Interference by cyclosporine with the endocrine function of the canine pancreas

Abstract

This study addresses itself to the eventual interference of cyclosporine (CsA) with the function of pancreatic beta cells in vivo. We have used dogs that had at least six weeks previously been subjected to segmental pancreatic autotransplantation. This model has been well established to be associated with stable normoglycemia but with incomplete endocrine reserve capacity, which renders it suitable for detecting eventual toxic drug effects. CsA was administered for 6 weeks in an oral dose of either 30 mg/kg/day (first series of 4 dogs) or 40 mg/kg/day (second series of 7 dogs). CsA trough levels in blood were determined at least weekly, and the mean of the levels in each dog ranged from 218 to 1274 ng/ml, with one exception (2191 ng/ml). The endocrine function was tested not only before and after 6 weeks of CsA administration, but also at 4 weeks after cessation of CsA administration. The postprandial insulin output was reversibly reduced in the first series (P less than 0.05) and the i.v. glucose-stimulated insulin output was reversibly reduced in the second series (P less than 0.001). Other parameters, like postprandial peak and mean blood glucose levels and K-values, showed reversible changes that, although not always statistically significant, were compatible with a reversible suppressive effect by CsA in all instances. Finally, we found that the severity of suppression as expressed in individual reduction of i.v. glucose-stimulated insulin output correlated with the individual mean CsA trough level (r = 0.71, P less than 0.015). It is concluded that CsA exerts a detrimental effect on the function of canine beta cells in vivo, which effect is reversible and dependent upon the CsA blood level.