With the ongoing rise in global temperatures, the prevalence of heat-stress-related chronic health disorders has increased. However, whether heat stress has an enduring impact on metabolic health remains unclear. Here, we report that mice exposed to heat stress were more susceptible to metabolic dysfunction upon subsequent exposure to an obesogenic diet. Upon heat stress, we found that elevated skin-derived kallikrein-related peptidase 14 (KLK14) imprinted hypothalamic LRRC7+ astrocytes. These astrocytes further suppressed neighboring paraventricular nucleus (PVN)OXT neuron activity via alkB homolog 1, histone H2A dioxygenase (ALKBH1)-mediated epigenetic modification of γ-aminobutyric acid (GABA) synthesis, thus driving visceral fat deposition in a sympathetic nervous-system-dependent manner. Heat stress exposure also increased susceptibility to metabolic dysfunction in human subjects, with vitamin A treatment limiting the production of KLK14 and ameliorating metabolic disturbances in humans and mice. Together, our findings reveal a skin-hypothalamus axis linking heat memory and metabolic dysfunction and highlight that global warming is exacerbating metabolic diseases.

Individual susceptibility to alcohol-related liver disease (ALD) varies substantially despite similar alcohol consumption patterns. Emerging evidence suggests metabolism-disrupting agents (MDAs) may synergistically amplify alcohol-induced hepatotoxicity, yet population-level evidence remains limited. This study investigated associations between 40 MDAs and ALD risk using integrated analytical approaches. We analyzed 13,472 National Health and Nutrition Examination Survey participants (2005–2016). Forty MDAs spanning per- and polyfluoroalkyl substances, phenolic compounds, phthalate metabolites, polycyclic aromatic hydrocarbon metabolites, and volatile organic compound metabolites were measured using standardized protocols. Multivariable logistic regression assessed MDA-ALD associations. Restricted cubic splines characterized dose-response relationships. Subgroup analyses identified vulnerable populations by sex, age, race/ethnicity, body mass index, and hyperlipidemia status. Machine learning algorithms including LightGBM were developed with nested cross-validation (to prevent data leakage during feature selection) to identify predictive biomarkers. Network toxicology integrated computationally predicted MDA targets with ALD gene expression data (GEO GSE28619), followed by pathway enrichment analyses. Three MDAs demonstrated robust positive associations: benzylmercapturic acid (BMA; OR: 1.56, 95

Prospective evidence linking greenness and cardiovascular disease (CVD) in rapidly urbanizing developing countries remains limited. Here, among 159,590 adults aged ≥40 years from the nationwide China Cardiometabolic Disease and Cancer Cohort with a median follow-up of 10.1 years, we examine the association between residential greenness, measured by satellite-derived normalized difference vegetation index (NDVI) within 500 m of residence, and incident CVD, and evaluate its joint effects with cardiovascular health as defined by Life’s Essential 8. Individuals in the highest quartiles of contemporaneous, one-year, and cumulative NDVI consistently show lower CVD risk compared with those in the lowest quartiles, although associations vary across subpopulations. Notably, individuals with high cardiovascular health scores living in low-NDVI areas exhibit similar CVD risk to those residing in high-NDVI areas. These findings highlight the complementary importance of both green infrastructure and healthy lifestyles in reducing CVD risk in rapidly urbanizing regions of China.

There is an urgent need to implement population-based actions to prevent diabetes mellitus (DM) in China. However, the current knowledge is limited on a prospective association of seafood intake with DM risk in Chinese adults. We aimed to determine the association between seafood consumption and the incident DM in a nationwide cohort of Chinese populations. A prospective cohort study of 104,816 participants, free of DM, aged ≥ 40 years across various geographical regions in China was conducted at baseline (China Cardiometabolic Disease and Cancer study). Habitual consumptions of seafood were assessed using a semi-quantitative food frequency questionnaire, and DM was diagnosed according to the WHO 1999 criteria. Primary outcomes were the incident DM, presented as hazard rations (HRs) with 95

