title: The higher diabetogenic risk of tacrolimus depends on pre-existing insulin resistance. A study in obese and lean Zucker rats.
abstract: 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.
authors: Research Unit, University Hospital of Canary Islands, Tenerife, Spain.
authors: A E
authors: AE
authors: Rodriguez-Rodriguez
authors: J
authors: J
authors: Triñanes
authors: S
authors: S
authors: Velazquez-Garcia
authors: E
authors: E
authors: Porrini
authors: M J
authors: MJ
authors: Vega Prieto
authors: M L
authors: ML
authors: Diez Fuentes
authors: M
authors: M
authors: Arevalo
authors: E
authors: E
authors: Salido Ruiz
authors: A
authors: A
authors: Torres
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007328:Insulin / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000235:genetics; D051381:Rats; D011924:Rats, Zucker; D060888:Real-Time Polymerase Chain Reaction; D016559:Tacrolimus / Q000627:therapeutic use*; D013851:Thinness / Q000150:complications / Q000235:genetics* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007166:Immunosuppressive Agents; C561967:Ins2 protein, mouse; D007328:Insulin; D012313:RNA; D016559:Tacrolimus