title: Tacrolimus reversibly reduces insulin secretion, induces insulin resistance, and causes islet cell damage in rats.
abstract: OBJECTIVE
  To investigate the diabetogenic effects of the immunosuppressive agent tacrolimus, the reversibility of these effects upon treatment discontinuation, and the underlying mechanisms in a rat model.
  
  
  METHODS
  60 healthy male rats were randomly divided into three groups for intragastric administration of tacrolimus either at 4 mg/kg/d or 2 mg/kg/d or an equal volume of normal saline (control). The treatment was administered for 5 months, followed by a 5-month period of no intervention. Fasting plasma glucose and insulin levels were used to calculate the homeostasis model assessment of ß-cell function (HOMA-ß) and insulin sensitivity index (ISI).
  
  
  RESULTS
  Tacrolimus treatment significantly increased blood glucose concentrations (p < 0.05) and lowered HOMA-ß and ISI (p < 0.01) in a time- and dose-dependent manner. Five months after tacrolimus treatment, significant islet cell injury was observed. However, 5 months after tacrolimus discontinuation, blood glucose concentrations significantly declined, HOMA-Î² and ISI levels significantly increased, and islet cell morphology noticeably improved.
  
  
  CONCLUSIONS
  In conclusion, tacrolimus treatment of healthy rats increased blood glucose concentrations in a time- and concentration-dependent manner. Development of tacrolimus-induced diabetes and reversibility after tacrolimus discontinuation may involve factors of and interactions between the insulin secretion pathway, local and/or systemic insulin resistance, and islet cell damage.
authors.forename: Chun
authors.initials: C
authors.lastname: Xu
authors.forename: Yu-Jian
authors.initials: YJ
authors.lastname: Niu
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Liu
authors.forename: Ya-Qin
authors.initials: YQ
authors.lastname: Teng
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Li
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Wang
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Yin
authors.forename: Le-Tian
authors.initials: LT
authors.lastname: Wang
authors.forename: Zhong-Yang
authors.initials: ZY
authors.lastname: Shen
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000633:toxicity*
chemical_list: D001786:Blood Glucose; D007166:Immunosuppressive Agents; D007328:Insulin; D016559:Tacrolimus