Progressive Metabolic Dysregulation from Prediabetes to Diabetes Revealed by Untargeted Metabolomics

Abstract

Type 2 diabetes (T2D) and prediabetes represent a progressive glycemic continuum associated with multi-pathway metabolic deterioration that often precedes clinical diagnosis. Early identification of molecular alterations underlying this transition is critical for prevention strategies. Untargeted gas chromatography–mass spectrometry (GC–MS) metabolomics combined with multivariate statistical analysis (PCA) was applied to serum samples from 188 participants stratified into Control (n = 48), Prediabetes (n = 113), and Diabetes (n = 27) groups according to ADA/WHO diagnostic criteria. Progressive metabolic alterations were observed across the glycemic continuum. Several amino acid-, lipid-, and organic acid-related features showed nominal differences between the study groups. However, none of the detected metabolomic features remained statistically significant after false discovery rate (FDR) correction, indicating that these findings should be considered exploratory. Diabetes was associated with widespread downregulation of amino acid-related features, long-chain and complex lipid species, and small organic acids relative to both control and prediabetes groups. PCA (PC1 = 35.9%) showed progressive metabolic stratification primarily driven by hyperglycemia, dyslipidemia, and blood pressure elevation. These exploratory findings suggest that the transition from prediabetes to diabetes may be accompanied by alterations in amino acid, lipid, and energy metabolism. The identified metabolomic features represent candidate metabolites that require validation in larger independent cohorts using targeted metabolomics.