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.
journal_name
Cell Metabjournal_title
Cell metabolismauthors
Koh A,Mannerås-Holm L,Yunn NO,Nilsson PM,Ryu SH,Molinaro A,Perkins R,Smith JG,Bäckhed Fdoi
10.1016/j.cmet.2020.07.012subject
Has Abstractpub_date
2020-10-06 00:00:00pages
643-653.e4issue
4eissn
1550-4131issn
1932-7420pii
S1550-4131(20)30370-3journal_volume
32pub_type
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