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The natural metabolite 4-cresol improves glucose homeostasis and enhances beta-cell function

  • Brial, F
  • Alzaid, F
  • Sonomura, K
  • Kamatani, Y
  • Meneyrol, K
  • Le Lay, A
  • Pean, N
  • Hedjazi, L
  • Sato, T-A
  • Venteclef, N
  • Magnan, C
  • Lathrop, M
  • Dumas, M-E
  • Matsuda, F
  • Zalloua, P
  • Gauguier, D
Publication Date
Jan 22, 2020
Spiral - Imperial College Digital Repository


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.

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