Cell:与糖尿病相关的菌群代谢物,损伤胰岛素信号

丙酸咪唑(ImP)是肠道菌群产生的组氨酸衍生代谢物,在2型糖尿病(T2D)患者血液中的含量较高;
在体外模拟发酵实验中, T2D患者粪菌发酵产生的ImP浓度更高;
鉴定出能生成ImP的42个菌株,其中67%的丰度在T2D患者中较高;
注射ImP可降低小鼠胰岛素受体(IRS)水平及其磷酸化水平,导致糖耐受损伤;
ImP通过激活p38γ促进p62磷酸化,使mTORC1活化,影响IRS,导致胰岛素信号受损,T2D患者肝脏中p62和mTORC1活化水平上升。
延伸阅读
Cell [IF:31.398]

Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1

微生物产生的丙酸咪唑通过mTORC1损伤胰岛素信号

2018-10-25, Article, 10.1016/j.cell.2018.09.055more

Abstract:
Interactions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidine-derived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes.

First Authors:
Ara Koh

Correspondence Authors:
Fredrik Bäckhed

All Authors:
Ara Koh,Antonio Molinaro,Marcus Ståhlman,Muhammad Tanweer Khan,Caroline Schmidt,Louise Mannerås Holm,Hao Wu,Alba Carreras,Heeyoon Jeong,Louise E Olofsson,Per-Olof Bergh,Victor Gerdes,Annick Hartstra,Maurits de Brauw,Rosie Perkins,Max Nieuwdorp,Göran Bergström,Fredrik Bäckhed