Effect Of Tacrolimus On Blood Glucose In Rats And Its Mechanism

ObjectivePost transplantation diabetes mellitus refers to a previous organtransplantation without diabetes, but postoperative disorders of carbohydratemetabolism, impaired fasting glucose, impaired glucose tolerance and diabetes,which is one of the most common complications after transplantation.PTDM can lead to increased incidence of cardio-cerebro-vasculardiseases, postoperative recurrent infections, graft loss function, which brings adecreased quality of life and long time suivival. A large amount of clinicalstudies show that: age, race, obesity, family history of diabetes, hepatitis Cinfection, corticosteroid dosage are risk factors of PTDM, and the application ofcalcineurin inhibitors (cyclosporine A and tacrolimus) is the main factors leadingto PTDM, of which the exact mechanism is still unclear,.The study aims toexplore the mechanism of tacrolimus causing PTDM by observng the effects ofdifferent concentrations of FK506on plasma glucose and insulin levels in rats.MethodPhase1:60male SD rats (87.5±7.6g) were randomly divided into threegroups,20rats in each group. Group A: high concentration of tacrolimus,dosage4mg/kg·d; Group B: low concentration of tacrolimus, dosage2mg/kg·d; group C: blank control group, the equal amounts of saline weregiven. All the rats were orally administered fastingly, and fed1hours later. Ratbody weight were measured weekly, and the fasting blood glucose andtacrolimus concentration were monitored monthly. After5months,10rats were randomly killed in fasting state in each group, cardiac punctured for blood,4%paraformaldehyde perfused in vivo for pancreas tissue. Serum insulin levelswere detected by radioimmunoassay method, Pancreatic tissue were forhistopathological observation. SPSS17.0statistical analysis software wereused for data analysis.Phase2: the remaining rats were renumbered: group a, group b, group c,corresponding to the original group of high concentration, low concentrationand blank control group, all the rats were placed on the same condition asbefore. blood glucose were also monitored monthly, another5months later,allthe remaining rats were treated as before.ResultPhase1：1.The blood tacrolimus concentrations in group A were significantly higherthan those in the group B, and the difference was statistically significant（P＜0.01）2. The blood glucose levels in group A and group B were significantlyhigher than those in the control group（P＜0.05）3. The insulin secretion index and sensitivity index in group A weresignificantly lower than those in C group(P <0.01)4. Compared with the control group, group A and B rats showed decreasedpancreatic islet cells numbers, and obvious necrosis and vacuolization.Phase2:1.The blood glucose levels decreased gradually in group a and b, and atthe end of the experiment, three groups rats showed no different blood glucoselevels (P <0.05).2. The insulin secretion index and sensitive index in group a and b wereslightly lower than that in group c, but the difference was not statisticallysignificant (P>0.05). 3. Compared with the control group, group a and b rats presented a smallamount of vacuoles,but no obvious necrosis.ConclusionTacrolimus can induce pancreatic islet cells necrosis, reduce insulinsecretion, increase insulin resistance,which lead to elevated blood glucose inrats. The glycemic effect is time-dependent and concentration-dependent, andreversible, which embodies restored glucose level and islet function aftertreatment discontinued.