title: Tacrolimus in pancreas transplant: a focus on toxicity, diabetogenic effect and drug-drug interactions.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Tacrolimus is a potent calcineurin inhibitor, an important pathway that regulates pancreatic development. Tacrolimus can induce β-cell apoptosis, decrease insulin exocytosis and reduce insulin gene transcription, which ultimately lead to impaired functional β-cell mass after pancreas transplant. Furthermore, insulin resistance can exacerbate the diabetogenic effect of tacrolimus due to inhibition of insulin gene transcription and β-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.
authors.affiliation: Federal University of São Paulo, Nephrology Division, Transplant Unit , Rua Botucatu 740, 2nd floor, São Paulo , Brazil +55 11 59041699 ; +55 11 55739652 ; erikabr@uol.com.br.
authors.forename: Erika B
authors.initials: EB
authors.lastname: Rangel
mesh_terms: D000818:Animals; D065095:Calcineurin Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000139:chemically induced / Q000601:surgery; D004347:Drug Interactions; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016035:Pancreas Transplantation; D016559:Tacrolimus / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: hyperglycemia; new-onset of diabetes after transplant; pancreas transplant; post-transplant diabetes mellitus; tacrolimus