Abstract: Objective To investigate potential mechanism of different doses of tacrolimus leading to the elevated blood glucose in rats. Methods Twenty SD rats were randomly divided into low dose group (0.1 mg/kg), middle dose group(0.5 mg / kg), high dose group (1.0 mg / kg) and control group (n = 5 for each group). The first three groups were injected subcutaneously with tacrolimus for one week, and the control group was given equal volume olive oil. Body weights of the rats were monitored every other day. After 1 week of drug intervention, intraperitoneal glucose tolerance test (2 g / kg) was performed. The fasting blood glucose (FBG), fasting insulin (FINS) and insulin resistance index (HOMA-IR) under steady state model were counted. Pathological tissue sections prepared from the tail of rat pancreas. The area of islet β cells was measured by immunohistochemical staining, and the expressions of insulin-secreting genes Epac, Rim2, Piccolo, Rab3a and Munck13 in islet tissue were detected by real-time quantitative PCR. Results Compared with the control group, the body mass decreased in tacrolimus intervention group, and the decreased weights were larger in middle and high dose groups than that of low dose group. Abnormal glucose tolerance was found in tacrolimus intervention group, and blood glucose level and area under curve were higher in middle and high dose groups than those in low dose group with a dose-dependent manner(P＜0.05). There were no significant differences in FBG, FINS and HOMA-IR between the four groups (P＞0.05). The results of immunohistochemistry showed that the number of β cells was not significantly decreased in the middle and high dose group than that of control group (P＜0.05), but there was no significant difference between the low dose group and the control group (P＞0.05). The transcription levels of secretory related proteins Epac, Rim2, Piccolo, Rab3a and Munck13 were decreased in low dose group compared with those of the control group (P＜0.05). Conclusion The abnormal glucose tolerance caused by low dose short-term intervention is related to the disorder of insulin secretion when the number of islet β cells does not decrease and there is no insulin resistance.

Key words: diabetes mellitus, insulin-secreting cells, glucose intolerance, rats, sprague-dawley, tacrolimus