Li HY, Wang Y, Ran M, Gao F, Zhu BY, Xiao HY, Xu C. Tacrolimus induces insulin receptor substrate 1 hyperphosphorylation and inhibits mTORc1/S6K1 cascade in HL7702 cells. World J Diabetes 2025; 16(2): 97910 [DOI: 10.4239/wjd.v16.i2.97910]
Corresponding Author of This Article
Chun Xu, MD, PhD, Chief Physician, Department of Endocrinology, The Third Medical Center of PLA General Hospital, No. 69 Yongding Road, Haidian District, Beijing 100039, China. xuchh2000-1@163.com
Research Domain of This Article
Endocrinology & Metabolism
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Diabetes. Feb 15, 2025; 16(2): 97910 Published online Feb 15, 2025. doi: 10.4239/wjd.v16.i2.97910
Tacrolimus induces insulin receptor substrate 1 hyperphosphorylation and inhibits mTORc1/S6K1 cascade in HL7702 cells
Hao-Yan Li, Yi Wang, Min Ran, Fei Gao, Bo-Yu Zhu, Hai-Ying Xiao, Chun Xu
Hao-Yan Li, Yi Wang, Min Ran, Fei Gao, Bo-Yu Zhu, Hai-Ying Xiao, Chun Xu, Department of Endocrinology, The Third Medical Center of PLA General Hospital, Beijing 100039, China
Co-first authors: Hao-Yan Li and Yi Wang.
Co-corresponding authors: Chun Xu and Hai-Ying Xiao.
Author contributions: Xu C and Xiao HY conceptualized and designed the research, and reviewed the manuscript; Li HY, Wang Y and Ran M wrote the manuscript; Gao F and Zhu BY collected data for review; All authors read and approved the final version of the manuscript. Li HY conducted Western blotting analysis and prepared the first draft of the manuscript. Wang Y was responsible for data analysis, literature search and the preparation of part of first draft. Both authors have made crucial and indispensable contributions towards the completion of the project and thus qualified as the co-first authors of the paper. Both Xu C and Xiao HY have played important and indispensable roles in the experimental design, data interpretation and manuscript preparation as the co-corresponding authors. Xu C applied for and obtained the funds for this research project. Xiao HY conceptualized, designed, and supervised the whole process of the project. This collaboration between Xu C and Xiao HY is crucial for the publication of this manuscript.
Institutional animal care and use committee statement: There are no human subjects or animals in this article and ethical approval is not applicable.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The data generated and analyzed during this study are available from the corresponding author upon reasonable request at haiying_xiao@126.com.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/License/by-nc/4.0/
Corresponding author: Chun Xu, MD, PhD, Chief Physician, Department of Endocrinology, The Third Medical Center of PLA General Hospital, No. 69 Yongding Road, Haidian District, Beijing 100039, China. xuchh2000-1@163.com
Received: June 12, 2024 Revised: August 28, 2024 Accepted: November 13, 2024 Published online: February 15, 2025 Processing time: 200 Days and 22.7 Hours
Abstract
BACKGROUND
Tacrolimus (FK506) is a key calcineurin inhibitor used to prevent organ transplant rejection and is effective in improving graft survival. However, it is linked to hyperglycemia and insulin resistance, contributing to new-onset diabetes after transplantation and negatively affecting islet function.
AIM
To study the effects of tacrolimus on the insulin signaling pathway of hepatocytes.
METHODS
HL7702 cells were treated with different concentrations of tacrolimus (0.1 mg/L, 1 mg/L, 5 mg/L) for 24 hours. The proteins involved in insulin signaling were detected by Western blotting.
RESULTS
Compared with the control group, phosphorylation of insulin receptor substrate (IRS) 1 at Ser 307 and Ser 323 were increased significantly when the tacrolimus concentration reached 1 and 5 mg/L. Phosphorylation of IRS1 at Ser 1101 was also increased, although not significantly. However, phosphorylation of Ribosomal protein S6 kinase beta-1 at Thr 389 was decreased significantly. The levels of phosphorylated glycogen synthase kinase 3α Ser 21 and Ser 9 were increased. Surprisingly, phosphorylation of glycogen synthase at Ser 641 was increased. There was no significant change in the activity of glycogen phosphorylase.
CONCLUSION
Tacrolimus has no direct effect on hepatic glucose metabolism, but inhibits IRS1-mediated insulin signaling. This may be one of the underlying mechanisms by which tacrolimus induces insulin resistance.
Core Tip: Tacrolimus, a calcineurin phosphatase inhibitor, prevents transplant rejection but induces insulin resistance and diabetes. This study explores its direct effects on insulin signaling in hepatocytes, revealing mechanisms involving calcineurin inhibition, dyslipidemia, and altered glucose metabolism.
