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

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.

• Authors: Ara Koh, Louise Mannerås-Holm, Na-Oh Yunn, Peter M Nilsson, Sung Ho Ryu, Antonio Molinaro, Rosie Perkins, J Gustav Smith, Fredrik Bäckhed
• Journal: Cell metabolism (Cell Metab) Vol. 32 Issue 4 Pg. 643-653.e4 (10 06 2020) ISSN: 1932-7420 [Electronic] United States
• PMID: 32783890 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Hypoglycemic Agents
• Imidazoles
• 5-imidazolepropionic acid
• Metformin
• Mitogen-Activated Protein Kinase 12
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Animals
• Cell Line
• Diabetes Mellitus, Type 2 (drug therapy, metabolism)
• Humans
• Hypoglycemic Agents (pharmacology)
• Imidazoles (administration & dosage, metabolism, pharmacology)
• Injections, Intraperitoneal
• Male
• Metformin (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinase 12 (metabolism)
• Phosphorylation (drug effects)