Background: Lifestyle changes worldwide have driven the prevalence of metabolic diseases, including obesity and type 2 diabetes, elevating cardiovascular risk and mortality while straining healthcare systems. Conventional risk assessments relying on single markers fail to capture metabolic heterogeneity or enable precise stratification. Although unsupervised clustering can identify metabolic phenotypes, existing studies are largely confined to single cohorts, lacking cross-population validation and limiting their generalizability. Objective: This study aims to identify metabolic phenotypes across populations, evaluate their associations with all-cause and cardiovascular mortality, and validate high-risk phenotype consistency across cohorts, providing evidence for risk stratification and personalized interventions. Methods: We included participants aged ≥18 years with complete metabolic data from UK Biobank (n = 370,063) and NHANES (1999–2018; n = 20,852). Lipid and glucose metabolism markers, liver enzymes, obesity indices, and hemodynamic indicators were integrated, standardized, and subjected to K-means clustering. Cox proportional hazards models assessed phenotype-mortality associations, restricted cubic splines evaluated nonlinear relationships, and R²-based modified SHAP analysis identified key drivers. Results: Clustering identified 5 and 4 metabolic phenotypes in UKB and NHANES, respectively, both capturing relatively healthy, dyslipidemic, obesity-related mixed, and hyperglycemic phenotypes, despite slight compositional differences in the latter. The hyperglycemic phenotype showed the highest all-cause mortality risk in both cohorts (UKB: HR = 2.475; NHANES: HR = 1.471), with consistent cardiovascular mortality patterns. The dyslipidemic phenotype showed no increased risk; lipid levels (LDL-C, TC) displayed L-shaped nonlinear associations with mortality. SHAP analysis identified blood glucose, HbA1c, and uric acid as primary drivers of the hyperglycemic phenotype, with strong cross-cohort consistency. Conclusion: Unsupervised clustering of multidimensional metabolic indicators consistently identifies phenotypes with divergent mortality risk across populations. The hyperglycemic phenotype represents the most robust high-risk group, while lipid levels show nonlinear associations with mortality.

BACKGROUND:The genetic architecture of circulating amino acids (AAs) and microbiota-related metabolites (MRMs) in relation to cardiometabolic disease remains poorly characterized in East Asian populations, limiting ancestry-specific insights. METHODS:In a prospective cohort of 2953 Chinese individuals, we performed a large-scale genome-wide association study (GWAS) of 28 serum AAs and 22 MRMs. We conducted a cross-ancestry comparison of variant-metabolite associations. Using colocalization and Mendelian randomization (MR), we further investigated causal roles of 50 AAs and MRMs in 25 cardiometabolic diseases from the BioBank Japan. Furthermore, we explored differences in the genetic regulation of these metabolites between incident T2DM cases and healthy controls. RESULTS:We identified 33 metabolite-variant associations, 22 of which were previously unreported, and revealed several loci specific to East Asian ancestry. Integrative colocalization and MR analyses established 49 causal relationships between metabolite levels and cardiometabolic diseases, most notably implicating genetically predicted N-acetyltryptophan to increased risk of type 2 diabetes. Moreover, we observed distinct patterns of genetic regulation between T2DM cases and controls, highlighting substantial heterogeneity of effects and dynamic gene-disease interplay. CONCLUSIONS:These findings offer crucial insights into the ancestry-specific genetic determinants of metabolic traits, and shed new light on their causal roles in the etiology of cardiometabolic diseases in East Asian populations.

Optimization of HbA1c, blood pressure and cholesterol, referred to as the “ABCs”, is central to the management of diabetes. However, the age-specific associations of these factors with mortality in patients with diabetes remains unclear. In this prospective cohort study, 43,732 Chinese adults aged ≥ 40 years with diabetes were included from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Participants were stratified by age (< 55, 55-<65, 65-<75, ≥ 75 years). Cox proportional hazards regression and Fine-Gray competing risk models were employed to estimate the associations of HbA1c, systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDL-C) with all-cause, cardiovascular, and non-cardiovascular mortality across age groups. Relative importance and population attributable fractions (PAFs) were computed for each metabolic factor. During a median follow-up of 10.1 years, 3,975 deaths were documented. Age significantly modified the associations of HbA1c, SBP, and LDL-C with all mortality outcomes (all P for interaction < 0.05). Among participants aged < 75 years, HbA1c showed graded positive associations with all-cause, cardiovascular, and non-cardiovascular mortality. The SBP thresholds associated with increased mortality risk were 140 mmHg in those aged < 65 years and 160 mmHg in those aged 65–<75 years. Among those aged ≥ 75 years, however, the patterns of these associations differed markedly. Elevated mortality risk was observed only at HbA1c ≥ 9

