Metabolic Trajectories and Clinical Outcomes in Prediabetes: A 2.5-Year Study of Reprogramming Patterns

Abstract Prediabetes is a dynamic state in which impaired glucose regulation (IGR) can revert to normoglycaemia or progress to type 2 diabetes (T2DM), yet the metabolic basis of these divergent trajectories remains unclear. We profiled serum metabolites in 975 individuals with IGR and 128 healthy controls over 2.5 years. IGR remission involved partial normalization of amino acid metabolism and attenuated fatty acid dysregulation, whereas progression to T2DM showed persistent branched-chain amino acid perturbation, acylcarnitine accumulation and amplified lipid dysregulation. Tetradecanedioic acid emerged as the most robust outcome-associated biomarker, validated across human cohorts, mouse progression and exercise-induced remission models, and two independent multicenter datasets, with graded accumulation across worsening glycaemic states. Tissue metabolomics and 13C6-glucose tracing linked these alterations to hepatic lipid disturbance and impaired glucose-derived TCA cycle flux in skeletal muscle, identifying fatty acid remodeling as an early and partially reversible axis distinguishing IGR remission from progression.