BackgroundThe incidence of arteriosclerosis is steadily increasing, and arteriosclerosis is closely associated with cardiovascular diseases. The objective of this research was to create and verify a tool for forecasting arteriosclerosis in middle-aged and elderly individuals within the community.MethodsA cohort study was conducted in multiple communities, and 4107 participants over 40 years of age were enrolled. The participants were randomly divided into a derivation cohort (n = 2875) and a validation cohort (n = 1232) at a ratio of 7:3. LASSO analysis and multivariate logistic regression were employed to analyze factors influencing arteriosclerosis and to establish a prediction model, which was visualized as a nomogram and then evaluated. The primary outcome is incident arteriosclerosis, defined as baPWV ≥ 1400 cm/s.ResultsOver an average follow-up period of 3.25 ± 1.14 years, 1688 subjects (41.0%) were diagnosed with arteriosclerosis. Independent risk factors for arteriosclerosis included age, BMI, hypertension, triglyceride levels, glycosylated hemoglobin, sex, and fasting blood glucose. The area under the receiver operating characteristic curve for the derivation and validation cohorts was 0.811 (95% CI: 0.795–0.827) and 0.816 (95% CI: 0.796–0.830), respectively. The Hosmer-Lemeshow test showed good model accuracy (P = 0.123, P = 0.428). Calibration curves illustrated high consistency between predicted and observed results. Decision curve analysis demonstrated favorable net benefits of the model.ConclusionThe predictive model established in this study holds promise for identifying arteriosclerosis in middle-aged and elderly individuals. Understanding the related risk factors and individualized prediction may assist physicians in early detection and intervention, ultimately improving patient prognosis.

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.

Importance Oral small-molecule glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may address limitations of injectable and peptide-based agents for type 2 diabetes. Objective To evaluate the efficacy and safety of HRS-7535, an oral nonpeptide GLP-1 RA, as add-on therapy among adults with type 2 diabetes inadequately controlled with metformin. Design, Setting, and Participants This 16-week, phase 2, double-blind, placebo-controlled randomized clinical trial was conducted at 44 centers in China. Adults aged 18 to 75 years with type 2 diabetes, hemoglobin A 1c (HbA 1c ) levels ranging from 7.5% to 11.0%, and receiving stable metformin therapy were enrolled between May 10 and December 18, 2023. Data were analyzed from May 8 to 22, 2024. Interventions Participants were randomized (1:1:1:1:1) to once-daily oral HRS-7535 (15, 30, 60, or 90 mg) or matching placebo. The 60- and 90-mg treatment groups used dose-escalation regimens. Main Outcomes and Measures The primary outcome was change in HbA 1c level from baseline to week 16. Secondary outcomes included changes in fasting plasma glucose level, 2-hour postprandial glucose level, body weight, and the proportion of patients achieving HbA 1c levels less than 7.0%. Safety outcomes included adverse events (AEs), hypoglycemia, and AEs of special interest. Results Of 194 randomized patients (mean [SD] age, 52.3 [11.0] years; 115 [59.3%] men; mean [SD] HbA 1c level, 8.5% [0.7]), 177 (91.2%) completed treatment. The mean changes in HbA 1c level at week 16 were −1.19% (95% CI, −1.54% to −0.84%) with the 15-mg dose, −1.59% (95% CI, −1.94% to −1.24%) with the 30-mg dose, −1.82% (95% CI, −2.16% to −1.48%) with the 60-mg dose, and −1.64% (95% CI, −1.97% to −1.30%) with the 90-mg dose compared with −0.25% (95% CI, −0.60% to 0.09%) with placebo; placebo-adjusted differences ranged from −0.94% (95% CI, −1.43% to −0.45%) to −1.57% (95% CI, −2.05% to −1.08%) (all P < .001). HbA 1c level less than 7.0% was achieved in proportions ranging from 48.7% (95% CI, 32.4%-65.2%) to 63.2% (95% CI, 46.0%-78.2%) of HRS-7535–treated patients vs 15.4% (95% CI, 5.9%-30.5%) with placebo. The 90-mg group had greater body weight reduction than placebo (−2.63% [95% CI, −3.72% to −1.54%] vs −1.30% [95% CI, −2.46% to −0.15%]). AEs occurred in 28 of 39 (71.8%) to 33 of 39 (84.6%) HRS-7535–treated patients and 28 of 39 (71.8%) placebo-treated patients and were predominantly mild to moderate gastrointestinal events. Level 1 hypoglycemia occurred in 9 HRS-7535–treated patients; no level 2 or 3 hypoglycemia, pancreatitis, or elevations of alanine aminotransferase or aspartate aminotransferase levels greater than 3 times the upper limit of normal occurred. Conclusions and Relevance In this randomized clinical trial of adults with type 2 diabetes inadequately controlled with metformin, oral HRS-7535 improved glycemic control and was associated with modest weight reduction, with a safety profile consistent with that of GLP-1 RAs. Because HRS-7535 is a nonpeptide oral GLP-1 RA that does not require fasting administration or injection, it may be a viable treatment option, pending confirmation in phase 3 trials. Trial Registration ClinicalTrials.gov Identifier: NCT05759897

