Université Paris Cité, INSERM U1132 Biologie de l'os et du cartilage (BIOSCAR), Paris, France.
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
PLoS One. 2024 Oct 24;19(10):e0310370. doi: 10.1371/journal.pone.0310370. eCollection 2024.
4-cresol (4-methylphenol, p-cresol) is a xenobiotic substance negatively correlated with type 2 diabetes and associated with health improvement in preclinical models of diabetes. We aimed at refining our understanding of the physiological role of this metabolite and identifying potential signalling mechanisms. Functional studies revealed that 4-cresol does not deteriorate insulin sensitivity in human primary adipocytes and exhibits an additive effect to that of insulin on insulin sensitivity in mouse C2C12 myoblasts. Experiments in mouse isolated islets showed that 4-cresol potentiates glucose induced insulin secretion. We demonstrated the absence of off target effects of 4-cresol on a panel of 44 pharmacological compounds. Screening large panels of 241 G protein-coupled receptors (GPCRs) and 468 kinases identified binding of 4-cresol only to TNK1, EIF2AK4 (GCN2) and RPS6KA3 (RSK2), a kinase strongly expressed in human and rat pancreatic islets. Islet expression of RPS6KA3 is reduced in spontaneously diabetic rats chronically treated with 4-cresol and Rps6ka3 deficient mice exhibit reduction in both body weight and fasting glycemia, modest improvement in glycemic control and enhanced insulin release in vivo. Similar to low doses of 4-cresol, incubation of isolated rat islets with low concentrations of the RPS6KA3 inhibitor BIX 02565 stimulates both glucose induced insulin secretion and β-cell proliferation. These results provide further information on the role of low 4-cresol doses in the regulation of insulin secretion.
4- 甲苯酚（4- 甲基苯酚，对甲酚）是一种与 2 型糖尿病呈负相关的外源性物质，与糖尿病临床前模型中的健康改善有关。我们旨在深入了解该代谢物的生理作用，并确定潜在的信号机制。功能研究表明，4- 甲苯酚不会降低人原代脂肪细胞的胰岛素敏感性，并且在小鼠 C2C12 成肌细胞中与胰岛素具有协同作用，增强胰岛素敏感性。在小鼠分离胰岛的实验中，4- 甲苯酚增强了葡萄糖诱导的胰岛素分泌。我们证明了 4- 甲苯酚对 44 种药理学化合物的无脱靶作用。对 241 种 G 蛋白偶联受体（GPCR）和 468 种激酶的大型筛选面板发现，4- 甲苯酚仅与 TNK1、EIF2AK4（GCN2）和 RPS6KA3（RSK2）结合，RSK2 在人和大鼠胰岛中强烈表达。长期用 4- 甲苯酚处理的自发性糖尿病大鼠胰岛中 RPS6KA3 的表达减少，并且 Rps6ka3 缺陷型小鼠的体重和空腹血糖降低，血糖控制适度改善，体内胰岛素释放增强。与低剂量的 4- 甲苯酚相似，用低浓度的 RPS6KA3 抑制剂 BIX 02565 孵育分离的大鼠胰岛可刺激葡萄糖诱导的胰岛素分泌和β细胞增殖。这些结果提供了关于低剂量 4- 甲苯酚在调节胰岛素分泌中的作用的更多信息。
