Aims Cardiovascular-kidney-metabolic (CKM) syndrome represents an integrated continuum of metabolic, kidney, and cardiovascular abnormalities. However, the stage-specific metabolic heterogeneity underlying this clinical framework remains incompletely characterised.Materials and Methods We performed plasma metabolomic profiling in 1374 participants from the China Multi-Ethnic Cohort across CKM stages 0-4. Participants from Chengdu and Chongqing provinces comprised the discovery cohort (n = 969), whereas those from Yunnan province comprised the validation cohort (n = 405). Stage-associated metabolites were identified using prespecified pairwise comparisons with OPLS-DA and covariate-adjusted limma analyses. Weighted correlation network analysis identified coordinated metabolic modules. Machine-learning models were developed to evaluate discrimination of advanced CKM (stages 3-4) using metabolite signatures independent of conventional CKM-defining variables.Results Among 858 endogenous metabolites, 261 unique metabolites were associated with CKM stages, revealing distinct metabolic patterns from early to advanced CKM. Stage 1 was characterised by altered lipid- and bile acid-related metabolites, stage 2 by broader lipid and amino-acid remodelling, and stage 3 by additional carbohydrate, aromatic amino-acid, secondary bile acid, host-microbial, and renal-handling signals. Metabolic separation between stages 3 and 4 was comparatively weak. WGCNA identified a CKM-associated turquoise module, with gamma-glutamylvaline as a hub metabolite. A model incorporating age, sex, and eight metabolites derived from the discovery cohort showed favourable performance for distinguishing advanced CKM from earlier stages and achieved an AUROC of 0.874 (95% CI, 0.802-0.931) in the validation cohort.Conclusions CKM stages exhibit distinct and non-linear metabolic signatures. A compact metabolomic panel independent of conventional CKM-defining variables may provide complementary molecular information for advanced CKM phenotyping and future risk stratification.
Aims Gestational diabetes mellitus (GDM) increases the risk of postpartum dysglycaemia. This study investigates candidate metabolites and perturbed metabolic pathways associated with postpartum prediabetes/diabetes among high-risk Indian/South-Asian women with prior GDM, a largely unexplored population.Materials and Methods In this nested case-control study within the Cohort of Indian Women with Hyperglycaemia in Pregnancy and their Families (CHIP-F), untargeted metabolomics (UPLC-MS/MS) was performed on plasma samples from 216 women with prior GDM, which included 22 participants with postpartum diabetes, 88 with prediabetes and 106 with normoglycaemia.Results Untargeted metabolomics combined with machine learning approach revealed distinct metabolic alterations associated with postpartum dysglycaemia (prediabetes/diabetes) among women with prior GDM. After adjustment for age, body mass index, family history of diabetes, and postpartum duration, each 1-standard deviation increase in the log-transformed concentrations of Tyrosine (aOR = 1.71, 95% CI: 1.01-2.91) and L-Kynurenine (aOR = 1.69, 1.02-2.80) was associated with higher odds of diabetes. Similarly, higher concentrations of 2-Aminoisobutyric acid (aOR = 1.50, 1.09-2.06), Butyrylcarnitine (aOR = 1.99, 1.44-2.75), L-Norleucine (aOR = 1.96, 1.41-2.72), and Propionylcarnitine (aOR = 1.94, 1.41-2.67) were associated with higher odds of prediabetes. Pathway analysis revealed potential dysregulation of aromatic amino acids (AAAs) metabolism in prediabetes. In diabetes, in addition to dysregulation of AAAs, potential lipid metabolic disturbances were also present.Conclusions This study identified distinct candidate metabolic signatures associated with postpartum prediabetes and diabetes in Indian/South-Asian women with a history of prior GDM, highlighting early disruptions in AAAs and lipid metabolism.
