[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.
Ippoliti
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GB
Dipartimento di Medicina Interna AO della provincia di Pavia, Divisione di Medicina Interna, Ospedale Civile di Voghera (PV), Italy. giovanbattista-ippoliti@asl.pavia.it
Viganò
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M
D000818:Animals; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism; D021983:Cyclophilins / Q000378:metabolism; D016572:Cyclosporine / Q000009:adverse effects* / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000139:chemically induced*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced; D005089:Exocytosis / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D016030:Kidney Transplantation; D051379:Mice; D011183:Postoperative Complications / Q000139:chemically induced*; D011446:Prospective Studies; D051381:Rats; D016559:Tacrolimus / Q000009:adverse effects* / Q000494:pharmacology; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D007328:Insulin; D016572:Cyclosporine; D021983:Cyclophilins; D022061:Tacrolimus Binding Protein 1A; D002118:Calcium; D016559:Tacrolimus