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.

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.

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.

Background: Frequent glucose monitoring is essential for diabetes management, yet non-invasive approaches have been limited by poor generalizability across patients. This study aimed to evaluate whether a depth-resolved Raman spectroscopy approach can provide consistent glucose prediction accuracy across physiological variability. Methods: We enrolled 200 patients with type 2 diabetes and acquired depth-resolved Raman spectra using a multiple μ-spatially offset Raman spectroscopy (mμSORS) system. An overall partial least squares (PLS) model was developed using 4768 paired venous plasma glucose and concatenated spectra at 100 μm (offset 2) and 150 μm (offset 3), and validated by subject-wise tenfold cross-validation. Model robustness was assessed through stratified analyses across physical characteristics, skin parameters, and serum biomarkers, with size-matched comparisons to control for sample size effects. Prediction accuracy was evaluated using mean absolute relative difference (MARD), root mean square error (RMSE), and consensus error grid (CEG). Results: The dataset covered a wide glucose range (3.8-31.6 mmol/L; 68.4-568.8 mg/dL) and substantial physiological heterogeneity. The overall PLS model achieved a MARD of 14.5% (CEG A + B: 99.4%), with no significant differences across stratified subgroups ( P > .05). Stratified subgroup models performed significantly worse than the overall model ( P < .05), yet after controlling for sample size, their performance was comparable with that of the overall model. Conclusion: A single, overall model for mμSORS-based glucose monitoring achieves high accuracy across diverse patient subgroups, demonstrating its strong robustness. These findings support the clinical potential of depth-resolved Raman spectroscopy for non-invasive glucose monitoring. Trial Registration: ClinicalTrials.gov NCT05921344; https://clinicaltrials.gov/study/NCT05921344 .

ObjectivesTo evaluate mortality and risk factors in moderate-to-severe diabetic foot ulcer (DFU) hospitalized patients and develop a prognostic tool.MethodsThis cohort study enrolled 485 eligible DFU patients (2009-2014), followed through 2024. Mortality was analyzed using Cox regression and Kaplan-Meier methods, focusing on peripheral artery disease (PAD) and other risk factors (p<0.05). A nomogram predicting 3-year mortality was developed based on multivariate Cox analysis.ResultsThe 3-year all-cause mortality rate in this cohort of 485 diabetic foot ulcer patients was 49.3%. The two most salient predictors of mortality were renal impairment and PAD severity. Patients requiring dialysis had a 3.05-fold increased risk of death, while the risk escalated sharply with PAD severity, reaching a 3.57-fold increase for severe PAD. The prognostic nomogram, which integrated these key factors, demonstrated strong predictive accuracy for 3-year survival, with a C-index of 0.79 and a 3-year AUC of 0.87.ConclusionsHospitalized patients with moderate-to-severe diabetic foot show high mortality, predominantly associated with dialysis, CKD, and PAD. The developed nomogram effectively predicts 3-year mortality risk.

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.

BACKGROUND:There are few large-scale prospective studies on directly measured visceral fat area (VFA) and diabetic kidney disease, with inconsistent findings across sex and BMI. We aimed to investigate the association between VFA and incident diabetic kidney disease risk and to examine how this association differs by sex and BMI. METHODS:This prospective cohort study included adults with diabetes from 640 centres in the China Metabolic Management Center (MMC) project. We included adult participants with diabetes who had baseline and follow-up diabetic kidney disease data, excluding those with prevalent diabetic kidney disease at baseline or missing baseline VFA data. Diabetes diagnosis was confirmed by an on-site physician at enrollment. Diabetic kidney disease was defined as albuminuria (urinary albumin-to-creatinine ratio ≥3·39 mg/mmol) or estimated glomerular filtration rate less than 60 mL/min per 1·73m2. VFA was measured by bioelectrical impedance analysis. Cox regression analysis was used to evaluate the association between VFA and diabetic kidney disease, with stratification by sex and BMI categories. The MMC project is registered at ClinicalTrials.gov, NCT03811470. FINDINGS:Between June 1, 2017, and June 26, 2024, we recruited 308 512 participants aged 18 years or older with a diagnosis of diabetes who had undergone baseline diabetic kidney disease assessment and had accessible follow-up records up to June 21, 2025. After excluding participants with baseline diabetic kidney disease (n=113 383), incomplete VFA measurements (n=41 979), or missing diabetic kidney disease assessment during follow-up (n=59 618), the final analytical cohort consisted of 93 532 participants. Participants had a median follow-up of 18·4 months (IQR 9·4-32·3) and a median age of 55·0 years (IQR 46·0-62·0). 57 865 [61·9%] of 93 532 participants were male and 35 667 (38·1%) were female. 27 486 (29·4%) of 93 532 participants developed diabetic kidney disease. VFA was significantly associated with increased diabetic kidney disease risk (per IQR [52 cm2] adjusted hazard ratio [aHR] 1·08, 95% CI 1·05-1·10; p<0·0001). Sex-stratified categorical analyses showed increased diabetic kidney disease risk in men at both low VFA (≤50 cm2; aHR 1·12, 1·06-1·19; p=0·0002) and high VFA greater than 100 cm2 (100-125 cm2; 1·06, 1·01-1·11; p=0·013), while women showed significantly increased risk only at VFA greater than 75 cm2 (75-100 cm2; 1·09, 1·03-1·14; p=0·0014). In male participants, a U-shaped relationship was consistently observed. Male participants without overweight (BMI <24 kg/m2) had elevated risks at VFA extremes (≤50 cm2 aHR 1·12, 95% CI 1·04-1·21; p=0·0045 and >125 cm2 aHR 1·25, 1·09-1·44; p=0·0019). This U-shape persisted in male participants with overweight (BMI 24-28 kg/m2), with significant risks at VFA 50 cm2 or less (aHR 1·15, 95% CI 1·01-1·31; p=0·039), 100-125 cm2 (1·10, 1·02-1·18; p=0·010), and greater than 125 cm2 (1·15, 1·06-1·24; p=0·0005). In male participants with obesity (BMI ≥28 kg/m2), risk was significantly elevated across all VFA categories, highest at both extremes (≤50 cm2 aHR 2·15, 95% CI 1·44-3·23; p=0·0002 and >125 cm2 aHR 1·31, 1·20-1·42; p<0·0001). In female participants, disease risk was elevated from VFA greater than 75 cm2 in both participants without overweight (75-100 cm2 aHR 1·10, 95% CI 1·02-1·19; p=0·011) and participants with overweight (75-100 cm2 1·10, 1·02-1·17; p=0·011), while obesity extended significant risk to lower VFA levels (50-75 cm2 aHR 1·22, 95% CI 1·02-1·46; p=0·033). INTERPRETATION:VFA is a significant risk factor for diabetic kidney disease, exhibiting distinct sex-specific patterns that persist across BMI strata. These findings support precise clinical risk stratification and identify low-VFA men as a previously overlooked high-risk population. FUNDING:Noncommunicable Chronic Diseases-National Science and Technology Major Project.

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

The prospective association of the triglyceride-glucose (TyG) index on carotid atherosclerosis (CA), particularly carotid intima-media thickness (CIMT), remains incompletely defined. A total of 6007 middle-aged and elderly participants were enrolled. Multivariable logistic regression models were used to assess the relationships between the TyG index and changes in CIMT by calculating odds ratios (ORs) and 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.