Evaluating mechanisms of post-transplant diabetes mellitus

Post-transplant diabetes mellitus (PTDM) is a frequent complication in renal transplantation. While both tacrolimus and ciclosporin are known to be associated with PTDM, the mechanisms underlying this metabolic disturbance and the relative contribution of concomitant corticosteroids have been unclear. At the University Hospital Maastricht, a series of studies have been conducted to investigate these issues. Administering tacrolimus to non-diabetic, dialysis patients was shown to result in a dose-related reduction in insulin secretion without altering insulin resistance. The patients who developed diabetes after transplantation already had impaired glucose metabolism pre-transplant. In a second study, corticosteroid withdrawal from tacrolimus-based immunosuppression reduced insulin resistance without changing insulin secretion. Moreover, reducing tacrolimus blood levels by 30% within the therapeutic window increased both insulin and C-peptide secretion by 24 and 36%, respectively. Accordingly, the effects of tacrolimus on insulin secretion are both dose dependent and reversible. A comparison of the effects of tacrolimus and ciclosporin on glucose metabolism revealed reduced insulin release with tacrolimus at week 3 post-transplant, but for the remainder of the 3 year follow-up there were no significant differences between the two treatment arms. Also, no difference was reported in glucose metabolism following conversion of stable renal recipients from ciclosporin to tacrolimus. Therefore, replacing tacrolimus with ciclosporin in patients experiencing glucose metabolism disturbances is unlikely to be helpful. In a recent study, early corticosteroid withdrawal from tacrolimus-based therapy resulted in a significantly lower incidence of new-onset diabetes mellitus than that achieved with a corticosteroid dose-tapering regimen. In conclusion, corticosteroid minimization plus dose-optimized tacrolimus immunosuppression is likely to be the best option for patients at risk of developing PTDM.