Mechanism of the diabetogenic action of cyclosporin A

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 = 10 075.9 +/- 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 decreased insulin production and impaired insulin action by a post-binding mechanism.