Toxic effects of cyclosporine on the endocrine pancreas of Wistar rats

Abstract

The widely used immunosuppressive drug cyclosporine exerts toxic effects on various parenchymal organs including the liver and kidney. This study was performed with the aim of testing whether cyclosporine also affects the endocrine pancreas. Daily cyclosporine doses of 50 mg/kg body weight over 3 weeks in rats enhanced the serum bilirubin and creatinine concentrations, led to light-microscopic destruction in the liver and kidneys, and resulted in the development of an impaired glucose tolerance--and, later on, of hyperglycemia. The pancreatic insulin content decreased to 33% of values observed in vehicle-treated controls, which can be ascribed to a 50% decrease of beta-cell volume and a slightly smaller reduction of islet insulin content. The reduction of the cyclosporine dose to 15 mg/kg body weight daily, which also reduced the popliteal lymph node weight gain after allogeneic stimulation, was not accompanied by serochemical or morphological alterations of livers or kidneys in the rats when treated for 3 weeks. However, the animals had already developed an impaired glucose tolerance, accompanied by a decrease in pancreatic insulin content (to 50% that of controls), a decrease of islet insulin content (to 70%) and a reduced pancreatic beta cell volume (to 72%). The findings let us conclude that pancreatic beta cells are sensitive to toxic effects of cyclosporine in vivo. We suggest that the measurement of glucose tolerance, as a sensitive parameter of a toxic cyclosporine action, should be included in the monitoring of grafted patients under cyclosporine treatment.