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Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation
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 inh...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546034/ https://www.ncbi.nlm.nih.gov/pubmed/32783890 http://dx.doi.org/10.1016/j.cmet.2020.07.012 |
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author | Koh, Ara Mannerås-Holm, Louise Yunn, Na-Oh Nilsson, Peter M. Ryu, Sung Ho Molinaro, Antonio Perkins, Rosie Smith, J. Gustav Bäckhed, Fredrik |
author_facet | Koh, Ara Mannerås-Holm, Louise Yunn, Na-Oh Nilsson, Peter M. Ryu, Sung Ho Molinaro, Antonio Perkins, Rosie Smith, J. Gustav Bäckhed, Fredrik |
author_sort | Koh, Ara |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7546034 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-75460342020-10-16 Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation Koh, Ara Mannerås-Holm, Louise Yunn, Na-Oh Nilsson, Peter M. Ryu, Sung Ho Molinaro, Antonio Perkins, Rosie Smith, J. Gustav Bäckhed, Fredrik Cell Metab Short Article 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. Cell Press 2020-10-06 /pmc/articles/PMC7546034/ /pubmed/32783890 http://dx.doi.org/10.1016/j.cmet.2020.07.012 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Short Article Koh, Ara Mannerås-Holm, Louise Yunn, Na-Oh Nilsson, Peter M. Ryu, Sung Ho Molinaro, Antonio Perkins, Rosie Smith, J. Gustav Bäckhed, Fredrik Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation |
title | Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation |
title_full | Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation |
title_fullStr | Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation |
title_full_unstemmed | Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation |
title_short | Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation |
title_sort | microbial imidazole propionate affects responses to metformin through p38γ-dependent inhibitory ampk phosphorylation |
topic | Short Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546034/ https://www.ncbi.nlm.nih.gov/pubmed/32783890 http://dx.doi.org/10.1016/j.cmet.2020.07.012 |
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