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The Higher Diabetogenic Risk of Tacrolimus Depends on Pre‐Existing Insulin Resistance. A Study in Obese and Lean Zucker Rats
Author(s) -
RodriguezRodriguez A. E.,
Triñanes J.,
VelazquezGarcia S.,
Porrini E.,
Vega Prieto M. J.,
Diez Fuentes M. L.,
Arevalo M.,
Salido Ruiz E.,
Torres A.
Publication year - 2013
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.12236
Subject(s) - tacrolimus , insulin resistance , endocrinology , medicine , calcineurin , insulin , discontinuation , diabetes mellitus , beta cell , islet , transplantation
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.