Background: Autoimmune diabetes (AD) results from a loss of immune tolerance leading to the destruction of β-cells in the pancreas. Heterogeneity in severity of β-cell damage among people with AD is well-recognized, with some patients retaining a certain amount of insulin-producing cells for years despite the presence of pancreatic autoimmunity. Cellular and molecular mechanisms driving the preservation of β-cell function in AD remain unclear.
Aim & Methods: To identify metabolic pathways associated with preservation of β-cell function we conducted a metabolomic study using gas and liquid chromatography-mass spectrometry (GC- and LC-MS) based platform on plasma samples collected from 32 subjects with adult-onset AD (median [Q1-Q3] age: 57 [52-62]; disease duration: 4.5 [3.0-9.0] years) with different severity of β-cell dysfunction, compared with data from people with rheumatoid arthritis (RA, n=28). Metabolome profiles of pancreatic islets from healthy donors after in vitro treatment with proinflammatory cytokines was also evaluated.
Results: Metabolomic analyses showed decreased plasma Kynurenine/Tryptophan ratio (KynTr), a marker of indoleamine 2,3 dioxygenase-1 (IDO1) activity, in people with AD compared to RA (0.023 vs 0.027, p=0.03). Among people with AD, KynTr was directly associated with fasting C-peptide levels (rho=0.365), independently of age, gender, body mass index, diabetes duration and Hba1c (p-value after adjustments= 0.003). Lower concentrations of Tryptophan was observed in pancreatic islets from healthy donors after treatment with proinflammatory cytokines.
Conclusions: While confirming that IDO1 impairment is involved in the pathogenesis of AD and in the regulation of inflammatory response of pancreatic islets, our results show that KynTr is a marker of beta-cell damage in AD. Overall, this suggests that the kynurenine pathway may be studied as a possible target for therapies aimed at preserving beta-cell function also after a diagnosis of AD
E. Maddaloni: Consultant; Abbott, Merck KGaA, PIKDARE S. p. A., Speaker's Bureau; Medical Technology & Devices. F. Dotta: None. P. Marchetti: None. R. Buzzetti: None. A. Gastaldelli: Advisory Panel; Pfizer Inc., Novo Nordisk, Merck Sharp & Dohme Corp., Boehringer Ingelheim International GmbH, Consultant; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Fractyl Health, Inc., Merck Sharp & Dohme Corp., Other Relationship; Pfizer Inc., Speaker's Bureau; Eli Lilly and Company. L. Navarini: Consultant; AbbVie Inc., Pfizer Inc., Bristol Myers, Celgene, MSD Life Science Foundation, Eli Lilly and Company, Novartis, Janssen Global Services, LLC. R. Amendolara: None. S. Fenizia: None. S. Pezzica: None. M. Tesi: None. L. D'onofrio: None. E. Bosi: None.
Italian Ministry of University and Research (PRIN 2017: 20175L9H7H)
