瑞典哥德堡大学和萨尔格伦斯卡大学医院Fredrik Bckhed和韩国成均馆大学Ara Koh研究小组合作取得进展。他们发现微生物丙酸咪唑通过p38γ依赖的AMP激活蛋白激酶（AMPK）磷酸化抑制影响二甲双胍的功能。 这一研究成果于2020年8月11日在线发表在《细胞-代谢》上。

研究人员发现在服用二甲双胍后仍血糖高的2型糖尿病患者中，微生物代谢产物丙酸咪唑的浓度更高。研究表明，在用咪唑丙酸酯预处理的小鼠中未观察到二甲双胍引起的葡萄糖浓度降低。

此外，研究还证明咪唑丙酸酯通过诱导抑制性AMPK磷酸化来发挥抑制AMPK的活性，这依赖于咪唑丙酸酯诱导的基底Akt活化。最后，该研究表明丙酸咪唑激活的p38γ是Akt的新型激酶，并证明p38γ激酶活性介导了丙酸咪唑对二甲双胍的抑制作用。

据了解，二甲双胍是2型糖尿病的一线治疗药物，但患者对此药的反应存在较大的个体差异。尚不完全清楚其作用机理，但AMPK的激活和肠道菌群改变似乎很重要。尚未有研究探索微生物代谢物对二甲双胍的抑制作用。

附：英文原文

Title: Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation

Author: Ara Koh, Louise Manners-Holm, Na-Oh Yunn, Peter M. Nilsson, Sung Ho Ryu, Antonio Molinaro, Rosie Perkins, J. Gustav Smith, Fredrik Bckhed

Issue&Volume: 2020-08-11

Abstract: Metformin is the first-line therapy for type 2 diabetes, but there are large inter-individual variations in responses to this drug. Its mechanism of action is not fully understood, but activation of AMP-activated protein kinase (AMPK) and changes in the gut microbiota appear to be important. The inhibitory role of microbial metabolites on metformin action has not previously been investigated. Here, we show that concentrations of the microbial metabolite imidazole propionate are higher in subjects with type 2 diabetes taking metformin who have high blood glucose. We also show that metformin-induced glucose lowering is not observed in mice pretreated with imidazole propionate. Furthermore, we demonstrate that imidazole propionate inhibits AMPK activity by inducing inhibitory AMPK phosphorylation, which is dependent on imidazole propionate-induced basal Akt activation. Finally, we identify imidazole propionate-activated p38γ as a novel kinase for Akt and demonstrate that p38γ kinase activity mediates the inhibitory action of imidazole propionate on metformin.

DOI: 10.1016/j.cmet.2020.07.012

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30370-3