Effect of immunosuppressive doses of cyclosporine on pancreatic beta cell function in pigs.
OBJECTIVE
To evaluate whether immunosuppressive doses of cyclosporine (CsA) have an adverse effect on the liver, kidney, and pancreatic beta cells of pigs.


METHODS
8 juvenile 8-week-old Landrace X Large White crossbred pigs.


METHODS
CsA (100 to 140 mg/kg) was administered orally to euglycemic pigs to reach whole blood trough concentrations of approximately 1500 ng/mL. To determine pancreatic beta cell function, plasma C-peptide and insulin concentrations were measured in response to i.v. administration of glucose, glucagon, arginine, and oral administration of glucose. Effects on liver and kidney were determined by monitoring serum measurements of liver function and serum creatinine concentrations, respectively.


RESULTS
Plasma concentrations of C-peptide were significantly lower in euglycemic CsA-treated pigs, compared with control pigs, following i.v. administration of glucose, glucagon, arginine, and oral administration of glucose. Furthermore, the glucose clearance rate was decreased in euglycemic CsA-treated pigs, compared with control pigs. Serum creatinine concentrations and 4 of 7 serum measurements of liver function were not adversely affected by CsA administration. Serum concentrations of bilirubin and albumin were significantly increased, and serum alanine aminotransferase activity was significantly decreased in CsA-treated pigs, compared with control pigs. Histologic evaluation of liver and kidney sections revealed no pathologic findings in CsA-treated or control pigs.


CONCLUSIONS
In our study, immunosuppressive doses of CsA caused an impairment of porcine pancreatic beta cell function, but did not have toxic effects on the kidney. However, on the basis of changes in serum bilirubin and albumin concentrations and alanine aminotransferase activity, subclinical toxic effects on the liver did occur when immunosuppressive doses of CsA were administered.
Dean
Sophia K
SK
Diabetes Transplant Unit, Prince of Wales Hospital, University of New South Wales, Sydney, Australia.
Scott
Hayley
H
Keogh
Gregory W
GW
Roberts
Simon
S
Tuch
Bernard E
BE
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001120:Arginine / Q000378:metabolism; D001663:Bilirubin / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000009:adverse effects* / Q000494:pharmacology; D005934:Glucagon / Q000378:metabolism; D005951:Glucose Tolerance Test / Q000662:veterinary; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests / Q000662:veterinary; D012709:Serum Albumin / Q000378:metabolism; D013552:Swine / Q000276:immunology* / Q000378:metabolism
D001786:Blood Glucose; D007166:Immunosuppressive Agents; D007328:Insulin; D012709:Serum Albumin; D016572:Cyclosporine; D002097:C-Reactive Protein; D005934:Glucagon; D001120:Arginine; D003404:Creatinine; D000410:Alanine Transaminase; D001663:Bilirubin