The Natural Metabolite 4-Cresol Improves Glucose Homeostasis and Enhances β-Cell Function

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 precl...

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Veröffentlicht in:Cell reports (Cambridge) 2020-02, Vol.30 (7), p.2306-2320.e5
Hauptverfasser: Brial, Francois, Alzaid, Fawaz, Sonomura, Kazuhiro, Kamatani, Yoichiro, Meneyrol, Kelly, Le Lay, Aurélie, Péan, Noémie, Hedjazi, Lyamine, Sato, Taka-Aki, Venteclef, Nicolas, Magnan, Christophe, Lathrop, Mark, Dumas, Marc-Emmanuel, Matsuda, Fumihiko, Zalloua, Pierre, Gauguier, Dominique
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Sprache:eng
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Zusammenfassung: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. [Display omitted] •Serum concentrations of 4-cresol are inversely correlated with type 2 diabetes•Non-toxic dose of 4-cresol reduces adiposity, glucose intolerance, and liver fat•4-Cresol stimulates insulin secretion and β-cell proliferation in vivo and in vitro•4-Cresol downregulates pancreatic and islet expression of the kinase DYRK1A Brial et al. identify the inverse correlation between diabetes and serum 4-cresol, a metabolite present in the environment and produced by intestinal bacteria. The administration of 4-cresol in models of diabetes reduces obesity and liver fat, improves glycemic control, and stimulates insulin secretion and β-cell proliferation.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2020.01.066