Optimal control of hemoglobin A1c (HbA1c), blood pressure, and cholesterol (ABC risk factors) is essential for reducing cardiovascular disease (CVD) risk in individuals with diabetes. However, age-specific contributions of these factors remain inadequately characterized. Using data from the China Cardiometabolic Disease and Cancer Cohort study, we assessed the associations between ABC risk factors and incident CVD among Chinese adults with diabetes, stratified by age groups of < 55, 55 to < 65, 65 to < 75, and ≥ 75 years. Cox proportional hazards models and population-attributable fractions (PAFs) were used to quantify the associations between ABC risk factors and incident CVD. During a median follow-up of 10.1 years, 4707 incident cases of CVD were documented. Higher levels of baseline HbA1c, systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDL-C) were significantly associated with increased CVD risk. Age modified these associations (P interaction < 0.05), with progressively attenuated hazard ratios (HRs) observed in older age groups. Compared with HbA1c < 7.0%, HbA1c ≥ 9.0% showed stronger CVD associations in adults aged < 55 years (HR = 2.42; 95% confidence interval [CI]: 1.98-2.97) than in those aged ≥ 75 years (HR = 1.50; 95% CI: 1.12-2.02), and SBP ≥ 140 mmHg and LDL-C ≥  4.1 mmol/L were significant only in younger groups. The leading contributor to PAFs for CVD was SBP (28.3%), followed by HbA1c (12.0%) and LDL-C (9.2%), with diminishing impacts across older groups. These results underscore the importance of age-specific management of ABC risk factors in diabetes care, with the benefit of stricter risk factor management in younger adults and the need for a more flexible approach in older populations.

ABSTRACT Background Metabolic diseases remain a fast‐growing global health burden. Besides other known factors, socioeconomic status (SES) has been recognized as a key determinant of metabolic health. This study aimed to investigate the association between SES and the prevalence of metabolic diseases in the Chinese population. Methods We analyzed data from a nationwide community‐based cross‐sectional study in China. SES was derived to a composite score (range 0–3) using three indicators (educational attainment, living conditions, and marital status), with higher scores indicating better SES. Chronic diseases were diagnosed through biochemical testing and clinical assessments. Logistic regression models were applied to estimate associations between SES scores and metabolic diseases. Results Among 201 532 participants, the lowest SES group had 87.1% higher odds of metabolic diseases than the highest SES group (odds ratio [OR] = 1.871, 95% confidence interval [CI]: 1.739, 2.016). One‐point decrease in SES score was associated with increased prevalence of hypertension (OR = 1.096, 95% CI: 1.080, 1.113) and obesity (OR = 1.112, 95% CI: 1.091, 1.134). In contrast, lower SES scores were linked to a reduced prevalence of dyslipidemia (OR = 0.931, 95% CI: 0.918, 0.945) and diabetes (OR = 0.974, 95% CI: 0.958, 0.990) after adjusting for covariates. We also observed that lower SES scores showed stronger associations with increased prevalence of obesity and hypertension in women but decreased risks of diabetes, dyslipidemia, and obesity in men. Conclusions Lower SES was associated with a higher prevalence of hypertension and obesity but a lower prevalence of dyslipidemia and diabetes, with significant gender differences.

Little has been found regarding the lifetime cumulative effect of reproductive factors on chronic kidney disease (CKD), and how this relationship varies with cardiovascular health (CVH) remains unexplored. This study aimed to assess the relationships of lifetime cumulative estrogen exposure reflected by reproductive factors, and LE8 CVH status with incident CKD among postmenopausal women. The study included 33,700 postmenopausal participants from the China Cardiometabolic Disease and Cancer Cohort (4 C) Study, enrolled between 2011 and 2012 with follow-up assessments conducted between 2014 and 2016 (median follow-up: 3.1 years). Lifetime cumulative estrogen exposure due to reproductive factors was evaluated through reproductive lifespan (RLS), endogenous estrogen exposure (EEE), and total estrogen exposure (TEE). Health behaviors information in Life’s Essential 8 (LE8) was collected by questionnaire and laboratory examination. The risk of CKD was analyzed with Cox proportional hazards models. Shorter lifetime cumulative estrogen exposure was associated with an increased risk of CKD (RLS, HR: 1.42, 95