Importance:Oral small-molecule glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may address limitations of injectable and peptide-based agents for type 2 diabetes. Objective:To evaluate the efficacy and safety of HRS-7535, an oral nonpeptide GLP-1 RA, as add-on therapy among adults with type 2 diabetes inadequately controlled with metformin. Design, Setting, and Participants:This 16-week, phase 2, double-blind, placebo-controlled randomized clinical trial was conducted at 44 centers in China. Adults aged 18 to 75 years with type 2 diabetes, hemoglobin A1c (HbA1c) levels ranging from 7.5% to 11.0%, and receiving stable metformin therapy were enrolled between May 10 and December 18, 2023. Data were analyzed from May 8 to 22, 2024. Interventions:Participants were randomized (1:1:1:1:1) to once-daily oral HRS-7535 (15, 30, 60, or 90 mg) or matching placebo. The 60- and 90-mg treatment groups used dose-escalation regimens. Main Outcomes and Measures:The primary outcome was change in HbA1c level from baseline to week 16. Secondary outcomes included changes in fasting plasma glucose level, 2-hour postprandial glucose level, body weight, and the proportion of patients achieving HbA1c levels less than 7.0%. Safety outcomes included adverse events (AEs), hypoglycemia, and AEs of special interest. Results:Of 194 randomized patients (mean [SD] age, 52.3 [11.0] years; 115 [59.3%] men; mean [SD] HbA1c level, 8.5% [0.7]), 177 (91.2%) completed treatment. The mean changes in HbA1c level at week 16 were -1.19% (95% CI, -1.54% to -0.84%) with the 15-mg dose, -1.59% (95% CI, -1.94% to -1.24%) with the 30-mg dose, -1.82% (95% CI, -2.16% to -1.48%) with the 60-mg dose, and -1.64% (95% CI, -1.97% to -1.30%) with the 90-mg dose compared with -0.25% (95% CI, -0.60% to 0.09%) with placebo; placebo-adjusted differences ranged from -0.94% (95% CI, -1.43% to -0.45%) to -1.57% (95% CI, -2.05% to -1.08%) (all P < .001). HbA1c level less than 7.0% was achieved in proportions ranging from 48.7% (95% CI, 32.4%-65.2%) to 63.2% (95% CI, 46.0%-78.2%) of HRS-7535-treated patients vs 15.4% (95% CI, 5.9%-30.5%) with placebo. The 90-mg group had greater body weight reduction than placebo (-2.63% [95% CI, -3.72% to -1.54%] vs -1.30% [95% CI, -2.46% to -0.15%]). AEs occurred in 28 of 39 (71.8%) to 33 of 39 (84.6%) HRS-7535-treated patients and 28 of 39 (71.8%) placebo-treated patients and were predominantly mild to moderate gastrointestinal events. Level 1 hypoglycemia occurred in 9 HRS-7535-treated patients; no level 2 or 3 hypoglycemia, pancreatitis, or elevations of alanine aminotransferase or aspartate aminotransferase levels greater than 3 times the upper limit of normal occurred. Conclusions and Relevance:In this randomized clinical trial of adults with type 2 diabetes inadequately controlled with metformin, oral HRS-7535 improved glycemic control and was associated with modest weight reduction, with a safety profile consistent with that of GLP-1 RAs. Because HRS-7535 is a nonpeptide oral GLP-1 RA that does not require fasting administration or injection, it may be a viable treatment option, pending confirmation in phase 3 trials. Trial Registration:ClinicalTrials.gov Identifier: NCT05759897.

Diabetic nephropathy (DN) remains a major cause of end-stage renal disease, driven by chronic immune activation and metabolic imbalance. Macrophages act as central regulators, undergoing multidimensional reprogramming across glucose, lipid, and protein metabolism. This complexity explains why single-pathway modulation fails to reverse their pathogenic phenotypes and supports combination metabolic interventions. Macrophages play a pivotal role in the progression of DN, mediating renal inflammation and oxidative stress while linking metabolic reprogramming to inflammatory injury and fibrosis within the diabetic kidney. These findings highlight the therapeutic potential of integrated metabolic and immunomodulatory strategies. Beyond their effector roles, macrophages actively communicate with intrinsic renal cells, coordinating immune-metabolic coupling and shaping disease progression. Emerging macrophage-targeted therapies extend beyond conventional drugs, encompassing exosome-based delivery, physical modulation, and microenvironmental reprogramming. Overall, this review provides an integrated framework connecting metabolism, oxidative stress, and intercellular communication, positioning macrophages as pivotal nodes and promising targets for precision intervention in DN.

