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.

Genome-wide meta-analysis in Japanese populations identifies novel variants at the TMC6–TMC8 and SIX3–SIX2 loci associated with HbA1c

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Metabolomics window into diabetic complications

“…Diabetes mellitus is a complex metabolic disorder that is associated with insulin resistance, impaired insulin signaling, β‐cell dysfunction, abnormal glucose levels, altered lipid metabolism, subclinical inflammation and increased oxidative stress. Diabetes mellitus has become a major global health problem with almost 415 million people affected in 2015, and a projected figure of 642 million by 2040 (International Diabetes Federation, 2015).…”

Kynurenine 3-monooxygenase is a critical regulator of renal ischemia–reperfusion injury

“…Interestingly, deleting of arylformamidase (Afmid) in mice leads to a glomerulosclerosis phenotype. However, the Afmid mouse also has a thymidine kinase promoter deleted and a glucose intolerance phenotype with reduced insulin secretion and therefore is not a clean model from which a direct inference of an effect on kynurenine metabolism on renal function can be drawn 31,32 . KMO depletion decreased plasma 3HK level and increased plasma KA level, which may be potentially protective against renal damage caused by IRI.…”