Inhibiting the calcineurin(CN)/NFAT-pathway in β-cells may contribute to posttransplant diabetes. The presumed higher diabetogenicity of Tac is thought to owe to an IC₅₀ for CN that is 10-15x lower than CsA. However, CsA trough levels are 10-20x higher than Tac. Other pathways may explain the presumed diabetogenicity of Tac. Clinical observations and experimental studies suggest that the diabetogenicity of Tac, rather than CsA, depends on an IR milieu, similar to T2DM. Thus, we hypothesized that Tac more than CsA alters nuclear factors necessary for β-cell identity & function, like MafA, PDX-1, and FoxO1, that is dependent on IR but independent of NFAT.

We cultured INS-1 cells with palmitate and glucose for 5 days to emulate IR, and Tac or CsA was added for last 48h. We also studied the effect of Tac vs CsA in obese (OZR) vs lean Zucker rats (LZR) for 12 days. Tac withdrawal and conversion to CsA were evaluated in both models. Nuclear presence of transcription factors for β-cell identity & function was determined by immunolocalization, and insulin was measured in medium or plasma after glucose challenge.

Glucose and palmitate increased nuclear FoxO1 but decreased nuclear MafA and insulin secretion in INS-1 cells; all these changes were magnified by Tac but not CsA. The addition of Tac on top of palmitate/glucose was the only treatment that reduced nuclear PDX-1 compared to control. Importantly, FoxO1 and MafA localization, as well as glucose-stimulated insulin secretion, recovered after Tac withdrawal or conversion to CsA. In OZR, Tac induced diabetes in all animals compared to only 40% for CsA. Neither Tac nor CsA caused diabetes in LZR. The onset of diabetes in Tac-treated OZR was accompanied by an increase in nuclear FoxO1 and decrease in nuclear MafA in β-cells, as well as a lower insulinogenic index compared to CsA-treated OZR, non-treated OZR, and LZR. Tac withdrawal/conversion to CsA improved diabetes similarly. Notably, nuclear NFAT localization was similar between Tac and CsA in all experiments.

We conclude that Tac, rather than CsA, interacts with an insulin resistant milieu to accelerate the change in nuclear localization of key transcription factors for β-cell identity & function that is reminiscent of T2DM, without altering NFAT localization.

CITATION INFORMATION: Triñanes J, Rodriguez A, de Koning E, de Fijter J, Carlotti F, Torres A, de Vries A, Porrini E. Tacrolimus (Tac), Rather Than Cyclosporine (CsA), Interacts with Insulin Resistance (IR) to Alter Key Transcription Factors for β-Cell Identity & Function without Altering NFAT Localization. Am J Transplant. 2016;16 (suppl 3).

« Back to 2016 American Transplant Congress