If diabetes occurs during TAC therapy, physicians should consider dose reduction, cessation of TAC administration, and use of alternative agents, such as cyclosporine, that have less diabetogenic potential than TAC. Additionally, a rapid tapering or cessation of corticosteroid also should be considered. The diabetogenic effect of TAC is usually considered to be dose dependent and reversible. Both insulin production and mRNA transcription completely recovered 7 days after the cessation of TAC in vitro; insulin secretion recovered when TAC concentration became <0.09 ± 0.11 ng/mL in rats. Furthermore, Sarkar et al reported a patient who showed recovered insulin secretion 12 weeks after cessation of TAC administration. In our case, endogenous insulin secretion and glycemic control improved dramatically 8 weeks after TAC withdrawal, consistent with previous reports.[3,15] Thus, our case also demonstrated that TAC-induced pancreatic beta cell toxicity is reversible and that insulin secretion recovers within several weeks of discontinuing TAC in vivo.
Since TAC is not only used as an immunosuppressant after organ or tissue transplantation but also for treating various inflammatory diseases, blood sugar levels should be routinely monitored in patients on TAC based on this case report and reported literatures. TAC-induced glycemic disorders including DKA might be life-threatening, even when trough levels of the drug are within the target range. In the future, accumulation of similar cases is necessary to analyze associated risks and background characteristics of TAC-induced DKA.
This study was not funded by any grants. The authors would like to thank Editage (Tokyo, Japan; www.editage.jp) for English language editing.
. Ammari Z, Pak SC, Ruzieh M, et al. Posttransplant tacrolimus
-induced diabetic ketoacidosis
: review of the literature. Case Rep Endocrinol 2018;2018:4606491.
. Tamura K, Fujimura T, Tsutsumi T, et al. Transcriptional inhibition of insulin by FK506 and possible involvement of FK506 binding protein-12 in pancreatic beta-cell. Transplantation 1995;59:1606–13.
. Sarkar S, Mondal R, Nandi M, et al. Tacrolimus
induced diabetic ketoacidosis
in nephrotic syndrome. Indian J Pediatr 2013;80:596–7.
. Wilkes MR, Sereika SM, Fertig N, et al. Treatment of antisynthetase-associated interstitial lung disease with tacrolimus
. Arthritis Rheum 2005;52:2439–46.
. American Diabetes Association. Hospital admission guidelines for diabetes mellitus. Diabetes Care 2003;26(suppl):S118.
. Starzl TE, Todo S, Fung J, et al. FK 506 for liver, kidney, and pancreas transplantation. Lancet 1989;2:1000–4.
. Tocci MJ, Matkovich DA, Collier KA, et al. The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. J Immunol 1989;143:718–26.
. Oetjen E, Baun D, Beimesche S, et al. Inhibition of human insulin gene transcription by the immunosuppressive drugs cyclosporin A and tacrolimus
in primary, mature islets of transgenic mice. Mol Pharmacol 2003;63:1289–95.
. Redmon JB, Olson LK, Armstrong MB, et al. Effects of tacrolimus
(FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion
in HIT-T15 cells. J Clin Invest 1996;98:2786–93.
. Wakasugi N, Uno S, Tanaka H, et al. Evaluation of treatment status and safety of tacrolimus
in patients with interstitial pneumonia
complicated with polymyositis or dermatomyositis. J N Remed Clin 2017;66:1237–49.
. Dittrich K, Knerr I, Rascher W, et al. Transient insulin-dependent diabetes mellitus in children with steroid-dependent idiopathic nephrotic syndrome during tacrolimus
treatment. Pediatr Nephrol 2006;21:958–61.
. Lanata CM, Mahmood T, Fine DM, et al. Combination therapy of mycophenolate mofetil and tacrolimus
in lupus nephritis. Lupus 2010;19:935–40.
. Webster AC, Woodroffe RC, Taylor RS, et al. Tacrolimus
versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ 2005;331:810.
. Montori VM, Basu A, Erwin PJ, et al. Posttransplantation diabetes: a systematic review of the literature. Diabetes Care 2002;25:583–92.
. Prokai A, Fekete A, Pasti K, et al. The importance of different immunosuppressive regimens in the development of posttransplant diabetes mellitus. Pediatr Diabetes 2012;13:81–91.