Abstract
OBJECTIVE: This study aimed to identify metabolites characterizing the progression from normal glucose metabolism (NORM) to prediabetes (PreT2D) and type 2 diabetes (T2D), focusing on stage-specific metabolic shifts (early: NORM to PreT2D; late: PreT2D to T2D) and mechanistic relevance. RESEARCH DESIGN AND METHODS: We analyzed 8,240 observations from the KORA cohort, profiling 104 targeted and 312 nontargeted metabolites across three time points: baseline (S4) and follow-ups (F4 and FF4) spanning 14 years. Trajectory analyses of 1,050 individuals identified 211 incident PreT2D and 112 incident T2D cases. Linear mixed-effects models (basic: adjusted for age, sex, BMI, lifestyle; sensitivity: additionally adjusted for glycemic factors like fasting glucose, and cardiovascular factors such as systolic blood pressure (BP) were used to evaluate metabolic differences across glycemic states. Mediation and Mendelian randomization (MR) analyses examined mechanistic and causal relationships. RESULTS: We identified 140 Bonferroni-significant metabolites (45 targeted, 109 nontargeted, 14 overlapping), including 68 early-stage metabolites (significant in PreT2D/T2D vs. NORM), primarily energy metabolism markers such as fatty acid oxidation metabolites (e.g., 37 lipids) and tricarboxylic acid cycle metabolites (e.g., citrate). Twenty late-stage metabolites (significant in T2D vs. PreT2D/NORM) included amino acids like branched-chain amino acids (BCAAs) and γ-glutamyl derivatives. Fewer significant associations were observed in incident cases. Sensitivity models validated 50% of early-stage but not late-stage metabolites. Fasting glucose mediated 35.1% of the γ-glutamyl-valine-T2D association, while MR analysis found no causal roles for C2, BCAAs, or γ-glutamyl-valine. CONCLUSIONS: Energy metabolism shifts occur early, while amino acid alterations emerge later stages. These stage-specific signatures may guide diabetes prevention strategies.