BACKGROUND:Albuminuria from low-grade to clinically elevated range confers cardiorenal risks. OBJECTIVES:The authors aimed to investigate the differential roles of lifestyle/metabolic factors in the association of fine-categorized and continuously measured urinary albumin-to-creatinine ratio (UACR) levels with cardiorenal outcomes. METHODS:A total of 82,509 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study were included, with a median follow-up of 3.0 years. Outcomes included incident cardiovascular disease (CVD), incident CKD, their composite, along with surrogate markers. Lifestyle factors included tobacco use, alcohol use, diet, physical activity and sleep. Metabolic factors included diabetes, hypertension, abdominal obesity, and elevated low-density lipoprotein cholesterol. Cox proportional hazard models were used to calculate hazard ratios. RESULTS:Compared to the lowest UACR, participants with mildly elevated UACR (≥10 to <30 mg/g) had a 39% higher risk of composite cardiorenal outcomes (multivariable-adjusted HR: 1.39, 95% CI: 1.29-1.50), whereas those with clinically elevated UACR (≥30 mg/g) had over double the risk (HR: 2.29, 95% CI: 2.12-2.47). A nonlinear J-shaped association was observed between continuous UACR and cardiorenal outcomes (Pnonlinearity = 0.0009), with UACR ≥10 mg/g already conferring risks, a pattern also reflected by the deterioration of PREVENT score and estimated glomerular filtration rate. Optimal lifestyle and metabolic status generally attenuated CVD risk related to low-grade albuminuria, while improvement of the latter additionally decreased CVD and cardiorenal risk, even in clinically elevated albuminuria (additive Pinteraction <0.0001). Hypertension showed the largest relative contribution to cardiorenal risk, particularly in UACR <30 mg/g. CONCLUSIONS:Our findings highlighted low-grade albuminuria as a key preventive window for cardiorenal outcomes requiring both aspects of modifiable risk factors, and the cardiovascular benefits of metabolic improvement in established albuminuria.

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

Adipose tissue serves as a crucial energy storage and metabolic organ in the human body. With the surging of elderly population in China comes significant challenges in preventing and managing age-associated diseases, while adipose tissue aging represents one of the pivotal initiating events for multi-organ senescence. To address these challenges, the Aging China Biomarkers Consortium (ABC) has established an expert consensus on biomarkers of adipose tissue aging by digesting literature and collecting insights from scientists and clinicians. This consensus provides a comprehensive evaluation of the key changes and characteristics, as well as biomarkers related to adipose tissue aging and proposes a systematic framework categorizing these biomarkers into functional, structural and humoral dimensions. Within each dimension, the ABC recommends clinically and empirically validated biomarkers and parameters for assessing both physiological and pathological changes in adipose tissue during aging, which aims to establish a foundation for future prediction, diagnosis, early warning and treatment for adipose tissue aging and its related diseases, with the ultimate goal of improving adipose tissue health and promoting healthy aging in elderly populations both in China and worldwide.

Understanding the hypothalamic–pituitary–gonadal (HPG) axis is essential for grasping human responses under extreme physiological and pathological conditions. The HPG axis regulates reproductive and gonadal hormone activities and significantly impacts the body’s response to acute and chronic illnesses. This review explores the fundamental functions of the HPG axis, modifications under critical conditions, and impacts on disease progression and treatment outcomes. In addition, it examines interactions between sex hormones and biomolecules like cytokines and gastrointestinal microorganisms, highlighting their roles in immune response regulation. Clinically, this knowledge can enhance patient prognoses. The review aims to provide a comprehensive framework, based on existing research, for understanding and applying the functions of the HPG axis in managing critical diseases, thereby broadening clinical applications and guiding future research.

AIMS:To investigate the associations of general and central obesity with premature mortality in a Chinese population. MATERIALS AND METHODS:A total of 162 776 participants from the China Cardiometabolic Disease and Cancer Cohort Study were included in the current analysis. General and central obesity were assessed using body mass index (BMI) and waist-to-hip ratio (WHR), respectively. Premature mortality was defined as all-cause mortality occurring before the age of 75 years, including cardiovascular disease (CVD)-related and non-CVD-related premature mortality. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS:During a median follow-up of 10.1 years, 5477 (3.36%) premature deaths were documented. Compared with normal weight (18.5 to <24 kg/m2), those with general obesity (BMI ≥28 kg/m2) were associated with elevated risk of CVD-related premature mortality (HR: 1.53; 95% CI: 1.30-1.82). Central obesity (WHR ≥0.95 for men or ≥0.90 for women) was associated with increased risks of all-cause (HR: 1.20; 95% CI: 1.11-1.31), CVD-related (HR: 1.51; 95% CI: 1.29-1.77) and non-CVD-related premature mortality (HR: 1.11; 95% CI: 1.01-1.22). These associations persisted after mutual adjustment for BMI and WHR. A significant interaction between BMI and WHR on the risk of premature mortality was observed (p for interaction = 0.028). Individuals with normal weight but central obesity exhibited the highest risk of all-cause premature death (HR: 1.21; 95% CI: 1.06-1.37), whereas the highest risk of CVD-related mortality was observed in those with both general and central obesity (HR: 1.89; 95% CI: 1.50-2.39). CONCLUSIONS:The combination of normal weight and central obesity significantly increases premature mortality risk, emphasizing the importance of integrating WHR into obesity assessments to improve risk stratification and prevention strategies among Chinese adults.

