@article{05effd5871bb4eb3aef4ab46046b1384,
title = "The Natural Metabolite 4-Cresol Improves Glucose Homeostasis and Enhances β-Cell Function",
abstract = "Exposure to natural metabolites contributes to the risk of cardiometabolic diseases (CMDs). Through metabolome profiling, we identify the inverse correlation between serum concentrations of 4-cresol and type 2 diabetes. The chronic administration of non-toxic doses of 4-cresol in complementary preclinical models of CMD reduces adiposity, glucose intolerance, and liver triglycerides, enhances insulin secretion in vivo, stimulates islet density and size, and pancreatic β-cell proliferation, and increases vascularization, suggesting activated islet enlargement. In vivo insulin sensitivity is not affected by 4-cresol. The incubation of mouse isolated islets with 4-cresol results in enhanced insulin secretion, insulin content, and β-cell proliferation of a magnitude similar to that induced by GLP-1. In both CMD models and isolated islets, 4-cresol is associated with the downregulated expression of the kinase DYRK1A, which may mediate its biological effects. Our findings identify 4-cresol as an effective regulator of β-cell function, which opens up perspectives for therapeutic applications in syndromes of insulin deficiency.",
keywords = "Goto-Kakizaki rat, gut microbiome, insulin secretion, metabolome, metabotype, mouse, obesity, pancreatic islets, type 2 diabetes, β-cells",
author = "Francois Brial and Fawaz Alzaid and Kazuhiro Sonomura and Yoichiro Kamatani and Kelly Meneyrol and \{Le Lay\}, Aur{\'e}lie and No{\'e}mie P{\'e}an and Lyamine Hedjazi and Sato, \{Taka Aki\} and Nicolas Venteclef and Christophe Magnan and Mark Lathrop and Dumas, \{Marc Emmanuel\} and Fumihiko Matsuda and Pierre Zalloua and Dominique Gauguier",
note = "Funding Information: The authors acknowledge financial support from the Soci{\'e}t{\'e} d{\textquoteright}acc{\'e}l{\'e}ration du transfert de technologies ( SATT-LUTECH ) and the European Commission for collection of the patient cohort ( FGENTCARD, LSHGCT-2006-037683 ) and experimental work in mice ( METACARDIS, HEALTH-F4-2012-305312 ). Funding Information: The authors acknowledge financial support from the Soci?t? d'acc?l?ration du transfert de technologies (SATT-LUTECH) and the European Commission for collection of the patient cohort (FGENTCARD, LSHGCT-2006-037683) and experimental work in mice (METACARDIS, HEALTH-F4-2012-305312). P.Z. F.M. M.L. M.-E.D. and D.G. conceived the study. P.Z. provided patients? serum samples. K.S. T.-A.S. and F.M. carried out targeted GC-MS metabolomic analyses. F.B. A.L.L. and N.P. carried out the mouse experiments. F.B. K.M. and C.M. incubated isolated islets. F.B. A.L.L. and F.A. performed the histology and gene expression analyses. Y.K. and L.H. performed the statistical analyses. P.Z. and D.G. wrote the manuscript. All of the authors have given approval to the final version of the manuscript. F.B. F.M. P.Z. and D.G. are named inventors on a patent related to this work (Ref. EP 17306326). K.S. and T.-A.S. are employees of Shimadzu (Kyoto, Japan). F.A. Y.K. K.M. A.L.L. N.P. L.H. N.V. C.M. M.L. and M.-E.D. declare no competing financial interests. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = feb,
day = "18",
doi = "10.1016/j.celrep.2020.01.066",
language = "British English",
volume = "30",
pages = "2306--2320.e5",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "7",
}
