RESUMO
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. MATERIALS AND 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-β 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.