RATIONALE & OBJECTIVE:Time in target range (TTR) for systolic blood pressure (SBP) and hemoglobin A1c (HbA1c) integrates information about average and variability of levels over time. Their impact on kidney outcomes has not been fully evaluated. This study investigated the association of HbA1c-TTR and SBP-TTR, individually and jointly, with kidney outcomes among patients with type 2 diabetes and hypertension. STUDY DESIGN:Post hoc observational cohort analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial data. SETTINGS & PARTICIPANTS:6,542 ACCORD participants with ≥ 3 HbA1c and SBP measurements during the first 12 months. EXPOSURE:HbA1c-TTR and SBP-TTR during the first 12 months after randomization, each categorized separately as either 100% or in tertiles among the remaining study participants. In addition, 4 categories jointly assessing TTR for HbA1c and SBP were created: both HbA1c-TTR and SBP-TTR ≤ 80%, HbA1c-TTR ≤ 80% and SBP-TTR > 80%, HbA1c-TTR > 80% and SBP-TTR ≤ 80%, and both HbA1c-TTR and SBP-TTR > 80%. OUTCOME:A composite kidney outcome, defined as incident albuminuria, estimated glomerular filtration rate decline ≥ 40% from baseline, or kidney failure. ANALYTICAL APPROACH:Associations of HbA1c-TTR and SBP-TTR, individually and in combination with kidney outcomes, were analyzed using Cox proportional hazards models. RESULTS:Compared with HbA1c-TTR of ≤ 49.6% (the lowest tertile), HbA1c-TTR of 100% was associated with a 20% lower risk of the composite kidney outcome (HR, 0.80 [95% CI, 0.68-0.94]). Compared with SBP-TTR of ≤50.7% (the lowest tertile), SBP-TTR of 100% was associated with a 32% lower risk of the composite kidney outcome (HR, 0.68 [95% CI, 0.58-0.80]). Participants with both HbA1c-TTR and SBP-TTR > 80% had a 29% (HR, 0.71 [95% CI, 0.61-0.83]) lower risk of the composite kidney outcome compared with participants with both HbA1c-TTR and SBP-TTR ≤ 80%. LIMITATIONS:Limited duration of follow-up and low number of kidney failure events. CONCLUSIONS:Longer time with HbA1c and SBP within target range was associated with a lower risk of adverse kidney events. PLAIN-LANGUAGE SUMMARY:The concept of "time in target range" (TTR), defined as the proportion of time within a defined range, has been proposed in managing diabetes and hypertension. The combined effect of hemoglobin A1c (HbA1c)-TTR and systolic blood pressure (SBP)-TTR on adverse kidney events remains unknown. We evaluated the association of HbA1c-TTR and SBP-TTR, both individually and in combination, with incident kidney outcomes among patients who were enrolled in a clinical trial. We found that higher HbA1c-TTR and SBP-TTR were individually associated with a lower risk of adverse kidney events in patients with type 2 diabetes and hypertension. Having more time with both HbA1c and SBP within target range was also associated with a lower risk of adverse kidney outcomes compared with having either 1 individual parameter or neither individual parameter within target range.

Whether physical activity modifies the associations of sarcopenia and basic/instrumental activities of daily living (ADL/IADL) disability with mortality remains unclear. The study included 64,146 participants from three nationally representative cohorts: Health and Retirement Study (HRS), Survey of Health, Aging and Retirement in Europe (SHARE), and China Health and Retirement Longitudinal Study (CHARLS). In HRS, the greater risk of mortality associated with each dysfunction was more pronounced in inactive participants, with multi-variable-adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) in Cox models of 3.88 (3.57-4.23) for sarcopenia, 1.82 (1.70-1.95) for ADL disability, and 1.95 (1.81-2.09) for IADL disability, while the corresponding HRs (95% CIs) were 3.32 (2.92-3.77), 1.39 (1.20-1.61), and 1.44 (1.26-1.65) in regularly active participants (all P for multiplicative interaction < 0.010). Consistent interaction patterns were observed in SHARE and CHARLS. This study revealed that regular activity meeting the WHO recommendations significantly mitigated the hazards of mortality associated with sarcopenia and ADL/IADL disability.

