Metabolic Effects of Cyclosporin A and FK 506 in Liver Transplant Recipients

Abstract

Postoperative diabetes is a reported feature of the immunosuppressive agents cyclosporin A and FK 506. To date, however, no randomized comparative studies of the metabolic effects of these two drugs have been performed. In this study, extended (300 min) oral glucose tolerance tests (75 g) were performed a median of 8 mo (range 5–9 mo) postoperatively in 20 clinically stable liver transplant recipients randomly allocated to maintenance immunosuppression with either cyclosporin A (with or without azathioprine) or FK 506. None of the patients had clinically overt diabetes antedating transplantation. To avoid the confounding effects of corticosteroids, prednisolone was withdrawn at least 6 wk beforehand in each case. Ten healthy volunteers matched for age and body mass index served as control subjects. Overall blood glucose concentrations after the glucose challenge were significantly elevated in both groups of transplant recipients (P < 0.005 and P < 0.001 for cyclosporin A and FK 506 treatment groups, respectively) compared with the healthy control subjects. Venous whole-blood glucose concentration (mean ± SE) 120 min after the ingestion of oral glucose was significantly higher in both the cyclosporin A (P < 0.05) and FK 506 (P < 0.01) treatment groups compared with the control subjects (6.6 ± 0.5 vs. 8.8 ± 0.9 vs. 5.2 ± 0.2 mM, respectively). According to 1985 WHO criteria, 4 of 10 cyclosporin A-treated patients had impaired glucose tolerance, whereas 3 of 10 FK 506–treated patients had diabetes with 4 others having impaired glucose tolerance. Overall plasma immunoreactive insulin concentrations were significantly elevated in both the cyclosporin A (P < 0.05) and FK 506 (P < 0.01) groups, as were C-peptide concentrations (P < 0.02 and P < 0.01, respectively). By contrast, fasting lactate concentrations were significantly lower (P < 0.05) in the transplant patients compared with the control subjects. Total blood ketone body concentrations were slightly higher in both transplant groups with an increased ratio of 3-hydroxybutryate:acetoacetate in the cyclosporin A–treated (P < 0.01) and FK 506–treated (P < 0.02) patients. In conclusion, successful liver transplantation in humans is associated with significant postoperative glucose intolerance and hyperinsulinemia. These metabolic abnormalities are independent of corticosteroid therapy and are more pronounced in patients treated with FK 506 than in comparable patients receiving cyclosporin A with or without azathioprine. Alterations in the circulating ketone body ratio suggest a relatively more reduced hepatic intramitochondrial redox state in liver transplant recipients treated with these immunosuppressive agents.