Deciphering Tacrolimus-Induced Toxicity in Pancreatic ß Cells.

ß 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 ß 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 ß cells, possibly by sharing common pathways of ß cell dysfunction. TAC-induced ß 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.

The higher diabetogenic risk of tacrolimus depends on pre-existing insulin resistance. A study in obese and lean Zucker rats.

Insulin resistance may interact with calcineurin inhibitors, enhancing the diabetogenic effect of tacrolimus compared with cyclosporine-A. We studied both drugs in insulin-resistant animals: obese Zucker rats (n = 45), and insulin-sensitive animals: lean Zucker rats (n = 21). During 11 days, animals received saline-buffer, cyclosporine-A (2.5 mg/kg/day) or tacrolimus (0.3 mg/kg/day). At Days 0 and 12 animals underwent intraperitoneal glucose tolerance test (0-30-60-120 min). Islet morphometry, beta-cell proliferation, apoptosis and Ins2 gene expression were analyzed. By Day 12, no lean animal had developed diabetes, while all obese animals on tacrolimus and 40% on cyclosporine-A had. In obese animals, tacrolimus reduced beta-cell proliferation and Ins2 gene expression compared with cyclosporine-A. Five days after treatment discontinuation, partial recovery was observed, with only 10% and 60% of the animals on cyclosporine and tacrolimus remaining diabetic respectively. Beta-cell proliferation increased in animals on tacrolimus while Ins2 gene expression remained unaltered. In conclusion, insulin resistance exacerbated the diabetogenic effect of tacrolimus compared with cyclosporine-A. This may be explained by greater inhibition of Ins2 gene and beta-cell proliferation by tacrolimus in the insulin resistant state. Discontinuation of the drugs may allow the recovery of the metabolic alterations.