한빛사 논문
성균관대학교 의과대학, 삼성서울병원, University of Gothenburg and Sahlgrenska University Hospital
Ara Koh1,2,*, Louise Mannerås-Holm2, Na-Oh Yunn3, Peter M. Nilsson4, Sung Ho Ryu3, Antonio Molinaro2, Rosie Perkins2, J. Gustav Smith2,5,6, Fredrik Bäckhed2,7,8,9,*
1Department of Precision Medicine, Samsung Biomedical Research Institute, Samsung Medical Center, School of Medicine, Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea
2Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
3Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
4Department of Internal Medicine, Clinical Sciences, Lund University, Malmö, Sweden
5Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden
6Wallenberg Center for Molecular Medicine and Lund University Diabetes Center, Lund University, Lund, Sweden
7Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
8Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Physiology, Gothenburg, Sweden
9Lead Contact
*Corresponding author
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.
Keywords : microbiota; microbial metabolites; imidazole propionate; diabetes; metformin; individual variations; AMPK; p38γ
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