Plasma metabolomics reveals progressive alterations across glycemic states

Abstract

BACKGROUND

Diabetes and prediabetes impose a major global health burden, yet conventional glycemic markers provide limited insight into early metabolic disturbances and the metabolic heterogeneity between isolated impaired fasting glucose (IFG) and isolated impaired glucose tolerance (IGT).

AIM

To investigate progressive metabolic alterations and the heterogeneity between isolated IFG and isolated IGT using plasma metabolomics.

METHODS

In this cross-sectional study, 200 participants were classified into four groups: (1) Normal glucose tolerance (NGT); (2) Isolated IFG; (3) Isolated IGT; and (4) Newly diagnosed diabetes (n = 50 each). Plasma metabolomic profiling was performed using ultra-performance liquid chromatography-tandem mass spectrometry. Multivariate analysis, differential metabolite screening, pathway enrichment, least absolute shrinkage and selection operator regression, logistic regression, receiver operating characteristic analysis, bootstrap internal validation, and correlation analysis were performed.

RESULTS

Global metabolic profiles showed a progressive shift from NGT through prediabetic states to diabetes. Eighteen shared core metabolites showed consistent differential abundance and confounder-adjusted trend evidence across the glycemic continuum and were mainly enriched in amino acid-, lipid-, and energy-related pathways. A five-metabolite candidate discriminative panel showed exploratory discriminative performance for isolated IFG, isolated IGT, and diabetes versus NGT, with area under the curve values of 0.820, 0.791, and 0.867, respectively. Exploratory analyses further suggested module-level and pathway-level differences between isolated IFG and isolated IGT.

CONCLUSION

These findings provide metabolomics-based evidence for progressive metabolic remodeling across glycemic states and identify candidate metabolic features that may help characterize early dysglycemia heterogeneity, pending validation in independent cohorts.

Keywords: Diabetes; Prediabetes; Metabolomics; Impaired fasting glucose; Impaired glucose tolerance

Core Tip: Conventional glycemic markers may not fully capture early metabolic disturbances. In this cross-sectional study, untargeted plasma metabolomics profiled 200 participants across different glycemic stages, including normal glucose tolerance, isolated impaired fasting glucose, isolated impaired glucose tolerance, and newly diagnosed diabetes. We identified 18 core metabolites consistently altered across stages. A five-metabolite candidate panel showed exploratory potential to distinguish early dysglycemia. Weighted gene co-expression network analysis suggested module-level differences between impaired fasting glucose and impaired glucose tolerance metabolic modules, which remain exploratory and require validation in independent cohorts. These findings provide candidate features for early stratification of dysglycemia.