Tacrolimus type 2 diabetes

The exact mechanisms of tacrolimus-induced diabetes are unknown. In one renal transplant patient with genetic susceptibility, tacrolimus was associated with insulin-dependent diabetes mellitus and the simultaneous occurrence of anti-glutamic acid decarboxylase antibody (54). Within 2 months after conversion from tacrolimus to ciclosporin, the antibody was no longer detected and the patient s insulin requirements fell dramatically. Tacrolimus-induced direct beta cell toxicity, with subsequent development of beta cell autoimmunity, was therefore suggested as a possible mechanism in patients with genetic susceptibility for type I diabetes. 

In a meta-analysis of 16 studies of patients who were taking tacrolimus (n — 1636) or ciclosporin (n = 1407) the incidence of type 1 diabetes mellitus was significantly higher among those taking tacrolimus (10% versus 4.5%)... 

Toxicity The principal adverse reactions to cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, hyperhpidemia, and gum hyperplasia. Hyperuricemia may lead to worsening of gout, increased P-glycoprotein activity, and hypercholesterolemia. Nephrotoxicity occurs in the majority of patients treated and is the major indication for cessation or modification of therapy. Hypertension occurs in -50% of renal transplant and almost all cardiac transplant patients. Combined use of calcineurin inhibitors and glucocorticoids is particularly diabetogenic, although this apparently is more problematic in patients treated with tacrohmus see below). Especially at risk are obese patients, African American or Hispanic recipients, or those with family history of type 2 diabetes or obesity. Cyclosporine, as opposed to tacrolimus, is more hkely to produce elevations in low-density lipoprotein (LDL) cholesterol. 

Clinical uses and pharmacokinetics Use of these immunosuppressants is a major factor in the success of solid organ transplantation. Cyclosporine is used in solid organ transplantation and in graft-versus-host syndrome in bone marrow transplants. Tacrolimus is used in liver and kidney transplant recipients and may be effective as rescue therapy in patients who fail standard therapy. Sirolimus is used alone or in combination with cyclosporine in kidney and heart transplantation. The agents, particularly cyclosporine, may also be effective in immune diseases, including rheumatoid arthritis, uveitis, psoriasis, asthma, and type 1 diabetes. 

Susceptibility factors Genetic There is a high incidence of new-onset diabetes melli-tus in transplant patients taking tacrolimus. One predisposing factor may be a polymorphism in the calpain-10 gene, which has previously been associated with an increased risk of type 2 diabetes in the general population. In 214 kidney transplant... 

---