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Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS
Published on: November 8, 2015
Tacrolimus induces insulin receptor substrate 1 hyperphosphorylation and inhibits mTORc1/S6K1 cascade in HL7702 cells
Hao-Yan Li1, Yi Wang1, Min Ran1
1Department of Endocrinology, The Third Medical Center of PLA General Hospital, Beijing 100039, China.
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.
Insights
Tacrolimus inhibits insulin signaling in liver cells by affecting insulin receptor substrate 1 (IRS1). This may explain how tacrolimus causes insulin resistance and hyperglycemia after organ transplantation.
Area of Science:
- Hepatology
- Immunology
- Endocrinology
Background:
- Tacrolimus (FK506) is vital for preventing organ transplant rejection.
- However, it is associated with hyperglycemia and insulin resistance, impacting islet function.
Purpose of the Study:
- To investigate the effects of tacrolimus on the hepatic insulin signaling pathway.
- To elucidate mechanisms of tacrolimus-induced insulin resistance.
Main Methods:
- HL7702 liver cells were exposed to varying tacrolimus concentrations (0.1-5 mg/L) for 24 hours.
- Western blotting was employed to analyze key insulin signaling proteins.
Main Results:
- Tacrolimus increased phosphorylation of insulin receptor substrate 1 (IRS1) at Ser 307 and Ser 323.
- It decreased phosphorylation of Ribosomal protein S6 kinase beta-1 and increased glycogen synthase kinase 3α phosphorylation.
- Glycogen synthase phosphorylation increased, while glycogen phosphorylase activity remained unchanged.
Conclusions:
- Tacrolimus inhibits IRS1-mediated insulin signaling in hepatocytes.
- This inhibition is a potential mechanism for tacrolimus-induced insulin resistance.
- Tacrolimus does not directly impact hepatic glucose metabolism.
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