Exercise Metabolomics Reveals Intensity-Dependent Metabolic Responses Associated with Cardiorespiratory Fitness in Adults with Type 1 Diabetes

Purpose: To characterize plasma metabolomic responses to maximal exercise and their associations with cardiorespiratory fitness (CRF) in adults with type 1 diabetes. Methods: In this exploratory pooled secondary analysis, 21 adults (67% female; age, 51.6 ± 13.2 years; HbA1c, 67.5 ± 7.0 mmol/mol) completed a cycle-ergometer test to exhaustion; metabolomic data were available for 20. Plasma collected at rest, anaerobic threshold (AT), peak exercise, and recovery underwent targeted and untargeted gas chromatography–mass spectrometry profiling. Peak oxygen uptake (V̇O2peak) quantified CRF. Linear mixed-effects models adjusted for age, sex, HbA1c, and diabetes duration. Results: At the AT, L-(+)-lactic acid and 2-hydroxyisobutyric acid increased relative to rest (both q ≤ 0.010). Peak exercise produced changes in glycolytic, tricarboxylic acid (TCA)-cycle, and purine metabolites, with enrichment of the TCA cycle and nucleotide metabolism. TCA-cycle enrichment persisted during recovery. In exploratory interaction analyses, higher V̇O2peak was associated with increases in L-(+)-lactic acid at AT (β = 0.032, q = 0.040) and peak exercise (β = 0.031, q = 0.024), and in malic acid at peak exercise (β = 0.063, q = 0.010) and recovery (β = 0.061, q = 0.015). Conclusions: These preliminary findings suggest the presence of intensity-dependent and fitness-associated metabolic responses to exercise in adults with type 1 diabetes. Given the small sample size, particularly for interaction analyses, these findings require confirmation in larger independent cohorts.