氟尿嘧啶对大鼠血糖代谢及胰腺病理结构的影响

Impact of 5-fluorouracil on glucose metabolism and pancreatic pathology in rats

目的 探讨结直肠癌常用化疗药物5-氟尿嘧啶（5-FU）对大鼠血糖代谢及胰腺病理结构的影响.方法 20只Wistar大鼠分为5-FU组（10只,腹腔注射5-FU 20 mg·kg-1·d-1,连续5 d）和对照组（10只,相同时间和相同剂量的生理盐水腹腔注射）,给药后第2和第7天行糖耐量试验,并以放射免疫法检测胰岛素分泌水平;以光镜和透射电镜分别观察胰岛细胞组织病理学及超微结构的变化.结果 给药后第2天,5-FU组和对照组空腹血糖分别为（7.6±1.9）和（4.6±0.6）mmol/L;给药后第7大,两组空腹血糖分别为（8.9±1.0）和（4.7±0.6）mmol/L,差异均有统计学意义（P＜0.01）.胰岛素分泌试验：5-FU注射后第2天,糖负荷后胰岛素释放缓慢,30 min时胰岛素水平低于对照组水平,60 min达到峰值,与对照组水平相当,其后下降较对照组缓慢,120和180 min时胰岛素分泌量高于对照组;5-FU注射后第7天,糖负荷后60 min胰岛素水平低于对照组,120 min方达到峰值,180 min时高于对照组水平.光镜下,5-FU处理后糖耐量异常的大鼠胰腺组织中未见明显病理学异常;透射电镜部分大鼠可见胰岛内分泌细胞内胰岛素颗粒减少,极少数可见内质网扩张、线粒体肿胀,溶酶体出现脂滴.结论 5-FU所导致的高血糖与其引起的胰岛素相对分泌不足有关.5-FU通过部分改变胰岛细胞超微结构引起β细胞功能受损可能是胰岛素分泌不足的原因.

Objective To explore the impact of 5-fluorouracil （5-FU） on glucose metabolism and pancreatic pathology. Methods Twenty Wistar rats were divided into 5-FU group （n =10,chemotherapy was administered intraperitoneally to animals at a dose of 20 mg/kg daily for continuous 5 days） and control group （n=10, sodium chloride was administered intraperitoneally to animals with the same dose at the same time ）. Glucose tolerance was evaluated 2 and 7 days following 5-FU treatment by serial measurement of blood glucose before and after an oral glucose load. Plasma insulin concentration was determined by radioimmunoassay. Pancreatic pathology was examined with morphological method and the ultrastructural changes of β cells were observed by transmission electron microscope. Results Fasting blood glucose level was significantly higher in the 5-FU group than that in the control group [（7.6±0.9） mmol/L vs. （4.6±0.6） mmol/L at day 2; （8.9±1.0） mmol/L vs. （4.7±0.6） mmol/L at day 7, P〈0.01]. Insulin releasing test indicated that the early phase insulin response to glucose load was significantly diminished in animals treated with 5-FU at day 2. Insulin level was significantly lower in the 5-FU group than that in the control group at 30 min （P〈0.01）. The peak secretion time of plasma insulin in 5-FU group was at 60 min, similar to the control group; and plasmainsulin level decreased more slowly. Plasma insulin level was higher in 5-FU groups than in control groups on 120 min and 180 min. At day 7, Insulin level was lower in the 5-FU group than that in the control group on 60 min, and the peak secretion time of plasma insulin was delayed to 120 min. Plasma insulin level was significantly increased in 5-FU group than that in control group on 180 min （P〈0.01）.No gross histopathological damage to the pancreas was observed at day 2 and 7 following administration of 5-FU. The structural changes of mitochondria were mainly the quantities of secretory granule diminished at day 7 under transmission electron microscope. Dilated rough endoplasmic reticula, swollen mitochondria,and the presence of adipose drops in lysosomes were found in few cells. Conclusions 5-FU-induced hyperglycemia appears to be mediated in part by a relatively deficient insulin secretion to glucose stimulation. A relative deficiency in insulin secretion following 5-FU treatment appears to be related to β cells function impairs with islet cell ultrastructural changes induced by 5-FU.