AIMS:To evaluate the association between longitudinal non-HDL-C exposure and the risks of major adverse cardiovascular events (MACEs) and all-cause mortality in type 2 diabetes patients on lipid-lowering therapy. MATERIALS AND METHODS:This post hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial included patients with type 2 diabetes who had non-HDL-C measured at baseline and four subsequent visits over 24 months. Longitudinal exposure was assessed using cumulative load, variability (standard deviation) and trajectory (slope). Outcomes were MACEs and all-cause mortality. Cox proportional hazard models were used to obtain hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS:Among 4673 participants with a median follow-up of 7.5 years, 695 MACEs and 842 deaths occurred. After adjusting for baseline and mean non-HDL-C levels, the highest quartile of cumulative load (HR, 1.81; 95% CI, 1.41-2.32), variability (HR, 1.27; 95% CI, 1.00-1.60) and the most rapidly increasing slope (HR, 1.26; 95% CI, 1.02-1.56) were each associated with increased risks of MACEs, compared to the lowest quartile. The association with all-cause mortality followed a similar pattern, except for the non-HDL-C slope. Stratified analyses showed that cumulative load and variability were associated with MACEs among participants with baseline non-HDL-C < 130 mg/dL, and with all-cause mortality among those with baseline ≥130 mg/dL. No significant associations with slope were observed within strata of baseline non-HDL-C. CONCLUSIONS:Longitudinal non-HDL-C exposure showed associations with both MACEs and mortality, independent of baseline non-HDL-C, underscoring the need for sustained and stable non-HDL-C control over time.

Hepatic steatosis measured by imaging fails to capture the variation in cardiometabolic risk and intervention response, which may be better characterized by metabolomic profiles. We aimed to construct metabolomics-based indices to define this variation. Using data from a three-arm lifestyle intervention randomized trial in adults with type 2 diabetes (T2D) and overweight/obesity, we constructed two novel indices from untargeted plasma metabolomics and MRI-measured liver fat: a metabolomics-based liver fat score (mliver fat), and the discordance between mliver fat and MRI-measured liver fat (Δliver fat). We examined their associations with cardiometabolic traits and intervention response. Both mliver fat and Δliver fat were associated with body composition, glucose indices, insulin sensitivity, and triglyceride, but only Δliver fat was independent of MRI-measured liver fat. Despite having comparable MRI-measured liver fat, compared with the participants with a high Δliver fat (mliver fat > MRI-measured liver fat), those with a low Δliver fat (mliver fat < MRI-measured liver fat) had a more favorable cardiometabolic profile and derived greater benefits and more sustained benefits from diet intervention, with more pronounced long-term improvements in weight, insulin sensitivity, and β-cell function. Among individuals with T2D, a metabolomics-based liver fat score, particularly the discordance between metabolomic and imaging assessments, identifies systemic metabolic heterogeneity and differential responsiveness to lifestyle interventions. Future research is warranted to evaluate its performance in improving risk stratification and personalizing lifestyle intervention. NCT03839667

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.

