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

• Published in: Cell metabolism Vol. 32; no. 4; pp. 643 - 653.e4
• Main Authors: Koh, Ara, Mannerås-Holm, Louise, Yunn, Na-Oh, Nilsson, Peter M., Ryu, Sung Ho, Molinaro, Antonio, Perkins, Rosie, Smith, J. Gustav, Bäckhed, Fredrik
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.10.2020; Cell Press
• Subjects: activated protein-kinase; akt; AMPK; Basic Medicine; Cell Biology; chemotherapy; diabetes; Endocrinology & Metabolism; Fysiologi; Fysiologi och anatomi; imidazole propionate; inactivation; increases; individual variations; insulin-resistance; mechanism; Medical and Health Sciences; Medical Biotechnology (Focus on Cell Biology (incl. Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy); Medicin och hälsovetenskap; Medicinsk bioteknologi (Inriktn. mot cellbiologi (inkl. stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci); Medicinska och farmaceutiska grundvetenskaper; metformin; microbial metabolites; microbiota; mtorc1; p38γ; Physiology; Physiology and Anatomy; Short; skeletal-muscle; sulfasalazine; microbiota; microbial metabolites; individual variations; imidazole propionate; metformin; AMPK; diabetes; p38γ
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2020.07.012

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. [Display omitted] •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.