Evaluating mechanisms of post-transplant diabetes mellitus

Abstract

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.

Glucose Metabolism in Renal Transplant Recipients

“…Posttransplantation diabetes is believed to be multifactorial, probably involving ␤ cell toxicity and increased insulin resistance (5,6). In addition to other risk factors, studies suggest that immunosuppressive regimens may account for a large degree of the increased risk for development of posttransplantation diabetes (1,3,4,7).…”

Influence of Early Posttransplantation Prednisone and Calcineurin Inhibitor Dosages on the Incidence of New-Onset Diabetes

“…Limited animal data and one trial suggested a dosage-dependent relationship (18,19), but in a meta-analysis of 35 trials, Heisel et al (7) failed to find any evidence of dosage dependence between Tac and NOD. Newer research suggested that once a patient develops NOD, it can often be reversed or its severity decreased by reducing the dosage of Tac and steroids (20,21), but these studies were unable to separate the effect of steroids and CNI.…”

Transplante de pâncreas e ilhotas em portadores de diabetes melito

“…No transplante renal isolado, o tacrolimo está associado à diminuição da secreção da insulina, o que tem correlação inversa com seu nível sérico (46)(47)(48). Nas primeiras três semanas após o transplante, ocorre redução em torno de 50% na secreção de insulina e do peptídeo C pelo pâncreas nativo (48,49).…”

“…Nas primeiras três semanas após o transplante, ocorre redução em torno de 50% na secreção de insulina e do peptídeo C pelo pâncreas nativo (48,49). No pâncreas transplantado, o tacrolimo também reduz a secreção de insulina de maneira dose-dependente, além de promover o edema citoplasmático, a vacuolização e a apoptose das ilhotas (50).…”