Loss of arylformamidase with reduced thymidine kinase expression leads to impaired glucose tolerance.
Loss of arylformamidase with reduced thymidine kinase expression leads to impaired glucose tolerance.
复制标题
芳基甲酰胺酶的丧失和胸苷激酶表达的减少会导致葡萄糖耐量受损。
DOI：
10.1242/bio.013342
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发表时间：
2015-10-02
期刊：
影响因子：
2.4
通讯作者：
Cox RD
中科院分区：
文献类型：
--
作者：
Hugill AJ;Stewart ME;Yon MA;Probert F;Cox IJ;Hough TA;Scudamore CL;Bentley L;Wall G;Wells SE;Cox RD
色氨酸代谢物在观察性研究中与2型糖尿病、认知障碍、炎症和免疫系统调节有关。色氨酸转化中的限速酶是芳基甲酰胺酶（Afmid），并且已经报道了该基因和胸苷激酶（Tk）的双敲除导致肾衰竭和异常免疫系统调节。为了进一步研究异常色氨酸催化酶和糖尿病之间的可能联系，并检查单个Afmid敲除的效果，我们进行了外显子2 Afmid基因敲除的代谢表型分析。这些小鼠表现出葡萄糖耐量受损，尽管它们的胰岛素敏感性与野生型动物相比没有变化。这种表型是由葡萄糖刺激的胰岛素分泌缺陷引起的，这些小鼠显示出随年龄增长胰岛质量减少。没有发现肾脏表型的证据，表明这一发表的表型是由于双敲除中Tk表达的丧失所致。然而，尽管在我们的实验中仅特异性去除Afmid的外显子2，我们也观察到Tk表达的一些减少，可能是由于该区域中的调节元件。总之，我们的研究结果支持异常色氨酸代谢和糖尿病之间的联系，并强调β细胞功能，以进一步进行机制分析。总结：tm1b缺失等位基因纯合子小鼠由于胰岛质量减少导致胰岛素分泌减少而导致葡萄糖耐量受损，但没有肾脏疾病的证据，提示色氨酸代谢异常与糖尿病之间存在联系。
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. Summary: Mice homozygous for a tm1b deleted allele have impaired glucose tolerance due to reduced insulin secretion associated with reduced islet mass, but no evidence of renal disease, suggesting a link between abnormal tryptophan metabolism and diabetes.