Multi-omics identification of amino acid and redox dysregulation in cystic fibrosis-related diabetes

BACKGROUND: Cystic fibrosis-related diabetes (CFRD) is one of the most common extrapulmonary complications of cystic fibrosis (CF), characterized by abnormal glucose tolerance due primarily to insulin insufficiency. CF-related prediabetes (CFRpD) represents an asymptomatic stage before CFRD onset, requiring routine screening for detection. We aimed to characterize the metabolic profiles underlying abnormal glucose tolerance in people living with CF (pwCF) and identify disrupted pathways associated with CFRD progression. METHODS: Fasting plasma samples from pwCF with normal glucose tolerance (CF-NGT), CFRpD, CFRD, and from healthy, normoglycemic controls without CF were analyzed using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics and lipidomics. Annotated metabolites were used for their individual profiles and pathway analysis. RESULTS: Plasma BCAAs, choline, and methionine were lower in CFRD compared to CF-NGT, and leucine, isoleucine, and methionine were also lower in CFRpD after adjusting for sex and CFTR modulator use. In addition, LPCs and the percentage of methionine oxidation (%OxMet) were significantly higher in CFRD. Lean mass and LMI correlated positively with BCAAs and methionine, though only valine was significant after adjusting for sex in pwCF. In agreement with individual metabolites, pathway analysis indicated disruptions in BCAA biosynthesis and one-carbon metabolism in CFRD. CONCLUSION: These findings suggest that impairments in branchedchain amino acid metabolism, redox balance, and one-carbon metabolism are associated with the pathogenesis of CFRD, including lower lean mass in the case of valine. These metabolites should be further tested as potential biomarkers of CF(p)RD and may provide mechanistic insights into CFRD pathogenesis and therapeutic avenues.