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Sorafenib decreases glycemia by impairing hepatic glucose metabolism

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

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Acknowledgements

We would like to thank Natural Science Basis Research Program in Shaanxi Province of China for supporting of this work.

Funding

This work was supported by Natural Science Basis Research Program in Shaanxi Province of China (No. 2018JM7105 to R.L.).

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Authors and Affiliations

  1. Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, 710061, Xi’an, P.R. China

    Jingjing Ma, Fang Sui, Yan Liu, Mengmeng Yuan, Hui Dang, Bingyin Shi & Peng Hou

  2. Department of Radio-Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, 710061, Xi’an, P.R. China

    Rui Liu

  3. Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, 710061, Xi’an, P.R. China

    Peng Hou

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  1. Jingjing Ma
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Contributions

P.H. conceived and designed the experiments. J.M., F.S., and Y.L. Performed the experiments. M.Y. and R.L. analyzed the data. B.S. and P.H. contributed reagents and materials. P.H. wrote the paper. All authors read and approved the final paper.

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Correspondence to Peng Hou.

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All animal experimental procedures were approved by the Animal Ethics Committee of Xi’an Jiaotong University.

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Ma, J., Sui, F., Liu, Y. et al. Sorafenib decreases glycemia by impairing hepatic glucose metabolism. Endocrine 78, 446–457 (2022). https://doi.org/10.1007/s12020-022-03202-9

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