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Summary: 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. : 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. Keywords: metabolome, gut microbiome, type 2 diabetes, obesity, insulin secretion, pancreatic islets, β-cells, metabotype, mouse, Goto-Kakizaki rat