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

Area of Science:

• Metabolism
• Microbiology
• Pharmacology

Background:

• Metformin is a primary treatment for type 2 diabetes, yet patient responses vary significantly.
• Its precise mechanism involves AMP-activated protein kinase (AMPK) and gut microbiota, but microbial metabolite influence is unclear.

Purpose of the Study:

• To investigate the inhibitory role of microbial metabolites on metformin's glucose-lowering action.
• To elucidate the molecular mechanisms by which imidazole propionate affects metformin efficacy.

Main Methods:

• Measured imidazole propionate levels in type 2 diabetes patients on metformin.
• Assessed metformin's glucose-lowering effect in mice pretreated with imidazole propionate.
• Investigated the impact of imidazole propionate on AMPK and Akt phosphorylation in vitro and in vivo.
• Identified p38γ kinase as a mediator of imidazole propionate's inhibitory effects.

Main Results:

• Elevated imidazole propionate levels were observed in patients with high blood glucose despite metformin treatment.
• Imidazole propionate pretreatment abolished metformin's glucose-lowering effect in mice.
• Imidazole propionate inhibited AMPK activity via Akt-dependent phosphorylation.
• p38γ kinase was identified as a novel kinase for Akt, mediating imidazole propionate's inhibitory action.

Conclusions:

• The gut microbial metabolite imidazole propionate impairs metformin's glucose-lowering efficacy.
• This inhibition occurs through p38γ-mediated Akt activation, leading to suppressed AMPK activity.
• Targeting imidazole propionate or its downstream pathways may enhance metformin therapy for type 2 diabetes.