Lipidome profile of cystic fibrosis-related diabetes, type 1 and type 2 diabetes mellitus: potential links to inflammation and glucose and lipid metabolism

Cystic fibrosis (CF) is a genetic disease that primarily affects the pancreas and lungs. CF dyslipidemia is characterized by decreased circulating lipids and increased ectopic lipid deposition in liver, pancreas, and lungs. Pancreatic exocrine insufficiency precedes the onset of CF-related diabetes (CFRD). We hypothesized that different mechanisms contribute to CFRD development and progression, including features of type 1 and type 2 diabetes mellitus (T1DM and T2DM). Thus, we compared their plasma inflammatory, metabolic/hormonal, and lipidomic profiles, using Luminex assays and untargeted mass spectrometry analyses. Then, we compared the lipidomic profiles of lung biopsies and plasma extracellular vesicles (EVs) of CFRD and patients with other lung diseases (LDs). Inflammatory cytokines (IL6 and IL1β) and chemokines (IL8 and MCP-1) were increased in the plasma of CFRD as compared with T1DM, whereas only cytokines increased when comparing with T2DM. Low insulin and C-peptide characterized CFRD and T1DM. Phosphatidylcholine, phosphatidylethanolamine, and storage lipids were reduced, and free fatty acids (FAs) were increased in CFRD plasma compared with T1DM and T2DM. When comparing CFRD with LD, systemic inflammation was increased to a similar extent. Increased levels of sphingolipids, glycerolipids, and acylcarnitines were found in lung biopsies of CFRD as compared with LD. Increased triacylglycerols in lung biopsies positively correlated with lung inflammatory infiltrates (CD68-positive cells) of patients with CFRD. In conclusion, CFRD is characterized by altered lipid metabolism, insulin deficiency, and insulin resistance, partially overlapping with both T1DM and T2DM. CFRD also involves ectopic lung lipids accumulation correlating with increased in situ inflammation.<b>NEW & NOTEWORTHY</b> CFRD is characterized by altered lipid metabolism, insulin deficiency, and insulin resistance, which are distinctive features that partially overlap with both T1DM and T2DM. Systemic inflammation with elevated free FA and reduced plasma lipids is also present in CFRD. Lipids are increased in lung biopsies, whose lipidomic profiles are similar to those of blood-derived EVs. CFRD develops ectopic lipid accumulation in the lungs, correlating with heightened local inflammation and reduced plasma lipid transport.