title: Loss of arylformamidase with reduced thymidine kinase expression leads to impaired glucose tolerance.
abstract: Tryptophan metabolites have been linked in observational studies with type 2 diabetes, cognitive disorders, inflammation and immune system regulation. A rate-limiting enzyme in tryptophan conversion is arylformamidase (Afmid), and a double knockout of this gene and thymidine kinase (Tk) has been reported to cause renal failure and abnormal immune system regulation. In order to further investigate possible links between abnormal tryptophan catabolism and diabetes and to examine the effect of single Afmid knockout, we have carried out metabolic phenotyping of an exon 2 Afmid gene knockout. These mice exhibit impaired glucose tolerance, although their insulin sensitivity is unchanged in comparison to wild-type animals. This phenotype results from a defect in glucose stimulated insulin secretion and these mice show reduced islet mass with age. No evidence of a renal phenotype was found, suggesting that this published phenotype resulted from loss of Tk expression in the double knockout. However, despite specifically removing only exon 2 of Afmid in our experiments we also observed some reduction of Tk expression, possibly due to a regulatory element in this region. In summary, our findings support a link between abnormal tryptophan metabolism and diabetes and highlight beta cell function for further mechanistic analysis.
authors.affiliation: Mammalian Genetics Unit, Medical Research Council Harwell, Oxford, Oxfordshire OX11 0RD, UK.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Hugill
authors.affiliation: Mary Lyon Centre, Medical Research Council Harwell, Oxford, Oxfordshire OX11 0RD, UK.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Stewart
authors.affiliation: Mammalian Genetics Unit, Medical Research Council Harwell, Oxford, Oxfordshire OX11 0RD, UK.
authors.forename: Marianne A
authors.initials: MA
authors.lastname: Yon
authors.affiliation: Mary Lyon Centre, Medical Research Council Harwell, Oxford, Oxfordshire OX11 0RD, UK Institute of Hepatology, Foundation for Liver Research, 69-75 Chenies Mews, London WC1E 6HX, UK.
authors.forename: Fay
authors.initials: F
authors.lastname: Probert
authors.affiliation: Institute of Hepatology, Foundation for Liver Research, 69-75 Chenies Mews, London WC1E 6HX, UK.
authors.forename: I Jane
authors.initials: IJ
authors.lastname: Cox
authors.affiliation: Mary Lyon Centre, Medical Research Council Harwell, Oxford, Oxfordshire OX11 0RD, UK.
authors.forename: Tertius A
authors.initials: TA
authors.lastname: Hough
authors.affiliation: Mary Lyon Centre, Medical Research Council Harwell, Oxford, Oxfordshire OX11 0RD, UK.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Scudamore
authors.affiliation: Mammalian Genetics Unit, Medical Research Council Harwell, Oxford, Oxfordshire OX11 0RD, UK.
authors.forename: Liz
authors.initials: L
authors.lastname: Bentley
authors.affiliation: Mammalian Genetics Unit, Medical Research Council Harwell, Oxford, Oxfordshire OX11 0RD, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Wall
authors.affiliation: Mary Lyon Centre, Medical Research Council Harwell, Oxford, Oxfordshire OX11 0RD, UK.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Wells
authors.affiliation: Mammalian Genetics Unit, Medical Research Council Harwell, Oxford, Oxfordshire OX11 0RD, UK r.cox@har.mrc.ac.uk.
authors.forename: Roger D
authors.initials: RD
authors.lastname: Cox
keywords: Arylformamidase; Diabetes; Insulin secretion; Kynurenine; Tryptophan