Deciphering Tacrolimus-Induced Toxicity in Pancreatic beta Cells
| Autor: | Ana Rodríguez-Rodríguez, Javier Triñanes, Germán Cuesto, Eduardo Salido, Armando Torres, Esteban Porrini, Yeray Brito-Casillas, Angel Acebes, A. P. J. de Vries, Ana M. Wägner |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Cell Nerve Tissue Proteins FOXO1 030230 surgery Pharmacology Tacrolimus Diabetes Mellitus Experimental 03 medical and health sciences 0302 clinical medicine Insulin resistance Thinness Insulin-Secreting Cells medicine Animals Insulin Immunology and Allergy Pharmacology (medical) Obesity Insulinoma Transplantation NFATC Transcription Factors business.industry Calcineurin NFAT medicine.disease Rats Rats Zucker stomatognathic diseases Glucose 030104 developmental biology medicine.anatomical_structure Diabetes Mellitus Type 2 Toxicity Cyclosporine Insulin Resistance business Immunosuppressive Agents |
| Zdroj: | American Journal of Transplantation, 17(11), 2829-2840 |
| Popis: | β Cell transcription factors such as forkhead box protein O1 (FoxO1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), pancreatic and duodenal homeobox 1, and neuronal differentiation 1, are dysfunctional in type 2 diabetes mellitus (T2DM). Posttransplant diabetes mellitus resembles T2DM and reflects interaction between pretransplant insulin resistance and immunosuppressants, mainly calcineurin inhibitors (CNIs). We evaluated the effect of tacrolimus (TAC), cyclosporine A (CsA), and metabolic stressors (glucose plus palmitate) on insulinoma β cells in vitro and in pancreata of obese and lean Zucker rats. Cells were cultured for 5 days with 100 μM palmitate and 22 mM glucose; CsA (250 ng/mL) or TAC (15 ng/mL) were added in the last 48 h. Glucose plus palmitate increased nuclear FoxO1 and decreased nuclear MafA. TAC in addition to glucose plus palmitate magnified these changes in nuclear factors, whereas CsA did not. In addition to glucose plus palmitate, both drugs reduced insulin content, and TAC also affected insulin secretion. TAC withdrawal or conversion to CsA restored these changes. Similar results were observed in pancreata of obese animals on CNIs. TAC and CsA, in addition to glucose plus palmitate, induced comparable inhibition of calcineurin and nuclear factor of activated T cells (NFAT); therefore, TAC potentiates glucolipotoxicity in β cells, possibly by sharing common pathways of β cell dysfunction. TAC-induced β cell dysfunction is potentially reversible. Inhibition of the calcineurin-NFAT pathway may contribute to the diabetogenic effect of CNIs but does not explain the stronger effect of TAC compared with CsA. |
| Databáze: | OpenAIRE |
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