title: Elevated anthranilic acid plasma concentrations in type 1 but not type 2 diabetes mellitus.
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.
authors.affiliation: Psychiatry and Inflammation Program, Department of Psychiatry, Tufts University School of Medicine/Tufts Medical Center, Boston, MA, 02111, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Oxenkrug
authors.affiliation: Brains On-Line LLC, CA, USA.
authors.forename: Marieke
authors.initials: M
authors.lastname: van der Hart
authors.affiliation: Psychiatry and Inflammation Program, Department of Psychiatry, Tufts University School of Medicine/Tufts Medical Center, Boston, MA, 02111, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Summergrad
keywords: anthranilic acid; kynurenine; tryptophan; type 1 diabetes; type 2 diabetes