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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. / Koh, Ara; Manneras-Holm, Louise; Yunn, Na-Oh; Nilsson, Peter M.; Ryu, Sung Ho; Molinaro, Antonio; Perkins, Rosie; Smith, J. Gustav; Backhed, Fredrik.

In: Cell Metabolism, Vol. 32, No. 4, 2020, p. 643-653.e4.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Koh, A, Manneras-Holm, L, Yunn, N-O, Nilsson, PM, Ryu, SH, Molinaro, A, Perkins, R, Smith, JG & Backhed, F 2020, 'Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation', Cell Metabolism, vol. 32, no. 4, pp. 643-653.e4. https://doi.org/10.1016/j.cmet.2020.07.012

APA

Koh, A., Manneras-Holm, L., Yunn, N-O., Nilsson, P. M., Ryu, S. H., Molinaro, A., Perkins, R., Smith, J. G., & Backhed, F. (2020). Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. Cell Metabolism, 32(4), 643-653.e4. https://doi.org/10.1016/j.cmet.2020.07.012

Vancouver

Koh A, Manneras-Holm L, Yunn N-O, Nilsson PM, Ryu SH, Molinaro A et al. Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. Cell Metabolism. 2020;32(4):643-653.e4. https://doi.org/10.1016/j.cmet.2020.07.012

Author

Koh, Ara ; Manneras-Holm, Louise ; Yunn, Na-Oh ; Nilsson, Peter M. ; Ryu, Sung Ho ; Molinaro, Antonio ; Perkins, Rosie ; Smith, J. Gustav ; Backhed, Fredrik. / Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. In: Cell Metabolism. 2020 ; Vol. 32, No. 4. pp. 643-653.e4.

Bibtex

@article{51c19ceb4ac6475688d4697b7c2ead14,
title = "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 p38 gamma as a novel kinase for Akt and demonstrate that p38 gamma kinase activity mediates the inhibitory action of imidazole propionate on metformin.",
keywords = "ACTIVATED PROTEIN-KINASE, SKELETAL-MUSCLE, INSULIN-RESISTANCE, AKT, SULFASALAZINE, INACTIVATION, CHEMOTHERAPY, INCREASES, MECHANISM, MTORC1",
author = "Ara Koh and Louise Manneras-Holm and Na-Oh Yunn and Nilsson, {Peter M.} and Ryu, {Sung Ho} and Antonio Molinaro and Rosie Perkins and Smith, {J. Gustav} and Fredrik Backhed",
year = "2020",
doi = "10.1016/j.cmet.2020.07.012",
language = "English",
volume = "32",
pages = "643--653.e4",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "4",

}

RIS

TY - JOUR

T1 - Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation

AU - Koh, Ara

AU - Manneras-Holm, Louise

AU - Yunn, Na-Oh

AU - Nilsson, Peter M.

AU - Ryu, Sung Ho

AU - Molinaro, Antonio

AU - Perkins, Rosie

AU - Smith, J. Gustav

AU - Backhed, Fredrik

PY - 2020

Y1 - 2020

N2 - 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 p38 gamma as a novel kinase for Akt and demonstrate that p38 gamma kinase activity mediates the inhibitory action of imidazole propionate on metformin.

AB - 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 p38 gamma as a novel kinase for Akt and demonstrate that p38 gamma kinase activity mediates the inhibitory action of imidazole propionate on metformin.

KW - ACTIVATED PROTEIN-KINASE

KW - SKELETAL-MUSCLE

KW - INSULIN-RESISTANCE

KW - AKT

KW - SULFASALAZINE

KW - INACTIVATION

KW - CHEMOTHERAPY

KW - INCREASES

KW - MECHANISM

KW - MTORC1

U2 - 10.1016/j.cmet.2020.07.012

DO - 10.1016/j.cmet.2020.07.012

M3 - Journal article

C2 - 32783890

VL - 32

SP - 643-653.e4

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 4

ER -

ID: 251251505