Metabolomic profile differs between LADA and type 1 diabetes identifying tryptophan metabolism as a pathway involved in the heterogeneity of autoimmune diabetes

AIMS/HYPOTHESIS: The heterogeneity of autoimmune diabetes may be associated with variable metabolic alterations. Our aim was to investigate differences in the metabolomic and lipidomic profile of autoimmune diseases and to identify pathways linked to beta cell damage. To this end, we compared latent autoimmune diabetes in adults (LADA) and type 1 diabetes, also comparing them with rheumatoid arthritis (RA), a related autoimmune condition, and healthy control participants. METHODS: Metabolomic and lipidomic analyses were performed for 136 individuals (49 with LADA, 44 with type 1 diabetes, 29 with RA and 14 control participants). Omics of pancreatic islets from healthy donors were also evaluated after in vitro treatment with proinflammatory cytokines. RESULTS: LADA and type 1 diabetes differed from RA in terms of lipidomics and metabolomics. Phosphatidylethanolamines, ceramides, lysophosphatidylcholine and several metabolites at the entry sites of the tricarboxylic acid cycle were higher in type 1 diabetes compared with LADA. In pancreatic islets treated with proinflammatory cytokines, tryptophan concentration was reduced by 80%, indicating the activation of tryptophan metabolism in response to the inflammatory stimulus. In people with autoimmune disorders, kynurenine/tryptophan ratio (Kyn/Trp), a marker of tryptophan pathway activation, was higher than in the control group (Kyn/Trp ratio in control group, median [25th-75th percentile]: 0.014 [0.012-0.019]), with a progressive decline from RA (0.027 [0.022-0.032]) to LADA (0.021 [0.018-0.024]) and then to type 1 diabetes (0.018 [0.014-0.022]), ANCOVA p<0.0001. In LADA, Kyn/Trp was directly associated with fasting C-peptide levels in the multivariate regression model accounting for confounders (p=0.038). CONCLUSIONS/INTERPRETATION: Metabolomic and lipidomic profiles differ between LADA and type 1 diabetes and vs RA, providing new insights into the heterogeneity of autoimmune diabetes. Our results confirm the involvement of tryptophan metabolism in autoimmune disorders, suggesting that the impaired activation of this pathway of immune tolerance in LADA is less pronounced than in type 1 diabetes, consistent with its milder degree of beta cell loss.