[Calcineurin inhibitors and mechanisms that are responsible for the appearance of post-transplant diabetes mellitus].

Calcineurin (CaN), a calmodulin-dependent heterodimer, is, together with NAF-T, involved in the regulation of the Ca++ pump and in the transmission of the activation signal of the immune response. The CaN inhibitor drugs, such as cyclosporin A (CyA), carried by cyclophillin, and tacrolimus, carried by FK-binding protein-12 (FKBP-12), inhibit the binding with the regulatory subunit CaNB. A meta-analysis, comparing tacrolimus with cyclosporin A, has evidenced that tacrolimus significantly increases the diabetes prevalence one year after renal transplant. The diabetogenic effect is due to a direct effect of both drugs on the beta pancreatic cell, in particular on intracellular Ca++ metabolism, which is involved in the insulin secretion and in the reduction of the number of the secretor granules. Some immunological-hystochemical studies, performed on murine pancreas, have evidenced that the FKBP-12 content is higher in beta cells than in alpha cells. This fact allows a high intracellular store of tacrolimus, and a consequently more toxic effect, inside the insulin secreting structures. On the contrary, the low FKBP-12 content of alpha cells involves a higher content of calcineurin and a higher resistance to toxic effects. Finally, an increased incidence of islet cell antibodies (ICA) has been evidenced in patients treated with tacrolimus, as opposed to those treated with CyA.