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Cell. 2018 Nov 1;175(4):947-961.e17. doi: 10.1016/j.cell.2018.09.055. Epub 2018 Oct 25.

Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1.

Author information

1
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
2
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
3
Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea.
4
Slotervaart Hospital, Amsterdam, the Netherlands.
5
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
6
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; VU University Medical Center, Free University Amsterdam, Amsterdam, the Netherlands.
7
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: fredrik@wlab.gu.se.

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.

KEYWORDS:

IRS; histidine; imidazole propionate; mTORC1; microbiome; p38γ; p62

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PMID:
30401435
DOI:
10.1016/j.cell.2018.09.055
[Indexed for MEDLINE]
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