Residential greenness has been linked to a reduced risk of type 2 diabetes (T2D), yet whether genetic susceptibility modifies this association remains unclear. Evidence on gene-environment interaction is limited, mainly cross-sectional, and largely from European-ancestry populations. Prospective data from Chinese populations examining the association between residential greenness and incident T2D, as well as glycemic traits, are scarce. In this study, we included 7861 middle-aged and older Chinese adults (aged ≥ 40 years), and assessed residential greenness using the Normalized Difference Vegetation Index (NDVI) derived from Moderate-Resolution Imaging Spectroradiometer (MODIS) satellite imagery, linking it to T2D incidence over a median follow-up of 3.8 years. Genetic susceptibility was assessed in 5389 participants with DNA data using a T2D-specific weighted genetic risk score based on 89 genome-wide significant single-nucleotide polymorphisms identified in East Asian populations, weighted by published effect estimates. Our results show that higher residential greenness was associated with a 44% reduction in T2D risk (hazard ratio [HR] = 0.56, 95% confidence interval [CI]: 0.48-0.66), as well as improved insulin sensitivity and β-cell function. Notably, genetic susceptibility significantly modified the association between residential greenness and T2D on both multiplicative (P for interaction = 0.019) and additive scales (relative excess risk due to interaction [RERI] = 0.19), with higher greenness conferring greater relative and absolute risk reductions among individuals at medium and high genetic risk. These findings underscore a protective role of residential greenness against T2D, with stronger effects in those at higher genetic risk, supporting environmental interventions to mitigate genetic predisposition in the prevention of T2D.

ARTICLE HIGHLIGHTS:A rare loss-of-function variant in ZNRF3 (p.V228L) is enriched in individuals with obesity and is associated with increased subcutaneous white adipose tissue (sWAT) accumulation and lower fasting glucose levels. Both adipocyte-specific Znrf3 knockout and global variant knock-in impair sWAT browning, increase sWAT expansion, and improve glucose tolerance in mice. These findings establish ZNRF3 as a genetic regulator of fat distribution and thermogenic capacity, informing precise phenotyping of obesity. GWAS has implicated ZNRF3 in human fat distribution, yet its role in adipose tissue biology remains unknown.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are emerging as promising therapies for cardiovascular-kidney-metabolic (CKM) related diseases in individuals with type 2 diabetes mellitus (T2DM) or obesity. But their effects in non-obese and non-diabetic individuals are unclear. This study triangulates evidence using Mendelian randomization (MR), polygenic scores (PGS) and observational analyses to estimate the associations of GLP-1R expression with chronic kidney disease (CKD), heart failure (HF) and metabolic dysfunction-associated steatotic liver disease (MASLD). For the MR analysis, instruments mimicking GLP-1R expression were identified using pancreas-specific cis-expression quantitative trait loci from GTEx (N ≤ 305). MR-Robust method was used as the primary MR approach. PGS and observational analyses were performed both in non-diabetic and non-obese individuals separately. A genome-wide association study (GWAS) for MASLD (14,231 cases and 348,091 controls) was performed in the general population using data from UK Biobank. GLP-1R expression showed robust effects on CKD (odds ratio [OR] 0.96, 95

BACKGROUND:The dose-response relationships between systolic and diastolic blood pressure (SBP and DBP) levels and risks of all-cause mortality, cardiovascular and renal outcomes in type 2 diabetes remain poorly characterized, particularly at lower blood pressure (BP) levels. OBJECTIVE:This study aimed to examine risk patterns of major clinical outcomes across a wide range of BP levels in participants with type 2 diabetes. METHODS:We systematically searched PubMed, Embase, and Web of Science from inception to November 30, 2024, for cohort studies assessing associations of BP levels with all-cause mortality, cardiovascular, and renal outcomes. One-stage mixed-effects dose-response meta-analysis was conducted to assess the curvilinear associations. RESULTS:A total of 89 cohorts from 113 articles of 5,875,364 participants with type 2 diabetes were identified. A J-shaped association was observed for SBP with all-cause mortality. J-shaped associations were also observed for SBP with cardiovascular events and for DBP with all-cause mortality, with flattened risks at lower BP levels. After excluding studies with participants who had baseline cardiovascular diseases or cancer, a significantly lower risk of cardiovascular events was observed at lower SBP levels, as well as a flattened risk of all-cause mortality. Positive linear or monotonic trends were observed for renal events, estimated glomerular filtration rate decline, and development or progression of albuminuria. CONCLUSIONS:In type 2 diabetes, BP is linearly or monotonically associated with most cardiovascular and renal outcomes. Low SBP does not appear to be associated with an elevated risk of all-cause mortality compared with higher BP targets, suggesting that previously reported associations are likely due to reverse causation and unmeasured confounding.

