Tacrolimus reversibly reduces insulin secretion in paediatric renal transplant recipients

Background. Conflicting reports exist about the mechanism of tacrolimus-induced post-transplant diabetes mellitus. Methods. We analysed intravenous glucose tolerance tests (IVGTT) of 14 paediatric renal transplant recipients on cyclosporin (CsA) microemulsion and 15 patients on tacrolimus (FK506). The groups were similar in age (13.2+/-4.2 vs 13.0+/-3.7 years), body mass index, serum creatinine concentrations (96+/-60 vs 97+/-44 mu mol/l), time after renal transplantation, and cumulative steroid dose over 12 weeks prior to the test (3.4 vs 3.5 mg/m(2)/day, NS, Mann-Whitney). Parameters of glucose tolerance included glucose, insulin, C-peptide concentrations, and RbA1c. The mean concentrations of the primary immunosuppressant were similar to treatments employed in other centres (CsA 165+/-59 ng ml and FK506 7.5+/-2.2 ng ml). Results. Baseline glucose concentrations were significantly higher on FK506 therapy compared with CsA microemulsion therapy. Baseline insulin concentrations and C-peptide concentrations were identical in both treatment groups. FK506 trough levels correlated negatively with k values (glucose constant decay) in the FK506 group. There was a significant reduction of the insulin first-phase concentrations, both after 1 min and after 3 min in the FK506 group compared with the CsA group (112+/-17 vs 237+/-57 mu U/ml, P = 0.034). In patients with repetitive IVGTTs, glucose constant decay and insulin production improved after lowering FK506 whole-blood trough levels. Conclusions. We conclude that post-transplant glucose intolerance could be due to a dose-dependent, direct effect of FK506 on the pancreatic beta cell function, which can be controlled by dose reduction.