Assessment of the metabolome across the glucose tolerance spectrum in adults with cystic fibrosis hospitalized for pulmonary exacerbations.

BACKGROUND

Cystic fibrosis-related diabetes (CFRD) is one of the most common co-morbidities among adults with cystic fibrosis (CF), yet the mechanisms determining its development remain unclear. This study explored the underlying biological mechanisms associated with CFRD development using plasma high-resolution metabolomics (HRM).

METHODS

This cross-sectional study included 52 adults with CF hospitalized for a pulmonary exacerbation. Participants were categorized into three glucose tolerance groups: normal glucose tolerance (n = 26), pre-diabetes (n = 9), and CFRD (n = 17), based on data abstraction from the electronic medical record. Untargeted metabolomics were performed on fasted plasma using dual column liquid chromatography and high-resolution mass spectrometry. Analysis of covariates and pathway enrichment analysis were used to define the metabolites and pathways that differentiated between glucose tolerance groups. A sub-set analysis was performed using highest confidence metabolites quantified by reference standardization.

RESULTS

Among the 2134 features in HILIC and 1909 in C18 modes, glucose tolerance status was significantly associated with 94 and 107 features (p < 0.05), which were significantly enriched within three and eleven pathways, respectively. These pathways included redox-related processes, such as glutathione metabolism and the tricarboxylic acid cycle, as well as pentose phosphate pathway. In the sub-set analysis, two per- and polyfluoroalkyl substances were identified as decreasing with worsening glucose intolerance group (FDR q = 0.07 and 0.11, respectively).

DISCUSSION: Untargeted metabolomics demonstrated several redox-related pathways differentiating between glucose tolerance categories among adults with CF during a pulmonary exacerbation. Future targeted research is warranted to determine biological mechanisms of CFRD pathophysiology, including the role of the environment.