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:With dementia posing an escalating public health threat, adopting healthy lifestyles is increasingly recognised as a key preventive measure for preserving cognitive function. However, the effect of multidomain lifestyle intervention on cognitive health remains inconclusive and likely heterogeneous. Aims:We aimed to investigate the heterogeneity in the associations between healthier lifestyles and cognitive outcomes (cognitive performance and incident dementia) across identifiable subpopulations and to use causal machine learning to identify participant characteristics predictive of greater benefit. Methods:Causal machine learning analyses were performed using two prospective cohorts. The English Longitudinal Study of Ageing (ELSA) (waves 4-9, 2008-2018) served as the discovery cohort and the Health and Retirement Study (HRS) (waves 9-14, 2008-2018) served as the validation cohort. Healthy lifestyles included smoking status, alcohol consumption, physical activity and social contact. Global cognitive z-scores were computed based on standardised tests of memory, executive function and orientation. Dementia diagnoses were ascertained by integrating physician evaluations with measures of cognitive and functional performance. Results:We analysed 8771 participants from ELSA and 8531 participants from HRS. High-benefit groups displayed substantially improved cognitive performance (ELSA: mean: 0.27, 95% confidence interval [CI] 0.24-0.30; HRS: mean: 0.51, 95% CI 0.48-0.54) and reduced risk of dementia (ELSA: hazard ratio [HR]: 0.28, 95% CI 0.21-0.34; HRS: HR: 0.22, 95% CI 0.17-0.27). Subgroups deriving greater benefits in cognitive performance were younger and had higher baseline cognitive reserve, superior physical and respiratory function, and better cardiometabolic profiles with particularly lower blood pressure. Those deriving greater benefits in incident dementia were likewise younger, with higher baseline cognition and superior vascular metrics, including lower blood pressure. Conclusions:The cognitive benefits of healthy lifestyles vary by individual characteristics, underscoring the potential of personalised prevention strategies. Future randomised clinical trials are warranted to validate these findings and refine intervention approaches.

ABSTRACT Background Metabolic disorders, particularly insulin resistance (IR), represent important complications in adults with 21‐hydroxylase deficiency (21OHD). Glucocorticoid (GC) therapy is a known risk factor, yet evidence from longitudinal analyses remains scarce. Methods In this study, based on a large, genetically characterized, single‐center cohort of Chinese adults with 21OHD, we performed both cross‐sectional and longitudinal analyses to investigate the risk factors for IR. Results We found that nearly one‐third of young adult 21OHD patients had IR. Current GC use remained independently associated with IR (OR 13.30, 95% CI 2.54–69.55; p = 0.002), whereas neither genotype nor androgen levels showed an association. We followed 52 patients without IR at baseline; incident IR occurred in 57.1% (4/7) of GC‐naive patients and 68.9% (31/45) of previously GC‐exposed patients, with median times to IR onset of 14.7 and 13.1 months, respectively. Importantly, dexamethasone use was independently associated with incident IR (HR 7.04, 95% CI 1.81–27.34; p = 0.005). Daily 1000 mg metformin therapy for 6 months did not significantly improve IR (median HOMA‐IR, 2.50–2.82; p = 0.460) and only provided a modest benefit in body weight (median BMI, 23.6–22.5 kg/m2; p = 0.046). Conclusion These findings suggest that ongoing GC therapy, particularly dexamethasone, is a risk factor for IR in adults with 21OHD, and new onset IR generally emerged within approximately 1 year after regular treatment.

