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Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1.

Cell | 2018

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.

Pubmed ID: 30401435 RIS Download

Mesh terms: Animals | Cells, Cultured | Diabetes Mellitus, Type 2 | Gastrointestinal Microbiome | HEK293 Cells | Histidine | Humans | Imidazoles | Insulin | Liver | Male | Mechanistic Target of Rapamycin Complex 1 | Mice | Mice, Inbred C57BL | Sequestosome-1 Protein | Signal Transduction | p38 Mitogen-Activated Protein Kinases

Additional research tools detected in this publication

Antibodies used in this publication

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This is a list of tools and resources that we have found mentioned in this publication.


Insulin Receptor beta (4B8) Rabbit mAb antibody (antibody)

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IRS-2 Antibody (antibody)

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Anti-phospho-IRS1 (Tyr608) mouse/ (Tyr612) human antibody (antibody)

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mTOR (7C10) Rabbit mAb antibody (antibody)

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Anti-p38 MAPK, phospho (Thr180 / Tyr182) Antibody, Unconjugated (antibody)

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RRID:AB_330339

This polyclonal antibody targets Phospho-IRS-1 (Ser636/639)

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Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb antibody (antibody)

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This monoclonal antibody targets Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb

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LAMP2 antibody [H4B4] - Lysosome Marker (antibody)

RRID:AB_470709

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Anti-IRS1 antibody (antibody)

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c-Myc (9E10) antibody (antibody)

RRID:AB_627268

This monoclonal antibody targets c-Myc (9E10)

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SAPK4 (C-19) antibody (antibody)

RRID:AB_656012

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p70 S6 Kinase Antibody (antibody)

RRID:AB_331676

This polyclonal antibody targets p70 S6 Kinase

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Sheep Anti-Mouse IgG ECL Antibody, HRP Conjugated (antibody)

RRID:AB_772193

This unknown targets Sheep Mouse IgG ECL HRP

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Akt (pan) (11E7) Rabbit mAb antibody (antibody)

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HA-probe (F-7) antibody (antibody)

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This polyclonal antibody targets 8 amino acid sequence (C-asp-tyr-lys-asp-asp-asp-asp-lys-N)

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RRID:AB_2750575

This monoclonal antibody targets DEPTOR/DEPDC6

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SQSTM1/p62 Antibody (antibody)

RRID:AB_10624872

This polyclonal antibody targets SQSTM1/p62

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Anti-GFP antibody (antibody)

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This polyclonal antibody targets GFP

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GraphPad Prism (tool)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

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MEGA Software (tool)

RRID:SCR_000667

Software integrated tool for conducting automatic and manual sequence alignment, inferring phylogenetic trees, mining web based databases, estimating rates of molecular evolution, and testing evolutionary hypotheses. Used for comparative analysis of DNA and protein sequences to infer molecular evolutionary patterns of genes, genomes, and species over time. MEGA version 4 expands on existing facilities for editing DNA sequence data from autosequencers, mining Web-databases, performing automatic and manual sequence alignment, analyzing sequence alignments to estimate evolutionary distances, inferring phylogenetic trees, and testing evolutionary hypotheses. MEGA version 6 enables inference of timetrees, as it implements RelTime method for estimating divergence times for all branching points in phylogeny.

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DESeq2 (tool)

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Software package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.

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HEK293 (cell line)

RRID:CVCL_0045

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R Project for Statistical Computing (tool)

RRID:SCR_001905

Software environment and programming language for statistical computing and graphics. R is integrated suite of software facilities for data manipulation, calculation and graphical display. Can be extended via packages. Some packages are supplied with the R distribution and more are available through CRAN family.

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