To investigate the mechanism of diabetogenic action of cyclosporin A (CsA), 7 male Wistar albino rats received 10 mg/kg/day of the drug for 4 weeks (CsA). The results were compared with controls (C); blood CsA levels measured weekly remained stable throughout the experiment (mean + SEM) (X = 2657.9 ± 155.1 ng/ml). Intravenous glucose load (0.75 g/kg) performed after 2 weeks of CsA therapy showed glucose intolerance in treated animals as evaluated by the glucose area under the curve (CsA = 409.2 ± 17.8 vs. C = 313.3 ± 12.6 umol · ml-1 · min-1) (p < 0.05) with insulin levels being similar in the two groups (CsA = 8603.9 ± 1645.5 vs. C = 9571.9 ± 828.5 pmol · ml-1 · min-1). After 4 weeks of CsA administration, glucose intolerance was maintained (CsA = 398.6 ± 35.6 vs. C = 301.7 ± 23.0 umol · ml-1 · min-1) (p < 0.05) associated with a significant decrease in insulin secretion (CsA = 4404.9 ± 2392.0 vs. C = 10075.9 ± 2861.0 pmol · ml-1 · min-1) (p < 0.05). These results suggest that CsA induced a state of insulin resistance preceeding the failure of insulin secretion. After 4 weeks, the pancreatic insulin content was also decreased (CsA = 0.7 ± 0.1 vs. C = 1.4 ± 0.5 mU/mg) (p < 0.05). Maximal insulin binding to isolated adipocytes was not affected by CsA (CsA = 7.4 ± 2.6 vs. C = 6.4 ± 2.0%), although glucose transport and oxidation decreased after CsA treatment (p < 0.05). In conclusion, glucose intolerance induced by CsA in Wistar albino rats is due to de creased insulin production and impaired insulin action by a post-binding mechanism.
Key words
Cyclosporin A - Pancreatic Insulin Content - Insulin Receptors - Glucose Transport
