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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Ara Koh
  • Louise Manneras-Holm
  • Na-Oh Yunn
  • Peter M. Nilsson
  • Sung Ho Ryu
  • Antonio Molinaro
  • Rosie Perkins
  • J. Gustav Smith
  • Bäckhed, Gert Fredrik

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.

OriginalsprogEngelsk
TidsskriftCell Metabolism
Vol/bind32
Udgave nummer4
Sider (fra-til)643-653.e4
Antal sider15
ISSN1550-4131
DOI
StatusUdgivet - 2020

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