Abstract
Experimental data suggested involvement of tryptophan (Trp) - kynurenine (Kyn) pathway (TKP) in mechanisms of autoimmune, type 1 (T1D), and metabolic, type 2 (T2D), diabetes. However, clinical evaluations of TKP metabolites were limited to T2D. We assessed Trp, Kyn and TKP metabolites: anthranilic (AA), kynurenic (KYNA) and xanthurenic (XA) acids, in plasma samples of fifteen T1D, thirty T2D patients and twenty eight non-diabetic subjects by HPLC-mass spectrometry. Trp concentrations were higher in T1D than in T2D and controls while Kyn concentrations were not changed suggesting down-regulation of indoleamine-2,3-dioxygenase (IDO), a rate-limiting enzyme of TKP, in T1D. AA concentrations were 2.3-fold higher in T1D than in T2D and in controls. KYNA and XA concentrations were higher in T1D than in controls, and in previously reported T2D. AA elevation might be a specific feature of T1D. TKP shift towards AA formation in T1D may result from riboflavin deficiency, that increases AA in rats and baboons, and is highly associated with T1D but not T2D. AA augments autoimmune-induced apoptosis of pancreatic cells (PC) by increasing formation of antibodies to PC auto-antigen. Marked increase of AA was reported in rheumatoid arthritis, another autoimmune disorder. Trp, an essential amino acid for humans, is synthesized from AA by diabetogenic intestinal microbiome. AA down-regulates IDO by inhibition of Trp entry into cells. Resulting elevation of Trp attenuates Trp depletion-induced protection of PC against autoimmunity. Further studies of TKP might offer new tools for prevention and treatment of T1D and other autoimmune disorders.
Highlights
About 40 millions worldwide are diagnosed with type 1 diabetes (T1D), an organ specific autoimmune disease and one of the leading causes of disability and mortality [1]
There were no differences in AA plasma concentrations between Type 2 diabetes (T2D) and controls
Our results are in agreement with literature data of no differences between saliva AA concentrations of T2D patients and controls [12] and between plasma AA concentrations in cardiovascular patients with- and with-out T2D [13]
Summary
About 40 millions worldwide are diagnosed with type 1 diabetes (T1D), an organ specific autoimmune disease and one of the leading causes of disability and mortality [1]. Type 2 diabetes (T2D) is metabolic disorder that afflicts more than 344 million people worldwide and the 8th leading cause of death in the world [1]. Both T1D and T2D are highly associated with obesity [2]. Dysregulation of tryptophan (Trp) – kynurenine (Kyn) metabolic pathway (TKP) was suggested to contribute to development of T1D [3], T2D [4] and obesity [5,6]. We are not aware of clinical assessments of AA in T1D – the major aim of the present study
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