Direct effects of cyclosporin A on human pancreatic beta-cells.

Abstract

Cyclosporin A (CyA) may induce clinical remission in newly diagnosed insulin-dependent diabetes mellitus patients. Recently, however, adverse effects of high doses of CyA on rodent islets have been reported in vivo and in vitro. The possible direct effects of CyA on the human endocrine pancreas were therefore evaluated. Islets isolated from eight necrokidney donors were cultured in the presence of a therapeutically relevant dose of CyA, i.e., 100 ng/ml. During a 5-day culture period the release of insulin was reduced by 36% (range 7-61%), whereas the islets' content of insulin was increased by 59% (range 3-268%). The glucagon content was not affected. Cyclosporin G inhibited the insulin release, whereas dihydrocyclosporin D had no consistent effects. Glucose-stimulated insulin release from perifused islets was markedly depressed in CyA-treated islets. This effect was not fully reversed 48 h after removal of the drug. We concluded that CyA has a direct inhibitory effect on insulin release from human pancreatic islets with a concomitant increase in the residual insulin content. If applicable to the in vivo condition, CyA may therefore, in addition to its immunosuppressive effect, have direct effects on the endocrine pancreas, which may be relevant for clinical application of the drug.