Tacrolimus in pancreas transplant: a focus on toxicity, diabetogenic effect and drug-drug interactions

Introduction: With further reduction in surgical complications and improvement in immunosuppressive protocols, pancreas transplant offers excellent outcomes for patients with diabetes. However, long-term survival of pancreas allograft is affected not only by rejection but also by immunosuppressive regimen toxicity. Areas covered: This article reviews the existing literature and knowledge of tacrolimus toxicity and focuses on its diabetogenic effect after pancreas transplant. Some clinically relevant drug-drug interactions with glucocorticoids and sirolimus are also highlighted. This review also summarizes the diabetogenic mechanisms of tacrolimus, the alternatives to minimize these effects, and the main differential diagnosis of hyperglycemia after pancreas transplant. Expert opinion: Tacrolimus is a potent calcineurin inhibitor, an important pathway that regulates pancreatic development. Tacrolimus can induce beta-cell apoptosis, decrease insulin exocytosis and reduce insulin gene transcription, which ultimately lead to impaired functional beta-cell mass after pancreas transplant. Furthermore, insulin resistance can exacerbate the diabetogenic effect of tacrolimus due to inhibition of insulin gene transcription and beta-cell proliferation. It is important to critically analyze the results of clinical studies and investigate new immunosuppressive drugs and/or novel drug combinations. It is equally important to comprehend and interpret experimental data. Therefore, minimization of side effects, based on safe approaches, can prolong pancreas allograft survival.