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Deciphering tacrolimus-induced toxicity in pancreatic β-cells.

Deciphering tacrolimus-induced toxicity in pancreatic β-cells.
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Triñanes J, Rodriguez-Rodriguez AE, Brito Y, Wagner A, De Vries APJ, Cuesto G, Acebes A, Salido E, Torres A, Porrini E,


Triñanes J, Rodriguez-Rodriguez AE, Brito Y, Wagner A, De Vries APJ, Cuesto G, Acebes A, Salido E, Torres A, Porrini E, (click to view)

Triñanes J, Rodriguez-Rodriguez AE, Brito Y, Wagner A, De Vries APJ, Cuesto G, Acebes A, Salido E, Torres A, Porrini E,

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American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2017 04 22() doi 10.1111/ajt.14323
Abstract

β-cell transcription factors like: FoxO1, MafA, PDX-1, NeuroD, are dysfunctional in type 2 diabetes (T2DM). PTDM resembles T2DM and reflects interaction between pre-transplant insulin resistance and immunosuppressants, mainly calcineurin inhibitors. We evaluated the effect of tacrolimus, cyclosporine-A and metabolic stressors (glucose+palmitate) on insulinoma β-cells (INS-1) in vitro and in pancreata of obese and lean Zucker rats. Cells were cultured for five days with 100μM palmitate and 22mM glucose; cyclosporin-A (250ng/mL) or tacrolimus (15ng/mL) were added the last 48h. Glucose+palmitate increased nuclear FoxO1 and decreased nuclear MafA. Tacrolimus on top of glucose+palmitate magnified these changes in nuclear factors whereas cyclosporin-A did not. On top of glucose+palmitate, both drugs reduced insulin content and tacrolimus also affected insulin secretion. Tacrolimus withdrawal or conversion to cyclosporin-A restored these changes. Similar results were observed in pancreata of obese animals on calcineurin inhibitors. Tacrolimus and cyclosporin-A, on top of glucose+palmitate induced a comparable inhibition of calcineurin-NFAT. Thus, tacrolimus potentiates glucolipotoxicity in β-cells, possibly by sharing common pathways of β-cell dysfunction. Tacrolimus-induced β-cell dysfunction is potentially reversible. The inhibition of calcineurin-NFAT pathway may contribute to the diabetogenic effect of calcineurin inhibitors but does not explain the stronger of tacrolimus compared with cyclosporine-A. This article is protected by copyright. All rights reserved.

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