Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P.R. China.
Department of Radio-Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P.R. China.
Endocrine. 2022 Dec;78(3):446-457. doi: 10.1007/s12020-022-03202-9. Epub 2022 Oct 7.
Sorafenib has been reported to reduce blood glucose levels in diabetic and non-diabetic patients in previous retrospective studies. However, the mechanism of which the hypoglycemic effects of sorafenib is not clearly explored. In this study, we investigated the effect of sorafenib on blood glucose levels in diabetic and normal mice and explored the possible mechanism.
We established a mouse model of type 2 diabetes by a high-fat diet combined with a low-dose of streptozotocin (STZ), to identify the hypoglycemic effect of sorafenib in different mice. Glucose tolerance, insulin tolerance and pyruvate tolerance tests were done after daily gavage with sorafenib to diabetic and control mice. To explore the molecular mechanism by which sorafenib regulates blood glucose levels, hepatic glucose metabolism signaling was studied by a series of in vivo and in vitro experiments.
Sorafenib reduced blood glucose levels in both control and diabetic mice, particularly in the latter. The diabetic mice exhibited improved glucose and insulin tolerance after sorafenib treatment. Further studies showed that the expressions of gluconeogenesis-related enzymes, such as PCK1, G6PC and PCB, were significantly decreased upon sorafenib treatment. Mechanistically, sorafenib downregulates the expression of c-MYC downstream targets PCK1, G6PC and PCB through blocking the ERK/c-MYC signaling pathway, thereby playing its hypoglycemic effect by impairing hepatic glucose metabolism.
Sorafenib reduces blood glucose levels through downregulating gluconeogenic genes, especially in diabetic mice, suggesting the patients with T2DM when treated with sorafenib need more emphasis in monitoring blood glucose to avoid unnecessary hypoglycemia.
索拉非尼在先前的回顾性研究中已被报道可降低糖尿病和非糖尿病患者的血糖水平。然而，索拉非尼降低血糖作用的机制尚不清楚。在本研究中，我们研究了索拉非尼对糖尿病和正常小鼠血糖水平的影响，并探讨了可能的机制。
我们通过高脂肪饮食联合小剂量链脲佐菌素（STZ）建立了 2 型糖尿病小鼠模型，以确定索拉非尼在不同小鼠中的降血糖作用。用索拉非尼对糖尿病和对照小鼠进行每日灌胃后，进行葡萄糖耐量、胰岛素耐量和丙酮酸耐量试验。为了探讨索拉非尼调节血糖水平的分子机制，我们通过一系列体内和体外实验研究了肝葡萄糖代谢信号通路。
索拉非尼降低了对照和糖尿病小鼠的血糖水平，尤其在后者中更为显著。索拉非尼治疗后，糖尿病小鼠的葡萄糖和胰岛素耐量得到改善。进一步的研究表明，索拉非尼治疗后，糖异生相关酶如 PCK1、G6PC 和 PCB 的表达显著降低。机制上，索拉非尼通过阻断 ERK/c-MYC 信号通路下调 c-MYC 下游靶基因 PCK1、G6PC 和 PCB 的表达，从而通过损害肝葡萄糖代谢发挥其降血糖作用。
索拉非尼通过下调糖异生基因降低血糖水平，尤其在糖尿病小鼠中更为显著，这提示 T2DM 患者在接受索拉非尼治疗时需要更密切地监测血糖，以避免不必要的低血糖。
