5-氟尿嘧啶诱导糖代谢和胰岛β细胞分泌功能异常

Abnormalities in glucose metabolism and pancreatic endocrine function induced by 5-fluorouracil in vitro and in vivo

目的:探讨化疗药物5-氟尿嘧啶(5-fluorouracil,5-FU)在体内外对糖代谢和胰岛β细胞功能的影响。方法:不同剂量5-FU(5.0、10.0、20.0和40.0mg/L)作用于NIT-1细胞,采用放射免疫法检测NIT-1细胞胰岛素分泌功能的变化。Wistar大鼠腹腔注射5-FU(20mg.kg-1.d-1,连续5d)后于第2天和第7天,分别行葡萄糖耐量试验,检测血糖,并采用放射免疫法检测胰岛素分泌水平。结果:在高浓度葡萄糖16.7mmol/L刺激下,5-FU5.0～20.0mg/L各组的NIT-1细胞胰岛素释放量依次下降,呈剂量依赖效应(P<0.01)。5-FU组处理后第2天和第7天,大鼠糖耐量曲线中所有检测时间点的血糖水平均明显高于对照组的血糖水平(P<0.01)。5-FU组第2天和第7天空腹胰岛素水平与对照组比较,差异无统计学意义(P>0.05)。5-FU组处理后第7天,糖负荷后60min时胰岛素释放水平为(25.32±6.07)mU/L,明显低于对照组的(33.98±4.94)mU/L(P<0.05),达到释放峰值的时间为120min,晚于对照组的60min。结论:5-FU引起的高血糖可能与其引起的高糖刺激下胰岛β细胞分泌胰岛素不足有关。

Objective：To explore the effects of 5-fluorouracil（5-FU） on glucose metabolism and the endocrine function of pancreatic beta-cells.Methods：The NIT-1 cells were treated with different concentrations（5.0,10.0,20.0 and 40.0 mg/L） of 5-FU.The insulin concentration in the culture medium was determined by radioimmunoassay.Twenty Wistar rats were divided into 5-FU group（intraperitoneally administered with 5-FU at a daily dose of 20 mg/kg for 5 days） and the control group（intraperitoneally administered with normal saline）.Glucose tolerance test was performed on d 2 and d 7 following 5-FU administration,and the plasma insulin concentration was determined by radioimmunoassay.Results：The high glucose（16.7 mmol/L）-induced release of insulin from NIT-1 cells was inhibited by 5.0 to 20.0 mg/L of 5-FU in a dose-dependent manner（P0.01）.Compared with the control group,on d 2 and d 7 following 5-FU administration,the plasma glucose levels were markedly increased at 30,60,120 and 180 min following a glucose load（P0.01）;however,the fasting plasma insulin levels were not significantly elevated or decreased（P0.05）.Postprandial plasma insulin level at 60 min following a glucose load on d 7 was significantly lower than that of the control group on d 2（25.32±6.07 vs 33.98±4.94,P0.05）.The peak secretion time of plasma insulin was delayed to 120 min.Conclusion：Hyperglycemia following 5-FU treatment appears to be related to a relative deficiency in insulin secretion response to glucose stimulation.