of multi-omics clocks, their clinical implementation remains limited by cost and complexity, underscoring the need for scalable and clinically actionable alternatives. Here, we developed a physical clock that integrates routine clinical biomarkers with multidimensional physical performance using ElasticNet regression in the large-scale PENG ZU cohort. This model was further reduced to a simplified 11-marker model, primarily capturing key domains of kidney function, glucose metabolism, and physical performance. Accelerated aging, as measured by physical clock-derived ΔPhysicalAge, was strongly associated with chronic disease incidence, functional decline, reduced intrinsic capacity, and mortality. Across independent validation in UKB Biobank and NHANES, it robustly predicted disease onset, disease-specific, and all-cause mortality. Notably, ΔPhysicalAge outperformed ΔPhenoAge in predicting major age-related diseases and enabled effective risk stratification even among individuals conventionally classified as low risk. We observed an association between postmenopausal HRT use and lower ΔPhysicalAge, providing preliminary evidence supporting the validity and responsiveness of the physical clock. To facilitate clinical translation, we established age- and sex-specific healthy reference intervals (HRI) derived from individuals with normal or decelerated aging, demonstrating that maintenance within these ranges is associated with substantially reduced mortality risk. Furthermore, modifiable lifestyle and psychosocial factors, including healthy diet, physical activity, health consciousness, and social engagement, were associated with slower aging, highlighting actionable intervention pathways. Together, the physical clock bridges the gap between biological aging assessment and real-world clinical practice, offering a clinically accessible tool for risk stratification and personalized intervention to promote healthy aging.

The population-level heterogeneity of obesity has yet to be systematically investigated. We aimed to apply the data dimensionality reduction tree (DDRTree) method to obese individuals and to examine how distinct phenotypic patterns align with different outcomes. To characterize the heterogeneity of obesity, a two-dimensional (2D) tree structure based on the DDRTree algorithm was employed. Associations between embedding dimensions and metabolic traits, obesity-related indices, and clinical outcomes were evaluated using multivariable linear, logistic, and Cox proportional hazards regression models. The DDRTree revealed distinct, dimension-specific phenotypic patterns. We found that dimension 1 was strongly associated with insulin resistance, dysglycemia, visceral adiposity, subclinical atherosclerosis, hyperuricemia, and early renal injury, including microalbuminuria (MAU) (all P < 0.001). Dimension 2 was more closely aligned with β-cell function and was associated with all-cause mortality (ACM) in the CHARLS cohort (P < 0.05). Individuals in the upper-right section of the tree exhibited a higher risk of vascular abnormalities, while the lower-right region clustered obese individuals with pronounced insulin resistance, hyperuricemia, and hyperglycemia. Obesity-related indices demonstrated heterogeneity: waist-based measures (WC, WHTR, ABSI, VAT) consistently aligned with Dimension 1, while lipid- and liver-related indices (LAP, VAI, FLI) showed enrichment along combined phenotypic gradients. Our findings demonstrate that DDRTree can be applied to obese populations to characterize continuous phenotypic heterogeneity and its associations with metabolic and clinical outcomes. This phenotypic mapping framework may support risk-oriented stratification of obese individuals in population-based settings. Not applicable. Not applicable.

AIMS:Recently, the European Association for the Study of Obesity (EASO) andLancet Diabetes & Endocrinologyhave proposed new frameworks for diagnosing obesity. This study aimed to examine the association between different defined obesity subgroups and clinical outcomes. METHODS:Using the UK Biobank, we enrolled individuals based on updated diagnostic criteria and described the variations in obesity prevalence under different definitions. We then calculated the proportion eligible for treatment. Furthermore, we compared the spectrums of obesity-related dysfunctions across definitions and conducted stratified analyses by sex and ethnicity. Finally, we assessed the associations between various obesity subtypes and the incidence of type 2 diabetes (T2D), cardiovascular events, end-stage renal disease (ESRD), and all-cause mortality with adjusted Cox proportional hazards models. RESULTS:Among 498,353 subjects (median age 58 [50, 63] years), 54.4% were female. The EASO and Lancet frameworks identified 29.6% and 63.4% of participants, respectively, as having obesity-representing increases of 4.8% and 38.6% over the BMI-based WHO definition. Hypertension, metabolic disorders, and musculoskeletal conditions were the most prevalent obesity-related dysfunctions overall, with variations by sex and ethnicity, particularly elevated among Asian populations. Notably, overweight as defined by EASO or Lancet criteria was not consistently a risk factor, in some context appeared protective. However, clinical obesity under the Lancet criteria conveyed the highest risk of progression to severe outcomes among all obesity subtypes, with significantly elevated hazards for T2D (HR = 12.33, 95% CI: 11.74-12.96), cardiovascular events (HR = 4.02, 95% CI: 3.89-4.16), ESRD (HR = 7.13, 95% CI: 6.11-8.33), and all-cause mortality (HR = 3.07, 95% CI: 2.99-3.15), exceeding risks associated with EASO- and WHO-defined obesity. CONCLUSION:New obesity criteria significantly increased diagnosed prevalence, especially among Asians. Notably, overweight by EASO or Lancet standards does not uniformly raise health risks. Consequently, the choice of diagnostic framework directly shapes risk stratification and informs personalized treatment strategies that should address body composition beyond weight alone.

Background The DNA-sensing receptor cyclic GMP-AMP synthase (cGAS)/Stimulator of Interferon Genes (STING) signaling pathway plays a critical role in mediating inflammation and cell death following myocardial ischemia, representing a promising therapeutic target. However, the systemic inhibition of cGAS/STING is limited by its protective physiological functions, highlighting the need for targeted delivery strategies. The safety and efficacy of nanoparticle-based delivery of cGAS/STING inhibitors to mitigate cardiac ischemia-reperfusion (I/R) injury remain unknown. Methods We constructed macrophage membrane-coated polydopamine nanoparticles for the preferential accumulation of the cGAS inhibitor RU.521 in the injured myocardium (RU.521-PDA@M). The PDA core was designed to respond to the ischemic myocardial microenvironment (e.g., low pH, elevated H2O2, and glutathione). Double-stranded DNA-transfected Raw264.7 macrophages and murine models of cardiac I/R were utilized. Results RU.521-PDA@M exhibited favorable physicochemical properties, biocompatibility and enhanced cardiac accumulation due to macrophage membrane coating. Both in vitro and in vivo, treatment with RU.521-PDA@M markedly suppressed the phosphorylation of key cGAS/STING pathway proteins (p-STING, p-TBK1 [TANK binding kinase 1], p-IRF3 [Interferon regulatory factor 3]) and reduced the expression of downstream inflammatory genes. In mice subjected to I/R, RU.521-PDA@M demonstrated superior efficacy over both free RU.521 and control treatments (PBS or blank nanoparticles), markedly attenuating cardiac fibrosis, improving cardiac function, and exhibiting no significant systemic toxicity, as evidenced by serum biochemistry and histopathology of major organs. Conclusions The macrophage membrane biomimetic drug-loaded nanoparticles established in this study represent a novel strategy for targeting the cGAS/STING signaling pathway following myocardial I/R. This approach offers new insights into the clinical translation of this promising mechanism.