Morphology of the endocrine pancreas in cyclosporine-treated glucose-intolerant Wistar rats.

The toxic effect of Cyclosporin A (CS-A) (1.25-50.0 mg/kg body weight) on the endocrine pancreas of Wistar rats was morphologically investigated. The treatment of animals with CS-A doses above 5 mg/kg for 2 weeks resulted in a disturbed glucose tolerance, a reduced B-cell volume density and degranulation, vacuolization and decreased mitotic activity of the B-cells. After withdrawal of the drug the impaired parameters were stepwise normalized, starting with regranulation of pancreatic B-cells, followed by a stimulation of mitotic activity, and increase of B-cell volume density. When continuing the CS-A treatment with doses lower than 5.0 mg/kg for longer periods we observed a decreased body weight gain and reduced pancreatic insulin content.

Reversibility of the acute toxic effect of cyclosporin A on pancreatic B cells of Wistar rats.

This study investigated if and to what extent the acute toxic effect of Cyclosporin A on pancreatic Wistar rat B cells is reversible. After 2 weeks of treatment rats developed marked glucose intolerance accompanied by reduced pancreatic insulin content due to a loss of B cells, diminished islet DNA synthesis and decreased B-cell insulin content. Cyclosporin A had accumulated in the pancreas. Three weeks after withdrawal of Cyclosporin A, pancreatic tissue concentrations of Cyclosporin A were still 100 times larger than in serum. Glucose tolerance, however, had already improved, associated with an increase of B-cell insulin content and apparent islet replication, and the insulin response of isolated islets was reduced. Five weeks after the withdrawal of Cyclosporin A, glucose tolerance was normal, but pancreatic insulin content and relative B-cell volume were still diminished in comparison to vehicle-treated controls. Eight weeks after withdrawal, the morphometric parameters had also been normalized. The results suggest that the loss of pancreatic B cells is caused by a toxic destruction, possibly combined with an apparent decrease of replicatory activity. The acute toxic effects of Cyclosporin A in pancreatic B cells are stepwise reversible.