Assessment of the Metabolome Across the Glucose Tolerance Spectrum in Adults with Cystic Fibrosis Hospitalized for Pulmonary Exacerbations

Abstract

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 homeostasis level groups: normal glucose tolerance (n=26), pre-diabetes (n=9), and CFRD (n=17), according to the prior diagnosis of CFRD or fasting glucose values from electronic medical record. Untargeted metabolomics were performed on fasted plasma using dual column liquid chromatography and high-resolution mass spectrometry in both HILIC and C18 modes. Analysis of covariates and pathway enrichment analysis were used to define the metabolites and pathways that differentiated between glucose tolerance groups.Results:Among the 2134 features in HILIC and 1909 in C18 modes, glucose tolerance status was significantly associated with 94 HILIC and 107 C18 features (p < 0.05). Among these, two were identified as per- and polyfluoroalkyl substances (PFASs). In the HILIC and C18 modes, three and eleven pathways, respectively, were significantly enriched with metabolites associated with glucose tolerance. These pathways included redox-related processes, such as glutathione metabolism and the tricarboxylic acid cycle, as well as pentose phosphate pathway.Discussion:Untargeted metabolomics demonstrated multiple metabolites and pathways differentiating between glucose tolerance categories among adults with CF during a pulmonary exacerbation. Future research is warranted to determine biological mechanisms of pollutants (PFASs) and oxidative stress on CFRD.

Note:
Funding declaration: This study was funded through grants from the National Institutes of Health (R03 DK117246, R01 DK133523, R01 DK125246, UL1 TR002378-Georgia Clinical and Translational Science Alliance, P30 ES019776- HERCULES, P30 DK125013- Georgia Cystic Fibrosis Research and Translation Core Center), and the Cystic Fibrosis Foundation (TANGPR11A0, ALVARE19A0).

Conflict of Interests: The authors declare no conflicts of interest related to this work.

Ethical Approval: The study was approved by each site’s Institutional Review Board, and informed consent was obtained from all participants. Study sites included Emory University, Case Western Reserve University, University of Iowa, University of Alabama at Birmingham, and University of Cincinnati.

Keywords: Cystic fibrosis, cystic fibrosis-related diabetes, metabolomics, redox, pollutants