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Cyclosporin A (50 mg/kg orally for 7 days) produced severe degranulation and hydropic degeneration of islet B cells in rats. These changes were accompanied by hyperglycaemia and hypoinsulinaemia, while the pancreatic insulin content decreased by 75%.

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.

The injection of 25 mg/kg i.p. cyclosporin (CsA) for 3 wk caused marked functional and morphological deteriorations of pancreatic islet cells in Wistar rats that were prevented by the combined administration of p-aminobenzoic acid-N-D-mannoside sodium salt (K-MAP). In this article, the toxic effect of CsA on pancreatic islet cells and the preventive effect of K-MAP on CsA-associated islet cell toxicity were investigated. Prolonged hyperglycemia and depressed insulin secretion after the glucose challenge observed in CsA-treated rats could be prevented by the combined administration of 300 and 900 mg/kg K-MAP. Cytoplasmic vacuolizations and a decrease in the number of mitochondria, intact endoplasmic reticula, secretory granules, and insulin-positive cells, as revealed by peroxidase-antiperoxidase staining, could also be prevented by the administration of 900 mg/kg K-MAP. This preventive effect of K-MAP on CsA-associated islet cell toxicity may suggest the combined use of K-MAP with CsA in pancreas transplantation and treatment of insulin-dependent diabetes.

The effect of 5, 10, and 20 mg/kg bw cyclosporine on rat endocrine and exocrine pancreatic function was studied. Glucose-dependent insulin secretion from the endocrine pancreas was shown to be significantly impaired 8 days after cyclosporine was given once daily at a dose as low as 5 mg/kg. CCK-8-stimulated amylase and lipase secretion were less sensitive to the noxious effect of cyclosporine being impaired at a dose of 10 mg/kg. Trypsin secretion was shown to be impaired at 20 mg/kg cyclosporine only. Our results demonstrate that cyclosporine causes dose-dependent impairment of both pancreatic endocrine and exocrine functions: the endocrine pancreas being more sensitive to the noxious action than the exocrine pancreas.

We have investigated the effects of an oral cyclosporin (CsA) treatment on "autoimmune" diabetes induced in CD1 male mice by 5 low doses (40 mg/kg/day) of streptozotocin (SZ). CsA (50, 25, or 12.5 mg/kg/day) induced significant hyperglycaemia and insulinopenia by the 3rd day after the last SZ injection, whereas mice receiving SZ only remained non diabetic at that time. Enhancement of SZ-induced diabetes by CsA was thus noted. Mice receiving CsA and SZ displayed a significantly higher number of degranulated and necrotic beta cells. Similarly, CsA enhanced "toxic" diabetes produced by a single high dose of SZ. Furthermore, mice treated with CsA alone displayed glucose intolerance, insulinopenia, and high pancreatic CsA content. These abnormalities were reversed by 2 weeks after CsA withdrawal. Islets isolated from CsA treated mice displayed in vitro decreased stimulated insulin secretion. During the period of administration, CsA led to a decrease of Lyt 1 +/Lyt 2 + ratio in spleen cells and prevented the insulitis in low dose SZ-treated mice. However, at CsA withdrawal, a rebound of insulitis occurred with a higher intensity. Immunohistochemical phenotyping on frozen pancreatic sections revealed that Lyt 1 + lymphocytes predominated on Lyt 2 + cells in the rebound insulitis. In this model: (1) CsA impairs glucose stimulated insulin release and alters beta cells. This reversible toxic effect accounts for enhancement of SZ-induced diabetes; (2) insulitis was slackened by CsA but developed, as a rebound, with CsA withdrawal associated with a prominence of Lyt 1 + lymphocytes.

Treatment with the immunosuppressive agent cyclosporin A frequently gives rise to functional alteration of the islets of Langerhans which may result in diabetes. Light microscopy, immunocytochemical, and electron microscopy investigations demonstrate degranulation, vacuolization, and destruction of endocrine pancreatic cells in treated animals. Similar changes, but of a milder degree, are observed in the A-cells. The morphological alterations described are likely to be the result of inhibition of synthesis and secretion in B-cells.

Cyclosporin 5, 10, and 20 mg/kg bw was given to rats once daily intragastrically and caused a dose dependent, significant decrease of glucose dependent insulin release from the arterially perfused isolated pancreas, without affecting animal behaviour, weight gain, microscopic appearances of the pancreas, or kidney function. Subcutaneous injection of a new synthetic prostaglandin analogue Rioprostil 7.5 micrograms/kg bw twice daily completely prevented the effect of cyclosporin 5 mg/kg bw and protected significantly against the effects of cyclosporin 10 and 20 mg/kg bw.

High Cyclosporin A doses (50 mg/kg b.w.) were given male Wistar rats either homozygous for RT1a or RT1u. Both rat strains are characterized by a similar diminished body weight gain. Cyclosporin A exerted in both strains an increased fed plasma glucose, decreased glucose tolerance and diminished pancreatic insulin content, however, the Wistar rat strain with the MHC RT1u was more sensitive to the effect of Cyclosporin A, indicated by a more marked alteration of pancreatic B-cells and a delayed recovery after drug withdrawal. We concluded that the MHC modulated either the Cyclosporin A metabolism (degradation) or the pancreatic B-cell sensitivity to toxic damage.

Cyclosporin A toxicity on pancreatic B-cells and its prevention by rioprostil, a prostaglandin E1 analogue, were studied in the model of the isolated perfused pancreas of rats treated with both compounds for 8 days. At toxic doses of cyclosporin (10 and 20 mg/kg b.wt), the B-cells showed severe hydropic degeneration of the endoplasmatic reticulum and slight degranulation of the B-cells. Accordingly, the insulin secretion was markedly impaired. Administration of rioprostil ameliorated the insulin secretion significantly, but not the ultrastructural changes. At therapeutic levels of cyclosporin (5 mg/kg b.wt), the hydropic degeneration and the drop in insulin secretion were completely prevented by rioprostil. This observation might have therapeutic implications in the treatment of patients, in particular those undergoing pancreatic transplantation.

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.

The combined effects of cyclosporin (CYA) and prednisolone (PSL) on the function and morphology of pancreatic B cells of Wistar rats were investigated. Four 13-day treatment groups were compared; these were the O group (olive oil alone, p.o.), the P group (PSL 3 mg/kg/day, i.m.), the C group (CYA 20 mg/kg/day, p.o.), and the PC group (PSL 3 mg/kg/day, i.m. plus CYA 20 mg/kg/day, p.o.). Glucose tolerance was equally impaired in the C and PC groups. The pancreatic insulin content in the C group was 49.7% of that of the O group, whereas that in the PC group was 81.1%. Morphometric analysis using modified aldehyde-fuchsin staining revealed that 'percent beta-granule area' in the islet was 17.5%, 15.0%, 6.5%, and 7.8% in the O, P, C, and PC groups, respectively. Ultrastructurally, pancreatic B cells in the PC group showed CYA damage; however, a significant number of B cells exhibited hypertrophy of the rough endoplasmic reticulum and the Golgi apparatus, suggesting concomitant B cell hyperactivity in this group. These findings suggest that PSL does not aggravate the toxic effects of CYA on pancreatic B cells during short-term treatment; rather, it might be protective.