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

Authors
  • 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
Source
Spiral - Imperial College Digital Repository
Keywords
License
Unknown

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.

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