北大姜长涛研究员团队:发现二甲双胍降糖新机制
作者:Lulu Sun, Cen Xie, Guang Wang, Yue Wu, Qing Wu, Xuemei Wang, Jia Liu, Yangyang Deng, Jialin Xia, Bo Chen, Songyang Zhang, Chuyu Yun, Guan Lian, Xiujuan Zhang, Heng Zhang, William H. Bisson, Jingmin Shi, Xiaoxia Gao, Pupu Ge, Cuihua Liu, Kristopher W. Kraus
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2018-11-07 22:19:02
目前2型糖尿病已成为危害人类健康的重要疾病,二甲双胍是临床上治疗2型糖尿病的一线用药,其作用靶点并不明确。北京大学基础医学院姜长涛课题组发现初诊2型糖尿病患者口服二甲双胍后,肠道菌群发生重塑,脆弱拟杆菌的丰度下降和结合型胆汁酸甘氨熊去氧胆酸GUDCA的含量升高。二甲双胍通过抑制脆弱拟杆菌产生的胆汁酸水解酶BSH活性,使GUDCA水平增加。进一步的机制研究揭示GUDCA是人法尼醇X受体FXR的内源性拮抗剂,具有潜在的治疗2型糖尿病的作用。二甲双胍通过肠道脆弱拟杆菌—胆汁酸GUDCA—肠FXR代谢轴发挥降糖作用。该研究解析了二甲双胍对于肠道菌群及其代谢产物的重塑作用;深入探究了肠道菌群作用于宿主的靶点及其功能;揭示了胆汁酸GUDCA与肠FXR作为治疗肥胖相关代谢性疾病的新靶点。
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Gut microbiota and intestinal FXR mediate the clinical benefits of metformin
作者:Lulu Sun, Cen Xie, Guang Wang, Yue Wu, Qing Wu, Xuemei Wang, Jia Liu, Yangyang Deng, Jialin Xia, Bo Chen, Songyang Zhang, Chuyu Yun, Guan Lian, Xiujuan Zhang, Heng Zhang, William H. Bisson, Jingmin Shi, Xiaoxia Gao, Pupu Ge, Cuihua Liu, Kristopher W. Kraus
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2018-11-07 22:19:02
导语
The anti-hyperglycemic effect of metformin is believed to be caused by its direct action on signaling processes in hepatocytes, leading to lower hepatic gluconeogenesis. Recently, metformin was reported to alter the gut microbiota community in humans, suggesting that the hyperglycemia-lowering action of the drug could be the result of modulating the population of gut microbiota. However, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of metformin remained elusive. Here, we performed metagenomic and metabolomic analysis of samples from individuals with newly diagnosed type 2 diabetes (T2D) naively treated with metformin for 3 d, which revealed that Bacteroides fragilis was decreased and the bile acid glycoursodeoxycholic acid (GUDCA) was increased in the gut. These changes were accompanied by inhibition of intestinal farnesoid X receptor (FXR) signaling. We further found that high-fat-diet (HFD)-fed mice colonized with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin treatment on glucose intolerance were abrogated. GUDCA was further identified as an intestinal FXR antagonist that improved various metabolic endpoints in mice with established obesity. Thus, we conclude that metformin acts in part through a B. fragilis–GUDCA–intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia.
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