Aims Acromegaly is a chronic, progressive disease characterised by excess growth hormone secretion and elevated circulating insulin-like growth factor 1 levels. Data on hepatic fat content and liver stiffness in adults with active or controlled acromegaly remain inconsistent.Methods We systematically searched PubMed and Scopus from inception through 15 June 2026 to identify studies comparing hepatic steatosis and liver stiffness in adults with acromegaly and in controls. Hepatic fat content was quantified using magnetic resonance imaging (MRI)-based techniques, and liver stiffness was assessed using vibration-controlled transient elastography or other elastography methods. Pooled effect sizes were reported as weighted mean differences (WMDs) with 95% confidence intervals.Results We identified 9 observational studies, including 190 patients with acromegaly and 235 age-, sex-, and BMI-matched controls. Compared with controls, patients with acromegaly had significantly lower hepatic fat content, as assessed by MRI-based techniques (six studies; random-effects WMD -3.04% [95% CI -4.81 to -1.26%]; I2 = 43.7%). This difference remained significant in patients with active acromegaly (6 studies; WMD -2.96% [95% CI -4.30 to -1.62]; I2 = 0%), but not in those with controlled acromegaly (four studies; WMD -2.57% [95% CI -6.72 to 1.59]; I2 = 70.3%). Liver stiffness measurements did not differ between patients with acromegaly and control subjects (four studies; WMD 0.94 kPa [95% CI -0.45 to 2.33], I2 = 87.9%). Sensitivity analyses yielded consistent findings.Conclusions Our meta-analysis suggests that patients with acromegaly have significantly lower hepatic fat content than controls, particularly among those with active disease, whereas liver stiffness does not appear to differ significantly between the groups.
Aims: With the rising prominence of GLP-1 receptor agonists, identifying predictors of optimal bariatric surgery candidates has become increasingly important. We investigated cross-sectional relationships between thyroid hormones and obesity-related parameters, and evaluated the predictive value of baseline thyroid hormones for weight loss (WL) and diabetes remission (DR) after bariatric surgery. Methods: This study included a cross-sectional cohort of 1567 euthyroid patients with overweight or obesity, of whom 1034 with complete 1 year postoperative data were included in the longitudinal analysis. Body composition was assessed using validated predictive equations and abdominal MRI. The primary outcomes were successful WL (total WL >= 25%) and DR (fasting glucose < 5.6 mmol/L and HbA1c < 6.0% without antidiabetic medications) during the 3 year follow-up. Results: Breakpoint analysis indicated that free triiodothyronine (FT3) plateaued beyond an age threshold while showing a linear correlation with fat-free mass index. Higher baseline FT3 tertiles were significantly linked to increased likelihood of achieving successful WL and DR at 1 year follow-up, with stronger associations in females. Optimal FT3 thresholds were identified as 4.75 (females) and 5.05 (males) for WL, and 4.57 (females) and 5.00 (males) for DR. Preoperative FT3 levels below these thresholds were significantly associated with reduced WL and DR over 3 years. Conclusions: Serum FT3 exhibits an age-related breakpoint effect, and low preoperative FT3, particularly in females, is a critical predictor of suboptimal short- and long-term WL and DR success post-bariatric surgery. Sex-specific FT3 thresholds may aid in preoperative risk stratification and inform personalised treatment decisions in the era of expanding obesity therapeutics.
BACKGROUND:Guidelines suggest that the risk of mortality in diabetic foot disease (DFD) is comparable to that of cancer; however, high-quality evidence is lacking. We aimed to compare the mortality of DFD with that of various cancers based on data from international cohorts. METHODS:We defined DFD according to the IWGDF 2023 guidelines, and cancer was defined based on the ICD-10 codes. We included 527, 1784, and 601 patients with DFD and 1219, 100,643, and 152 patients with cancer from the National Health and Nutrition Examination Survey (NHANES), UK Biobank (UKB), and Chongqing Diabetes Registration (CDR) cohorts, respectively. We compared the risk of mortality between DFD and overall or site-specific cancers in the same cohort. RESULTS:Patients with DFD showed 38%, 45%, and 499% higher risks of mortality than patients with overall cancer in the NHANES, UKB, and CDR. For site-specific cancer, the risk of mortality was significantly higher in DFD than in skin cancer (hazard ratio 10.69, 95% CI: 1.37-2.07 in NHANSE; 3.8, 3.72-448 in UKB), breast cancer (1.35, 1.0-1.83 in NHANSE; 1.95, 1.67-227 in UKB), and prostate cancer (1.4, 1.8-179 in NHANSE; 2.61, 2.35-289 in UKB). The mortality rate of DFD is similar to that of most types of cancer, such as colon cancer, lymphoma, and kidney cancer, and is lower than that of a minority of cancers, including lung, pancreatic, and liver cancers. CONCLUSION:Patients with DFD have a higher risk of mortality than overall cancer, particularly skin, breast, and prostate cancers.