Obesity exhibits a high heritability with heterogeneity; however, the genetic variants identified as obesity-causing factors are still underexplored. By performing deep sequencing on 2295 cases of young-onset obesity from East Asian populations and 2292 lean controls, we identified five genes (TUB, NR4A3, HIST1H4D, DXO, and TELO2) with an excess burden of rare predicted loss-of-function (LoF) variants in cases. Among the variants, TUB p.R364G was identified as a potential deleterious variant that disrupted TUB protein's subcellular localization. Knock-in mice carrying the homologous p.R363G variant exhibited hyperphagia and obesity in an allele dose-dependent manner when fed a high-fat diet. The TUB p.R363G variant also blunted responses to leptin-induced suppression of food intake, leading to leptin resistance in mice. Furthermore, we demonstrated that TUB acted as a positive regulator of the leptin pathway through its interaction with STAT3, and this interaction was impaired by the p.R364G variant. TUB silencing mitigated the inhibitory effects of leptin on the activities of agouti-related protein (AgRP)-expressing neurons. Consistently, conditional ablation of TUB in AgRP+ neurons in mice led to hyperphagic obesity and attenuated leptin-induced appetite suppression in mice. Thus, our study demonstrates that rare LoF variants in TUB predispose to young-onset obesity in humans, likely through impairing leptin sensitivity in AgRP+ neurons.

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.

Cyclic Cushing syndrome, a rare endocrine disorder marked by periodic fluctuations of cortisol secretion and clinical manifestations, is diagnostically challenging. This study integrates clinical and multi-omics data to advance early diagnosis. We analyzed four patients with pituitary cyclic Cushing syndrome and fifty-six patients with conventional Cushing disease. Proteomics profiling identified differentially expressed proteins; Annexin A1 expression was validated via immunohistochemistry, immunofluorescence, and enzyme-linked immunosorbent assay. Single-cell RNA sequencing mapped its cellular origin. Annexin A1 expression was significantly elevated in pituitary tumors and serum of patients with cyclic Cushing syndrome. Serum Annexin A1 measured during the remission phase in patients with cyclic Cushing syndrome demonstrated promising diagnostic ability, and a related diagnostic approach was proposed. Single-cell transcriptomics revealed a distinct Annexin A1-enriched tumor subpopulation, predominantly in patients with cyclic Cushing syndrome. Multi-omics and clinical integration identify Annexin A1 as a diagnostic biomarker for cyclic Cushing disease.

Background : With urbanization accelerating, traffic noise has become a significant environmental factor in daily urban life. Objective : This study investigates the effects of short-term traffic-noise exposure on energy metabolism and physiological status in healthy individuals, systematically characterizing the metabolic pathways induced by noise and exploring the protective role of mask sound (natural mixed sound) intervention. Methods : A randomized crossover design was employed, with 26 healthy adults exposed to three types of sound environments: quiet (46.52 dBA (± 0.31), 8:00 AM - 7:00 AM the next day), traffic noise (76.23 dBA (± 1.21), 8:00 AM - 10:00 PM), and mask sound (76.15 dBA (± 1.32), 8:00 AM - 10:00 PM). Continuous monitoring tracked energy metabolism, physiological indicators, hormone levels, and subjective feelings, with comparisons across environments. Results : Short-term traffic noise amplified sympathetic, HPA, and HPT axis activity, raising heart rate and blood pressure (HR +2.95%, diastolic BP +3.09%). Glycemic regulation worsened (glucose up 7.72%), metabolic flexibility declined (ΔNPRQ postprandial − fasting −42.11%), and rhythms/mood were disrupted. Women exhibited more pronounced autonomic and metabolic disturbances. Mask sound modestly mitigated adverse effects, improving cardiovascular measures (HR +2.55% decline, diastolic BP +0.3%), lowering insulin resistance (glucose down 4.39%), and enhancing metabolic flexibility (ΔNPRQ postprandial–fasting +41.67%), though protection was weaker in women. Conclusions : We concluded that short-term traffic noise triggers broad neuroendocrine activation and may elevate the risk of cardiovascular and metabolic diseases, particularly in women. Mask sound intervention effectively attenuates acute metabolic and physiological damage, suggesting potential nonpharmacological benefits for noise protection. Trial registration : ChiCTR2500098645

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