Stimulation of insulin secretion induced by low 4-cresol dose involves the RPS6KA3 signalling pathway

• DOI: 10.1371/journal.pone.0310370
• Publication Date: 2024-10-24T17:42:27Z
• Authors: François Brial; Géraldine Puel; Laurine Gonzalez; Jules Russick; Daniel Auld; Mark Lathrop; Roseline Poirier; Fumihiko Matsuda; Dominique Gauguier
• Keywords: Male; Ribosomal Protein S6 Kinases, 90-kDa; Rats; Cell Line; Cresols; Mice; Islets of Langerhans; Glucose; Diabetes Mellitus, Type 2; Insulin Secretion; Adipocytes; Animals; Humans; Insulin; Research Article; Signal Transduction

4-cresol (4-methylphenol, p-cresol) is a xenobiotic substance negatively correlated with type 2 diabetes and associated health improvement in preclinical models of diabetes. We aimed at refining our understanding the physiological role this metabolite identifying potential signalling mechanisms. Functional studies revealed that does not deteriorate insulin sensitivity human primary adipocytes exhibits an additive effect to on mouse C2C12 myoblasts. Experiments isolated islets showed potentiates glucose induced secretion. demonstrated absence off target effects panel 44 pharmacological compounds. Screening large panels 241 G protein-coupled receptors (GPCRs) 468 kinases identified binding only TNK1, EIF2AK4 (GCN2) RPS6KA3 (RSK2), kinase strongly expressed rat pancreatic islets. Islet expression reduced spontaneously diabetic rats chronically treated Rps6ka3 deficient mice exhibit reduction both body weight fasting glycemia, modest glycemic control enhanced release vivo. Similar low doses 4-cresol, incubation concentrations inhibitor BIX 02565 stimulates secretion β-cell proliferation. These results provide further information regulation