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

Canagliflozin reduces albuminuria in patients with diabetic kidney disease (DKD) beyond its glucose-lowering effect, but the mechanisms remain unclear. We analyzed 85 patients treated with canagliflozin and 85 controls over 26 weeks to explore whether the gut microbiome and its metabolites contribute to renoprotection. Canagliflozin remodeled the gut microbiota, notably enriching Roseburia intestinalis and increasing plasma melibiose levels. In mice, canagliflozin alleviated glomerular endothelial injury and albuminuria. Similar effects were replicated by fecal microbiota transplantation, Roseburia intestinalis, or melibiose administration. Mechanistically, melibiose bound to and activated glyoxalase 1, reduced methylglyoxal, and suppressed the AGE-RAGE pathway, preserving glomerular endothelial integrity. Furthermore, oral melibiose precursor supplementation reduced albuminuria in patients with early-stage DKD. These findings suggest the involvement of a gut-kidney axis in the renoprotective effects of canagliflozin and indicate that melibiose may serve as a potential therapeutic strategy for DKD.

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.

Objective:The KLF11 gene can cause maturity-onset diabetes of the young type 7 (MODY7). Currently, there are few reports on MODY7 cases and their clinical and functional characteristics. This study aimed to analyze the clinical and functional features of the KLF11 R29Q variant to provide a basis for the diagnosis and treatment of this disease. Methods:Clinical baseline data of patients were collected, and high-throughput sequencing (NGS) was used to screen probands clinically suspected of harboring KLF11 variants, with validation performed in their family members. A luciferase reporter assay was used to test whether the KLF11 R29Q variant binds to the insulin promoter. Real-time PCR, western blotting, and glucose-stimulated insulin secretion (GSIS) assays were employed to analyze insulin expression and insulin secretion activity in β-cell lines. Results:1) Clinical data showed that Proband 1 presented with insulin dependence, severe hyperlipidemia, diabetic retinopathy, and cataract at the initial stage of the disease. A relatively high dose of insulin was required and could not be completely discontinued; after insulin treatment, glucose and lipid metabolic disorders and visual acuity were improved. Proband 2 exhibited poor islet function at early onset, accompanied by diabetic autonomic neuropathy and peripheral neuropathy, and glycemic control remained unsatisfactory despite insulin therapy. 2) Genetic testing demonstrated that the heterozygous KLF11 R29Q variant was identified in Proband 1, her father, and her elder sister, as well as in Proband 2 and her mother. The elder sister of Proband 1 was in a prediabetic state, whereas this variant was not detected in Proband 1's mother or younger brother. The mother of Proband 2 had normal blood glucose levels and displayed no diabetes-related clinical manifestations. 3) Protein three-dimensional structure predictions indicated that the KLF11 R29Q mutation affects the electrostatic potential on the surface of the KLF11 protein molecule, disrupting its tertiary structure and compromising protein stability. 4) Cell-based luciferase reporter assays using wild-type and mutant constructs demonstrated that the KLF11 R29Q variant had impaired insulin promoter regulatory activity. Furthermore, real-time PCR, western blotting, and GSIS analyses indicated that this variant impairs insulin expression in pancreatic β-cells and inhibits insulin secretion. Conclusion:We studied a KLF11 R29Q single-gene mutation associated with MODY7. The study confirmed that this variant has impaired insulin promoter regulatory activity and inhibits insulin expression and secretion.

