The Higher Diabetogenic Risk of Tacrolimus Depends on Pre-Existing Insulin Resistance. A Study in Obese and Lean Zucker Rats
| Autor: | Ana Rodríguez-Rodríguez, E. Salido Ruiz, M. L. Diez Fuentes, M. J. Vega Prieto, S. Velazquez-Garcia, Esteban Porrini, Javier Triñanes, Armando Torres, Miguel Arévalo |
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| Rok vydání: | 2013 |
| Předmět: |
Blood Glucose
medicine.medical_specialty medicine.medical_treatment chemical and pharmacologic phenomena Real-Time Polymerase Chain Reaction Tacrolimus Diabetes Mellitus Experimental Insulin resistance Thinness Insulin-Secreting Cells Internal medicine Diabetes mellitus medicine Animals Hypoglycemic Agents Insulin Immunology and Allergy Pharmacology (medical) Obesity Cell Proliferation Transplantation Glucose tolerance test geography geography.geographical_feature_category medicine.diagnostic_test business.industry Glucose Tolerance Test medicine.disease Islet Rats Rats Zucker Calcineurin surgical procedures operative Endocrinology Gene Expression Regulation Apoptosis RNA Insulin Resistance business Immunosuppressive Agents |
| Zdroj: | American Journal of Transplantation. 13:1665-1675 |
| ISSN: | 1600-6135 |
| DOI: | 10.1111/ajt.12236 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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