Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation.
Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation.
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DOI：
10.1016/j.cmet.2020.07.012
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发表时间：
2020-10-06
期刊：
影响因子：
29
通讯作者：
Bäckhed F
中科院分区：
文献类型：
--
作者：
Koh A;Mannerås-Holm L;Yunn NO;Nilsson PM;Ryu SH;Molinaro A;Perkins R;Smith JG;Bäckhed F
二甲双胍是2型糖尿病的一线治疗药物，但对这种药物的反应存在很大的个体差异。其作用机制尚未完全了解，但AMP活化蛋白激酶（AMPK）的激活和肠道微生物群的变化似乎很重要。此前尚未研究微生物代谢产物对二甲双胍作用的抑制作用。在这里，我们发现，浓度较高的微生物代谢产物咪唑丙酸盐与2型糖尿病患者服用二甲双胍谁有高血糖。我们还表明，二甲双胍诱导的血糖降低没有观察到在小鼠咪唑丙酸酯预处理。此外，我们证明咪唑丙酸酯通过诱导抑制性AMPK磷酸化来抑制AMPK活性，这依赖于咪唑丙酸酯诱导的基础Akt激活。最后，我们鉴定了咪唑丙酸盐激活的p38γ作为Akt的新型激酶，并证明p38γ激酶活性介导咪唑丙酸盐对二甲双胍的抑制作用。咪唑丙酸盐在二甲双胍合并高血糖的T2 D受试者中更高咪唑丙酸盐损害二甲双胍在小鼠中的降糖作用咪唑丙酸盐通过p38γ和Akt抑制二甲双胍诱导的AMPK活化抑制p38γ阻断咪唑丙酸盐对二甲双胍的抑制作用Koh et al.显示咪唑丙酸盐（一种微生物代谢物）损害抗糖尿病药物二甲双胍降糖作用，并通过激活p38γ/Akt/抑制性AMPK丝氨酸磷酸化抑制二甲双胍诱导的AMPK激活。他们进一步表明，二甲双胍的作用通过阻断咪唑丙酸盐激活的p38γ而恢复。
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. Imidazole propionate is higher in T2D subjects on metformin with high blood glucose Imidazole propionate impairs the glucose-lowering effect of metformin in mice Imidazole propionate inhibits metformin-induced AMPK activation via p38γ and Akt Inhibition of p38γ blocks the inhibitory action of imidazole propionate on metformin Koh et al. show that imidazole propionate, a microbial metabolite, impairs the glucose-lowering effect of the anti-diabetic drug metformin and inhibits metformin-induced AMPK activation by activating p38γ/Akt/inhibitory AMPK serine phosphorylation. They further show that metformin action is restored by blocking imidazole propionate-activated p38γ.
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作者：
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DOI：
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发表时间：
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