The kidneys play a vital role in maintaining systemic homeostasis by eliminating waste products, modulating metabolic homeostasis, and performing endocrine functions. Aging, characterized by hallmarks including oxidative stress, chronic inflammation, and metabolic dysregulation, constitutes a major predisposing factor for the pathogenesis of renal diseases. Amino acids serve as critical regulators of cellular metabolism, stress responses, and immune regulation, rendering amino acid metabolism intimately linked to the aging process. This review focuses on the multifaceted interplay between amino acid metabolism and renal aging, with particular emphasis on its implications in chronic kidney disease and related disorders: In senescent cells, accumulated branched-chain amino acids activate the mammalian target of rapamycin complex 1 (mTORC1), while tryptophan metabolites activate the aryl hydrocarbon receptor (AhR). Taurine deficiency impairs mitochondrial function and antioxidant defenses. Glutamine metabolism regulates the clearance of senescent cells through mechanisms including modulation of lysosomal pH and apoptosis. Glycine enhances glutathione synthesis and mitigates oxidative and inflammatory damage. In addition to modulating the aging process, urea cycle amino acids exhibit altered levels in kidney diseases and frequently serve as indicators of disease severity. Furthermore, we propose several promising therapeutic strategies, including nutritional interventions directed at specific amino acids and pharmacological therapies that target the modulation of amino acid metabolism. The relationship between amino acid availability and aging in kidney disease is not merely linear but involves a complex and dynamic interplay. Elucidating these mechanisms with advanced methods is key to developing novel clinical interventions and building a theoretical foundation for translational research.

Abstract The increasing global prevalence of diabetes mellitus (DM) necessitates the development of innovative therapeutic strategies that effectively address its symptoms and alleviate its enduring pathological consequences. Stem cells (SCs), which have biological advantages such as multidirectional differentiation capabilities and immune regulatory functions, exhibit tremendous potential for diabetes treatment. Human embryonic SCs or induced pluripotent SC-derived insulin-producing cells offer a promising source for islet cell replenishment in the treatment of insulin-depleted diabetes; however, immune rejection and safety concerns remain significant challenges in further clinical applications. Transplantation of hematopoietic and mesenchymal SCs also shows remarkable potential for the treatment of diabetes. These cells possess the ability to modulate the immune system, stimulate endogenous β-cell regeneration, and preserve residual β-cell function, ultimately leading to enhanced pancreatic islet function and reduced insulin resistance. However, safety and efficacy considerations for SCs remain paramount. This review comprehensively summarizes the recent advancements and molecular mechanisms of SCs in the treatment of DM, underscoring the feasibility, benefits, and current limitations of SC therapy for DM, and offering a lucid perspective on their therapeutic possibilities.

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.

GZR18 is a long-acting glucagon-like peptide-1 receptor agonist that is under development for the treatment of type 2 diabetes mellitus (T2DM). In this randomized, double-blind, placebo-controlled phase 1b/2a trial in Chinese adults with T2DM, the safety and efficacy of once-weekly GZR18 are evaluated using different dose-titration regimens in two separate parts: Part A (0.5-4 mg over 26 weeks) and Part B (1.5-13 mg over 23 weeks). Overall, 72 participants are enrolled, of whom 62 complete the trial. GZR18 significantly reduces glycated hemoglobin (HbA1c) in both parts (Part A: -1.32% for GZR18 versus 0.86% for placebo; Part B: -1.81% for GZR18 versus 0.12% for placebo). Improvements in body weight and other metabolic parameters are also observed. GZR18 is safe and well tolerated, with mostly mild-to-moderate gastrointestinal adverse events; no severe hypoglycemia or treatment-related serious adverse events occurred. These findings support further development of GZR18 in larger, longer-term trials. The trial is registered at ClinicalTrials.gov (NCT06256523).

AIMS:In China, information on individuals who test positive for islet autoantibodies (IAb), including single IAb-positive individuals and those with early-stage Type 1 diabetes (T1D), and their risk of progression to Stage 3 T1D is limited. The goal of this study is to assess the risk of progression to T1D in first-degree relatives (FDRs) of people with T1D in China. MATERIALS AND METHODS:This prospective, longitudinal study, being conducted at approximately 50 hospitals in China, will screen FDRs of individuals with T1D to identify those at risk for developing the disease by testing for the presence of IAb in the blood. IAb-positive individuals will undergo further testing for up to 5 years, with the primary objective of assessing their risk of Stage 3 T1D onset. During the monitoring period, participants with single IAb-positivity will be tested for glycated haemoglobin (HbA1c) and IAb every year; those with multiple IAb-positivity will have an HbA1c and oral glucose tolerance test (OGTT) every year (Stage 1 T1D), or OGTT or random blood glucose test in alternate 6-monthly intervals and HbA1c every 3 months (Stage 2 T1D). Participants who develop Stage 3 T1D during monitoring can undergo extended follow-up to assess changes in β-cell function, glycaemic outcomes and IAb status during the first 12 months after diagnosis. The study plans to enrol 5500 participants; enrolment is ongoing. CONCLUSIONS:Through early screening and monitoring of disease progression in FDRs of T1D probands, this study will provide a comprehensive understanding of T1D progression in the Chinese population. TRIAL REGISTRATION:Chinese Clinical Trial Registry identifier: ChiCTR2600119032.

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.

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.

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