TY - JOUR
T1 - Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1
AU - Koh, Ara
AU - Molinaro, Antonio
AU - Ståhlman, Marcus
AU - Khan, Muhammad Tanweer
AU - Schmidt, Caroline
AU - Mannerås-Holm, Louise
AU - Wu, Hao
AU - Carreras, Alba
AU - Jeong, Heeyoon
AU - Olofsson, Louise E.
AU - Bergh, Per-Olof
AU - Gerdes, Victor
AU - Hartstra, Annick
AU - de Brauw, Maurits
AU - Perkins, Rosie
AU - Nieuwdorp, Max
AU - Bergström, G. ran
AU - Bäckhed, Fredrik
PY - 2018
Y1 - 2018
N2 - 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. Imidazole propionate, a metabolite produced by the gut microbiota, is elevated in type 2 diabetes and can directly impair glucose tolerance and insulin signaling.
AB - 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. Imidazole propionate, a metabolite produced by the gut microbiota, is elevated in type 2 diabetes and can directly impair glucose tolerance and insulin signaling.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85055083712&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30401435
U2 - https://doi.org/10.1016/j.cell.2018.09.055
DO - https://doi.org/10.1016/j.cell.2018.09.055
M3 - Article
C2 - 30401435
SN - 0092-8674
VL - 175
SP - 947-961.e17
JO - Cell
JF - Cell
IS - 4
ER -