Context Emerging studies have revealed associations between dietary medium-chain fatty acids (MCFAs) and glucose homeostasis. However, the relationship between serum MCFAs and the incidence of diabetes, and potential interactions with genetic predisposition, remains unclear in prospective cohort studies.Objective This work aimed to investigate associations and genetic susceptibility between serum MCFAs and diabetes risk.Methods We investigated baseline serum MCFAs (n = 5) in a nested case-control study comprising incident diabetes cases (n = 1707) and matched normoglycemic control individuals (n = 1707) from the China Cardiometabolic Disease and Cancer Cohort Study. Associations between MCFAs and type 2 diabetes mellitus (T2DM) were examined, both overall and stratified by diabetes genetic susceptibility. Genetic risk scores (GRS) were calculated based on 86 T2DM-associated genetic variants.Results In the fully adjusted conditional logistic regression model, serum octanoic acid and nonanoic acid exhibited inverse dose-response relationships with diabetes risk, showing odds ratios (95% CI) of 0.90 (0.82-0.98) and 0.84 (0.74-0.95), respectively. Subgroup analysis demonstrated that inverse associations between MCFAs and incident diabetes were more pronounced among individuals with physical inactivity (Pinteraction = .042, .034, and .037, for octanoic, nonanoic and decanoic acid, respectively). Moreover, inverse associations of octanoic acid with diabetes risk were notably enhanced among individuals with high genetic risk compared to those with low genetic risk. Statistically significant interactions were observed between octanoic acid and GRS on T2DM risk (Pinteraction = .003).Conclusion These findings provide evidence supporting inverse associations between serum MCFAs and T2DM risk, and reveal potential interplay between genetic susceptibility and circulating octanoic acid in modulating diabetes risk.

The heterogeneous and complex nature of prediabetes presents a major challenge in identifying individuals predisposed to developing incident diabetes and related complications. We aimed to identify phenotypic subgroups of prediabetes at risk and to explore their distinct associations with cardiometabolic outcomes. This study included 79,000 individuals with prediabetes from the three large-scale prospective cohorts in China. Phenotypic heterogeneity was identified using a soft-clustering algorithm based on the proximity network derived from uniform manifold approximation and projection (UMAP), combined with graph-clustering and Gaussian mixture models. Associations between phenotype probabilities and the incidence of type 2 diabetes (T2D), cardiovascular disease (CVD), and kidney events were assessed to evaluate risk differences across the identified profiles. Six phenotypic profiles were identified, including five with distinct metabolic features (representing 70

Introduction and Objective: Mazdutide (MAZ) is a once-weekly GLP-1 and glucagon receptor dual agonist in development for type 2 diabetes (T2D). This trial assessed the efficacy and safety of MAZ vs placebo (PBO) in patients with T2D inadequately controlled by diet and exercise alone. Methods: In this randomized, 24-week double-blind, placebo-controlled phase 3 trial, 320 patients with T2D (mean baseline HbA1c 8.24%, age 50.4 yrs, diabetes duration 1.9 yrs, body weight 77.7 kg) were randomised 1:1:1 to receive MAZ 4 mg, 6 mg or PBO. Primary endpoint was mean change in HbA1c from baseline at week 24. Secondary endpoints included proportion of patients achieving HbA1c and weight reduction targets and mean percentage change in weight from baseline at week 24. Results: At week 24, MAZ was superior to PBO in mean HbA1c change from baseline (LSM treatment difference: −1.43% [95% CI −1.73, −1.13] for MAZ 4 mg; −2.02% [−2.32, −1.72] for MAZ 6 mg; both p<0.0001). MAZ was superior to PBO in proportion of patients achieving HbA1c <7.0%, weight reduction ≥5%, both HbA1c <7.0% and body weight reduction ≥5%, as well as mean percentage change in weight from baseline at week 24 (Table). The most common adverse events were gastrointestinal and mostly mild to moderate in severity. No severe hypoglycemia was reported. Conclusion: In Chinese patients with T2D, MAZ as monotherapy demonstrated robust and clinical meaningful HbA1c and body weight reduction. D. Zhu: Consultant; Innovent Biologics. J. Zhao: None. H. Cai: None. X. Chu: Consultant; Innovent Biologics. S. Xiu: Consultant; Innovent Biologics. C. Song: Consultant; Innovent Biologics. Z. Cheng: None. H. Cao: None. H. Jiang: None. L. Zhang: None. F. Xue: None. H. Deng: Employee; Innovent Biologics. H. Li: None. L. Li: Employee; Innovent Biologics. Stock/Shareholder; Innovent Biologics. L. Qian: Employee; Innovent Biologics. Innovent Biologics, Inc.