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Microbially Produced Imidazole Propionate Impairs Insulin Signaling Through mTORC1

Microbially Produced Imidazole Propionate Impairs Insulin Signaling Through mTORC1

Ara Koh, Antonio Molinaro, Marcus Ståhlman, Muhammad Tanweer Khan, Caroline Schmidt, Louise Mannerås-Holm, Hao Wu, Alba Carreras, Heeyoon Jeong, Louise E Olofsson, Per-Olof Bergh, Victor Gerdes, Annick Hartstra, etc.

Cell. 2018 Nov 1;175(4):947-961.e17.

PMID: 30401435

Abstract:

Interactions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidine-derived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP288324-A	Imidazole		288-32-4	Price

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