IMPAIRMENT OF STIMULATED INSULIN RELEASE FROM THE ISOLATED PERFUSED RAT PANCREAS BY CYCLOSPORINE PRETREATMENT

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Abstract
Cyclosprine was fed to male Wistar rats in a dose of 5, 10, or 50 mg/kg b.wt for 7 days, and the effect on insulin secretion from the isolated perfused pancreas was investigated. Dose-dependently plasma inuslin and pancreatic insulin content decreased while whole-blood CsA levels increased. An increase in blood glucose was only observed after feeding 50 mg/kg b.wt. CsA resulting in whole-blood CsA levels of 7735 ng/ml. Glucose (20 mM)-stimulated total insulin secretion (ng/50 min) was not affected during feeding 5 mg/kg b.wt. CsA, but was significantly reduced after feeding 10 or 50 mg/kg b.wt. CsA. The biphasic insulin secretion was reduced after 5 mg/kg b.wt. during the initial peak (0-10 min) but not during the second peak (10-50 min), whereas after 10 or 50 mg/kg b.wt. CsA both peaks were markedly reduced. The arginine (20 mM) and the arginine (20 mM)-plus-glucose (20 mM) stimulated insulin secretion was less affected after feeding 10 mg/kg b.wt. CsA than after stimulation with glucose (20 mM) alone. The addition of CsA to the perfusate did not influence glucose-stimulated insulin release from normal rat pancreas. Our results demonstrate a toxic effect of CsA on the pancreatic beta cell that is dose dependent and possibly influences both insulin secretion and biosynthesis.