二甲双胍对直肠异常隐窝病灶抑制作用的研究

[目的]探讨二甲双胍对直肠异常隐窝病灶(Aberrant Crypt Foci,ACF)的抑制作用及其可能机制.[方法]入选经消化内镜发现直肠ACF的非糖尿病患者86例,随机分成二甲双胍组、塞来昔布组及对照组.二甲双胍组口服二甲双胍500 mg 2次/d,塞来昔布组口服塞来昔布200 mg 2次/d,对照组不服用二甲双胍及塞来昔布.在治疗前及治疗后2个月行肠镜检查,予0.4%美兰染色直肠,用放大肠镜观察直肠中亨氏瓣到齿状线之间的ACF个数及形态,分析各组直肠ACF个数在治疗前、后的变化.同时用活检钳在直肠上亨氏瓣到中亨氏瓣之间随机取得直肠正常黏膜处的标本,应用PCNA(proliferating cell nuclear antigen)免疫组化染色及TUNEL(transferase deoxynucleotidyl uridine end labeling)染色法检测直肠正常黏膜的增殖及凋亡情况.[结果]3组治疗前ACF均数及临床特征比较均差异无统计学意义(P>0.05).二甲双胍组、塞来昔布组的ACF均数分别从治疗前的7.30±2.51、7.60±2.34减少至治疗后的4.77±1.57、5.83±1.46(P<0.05),且相对于塞来昔布组,二甲双胍组对ACF的抑制作用更明显(P<0.05).对照组的ACF均数在治疗前后分别为7.40±2.11、7.43±2.13,差异无统计学意义(P>0.05).二甲双胍组、塞来昔布组的增殖指数分别从治疗前的48.87±1.78、49.93±2.59减少至治疗后的27.20±1.71、36.97±1.43(P<0.05),且二甲双胍组显著低于塞来昔布组(P<0.05).对照组的增殖指数在治疗前后分别为49.17±2.35、49.23±2.42,差异无统计学意义(P>0.05).3组治疗后的凋亡指数分别为3.00±1.14、2.93±0.78、3.07±1.08,与本组治疗前相比均差异无统计学意义(P>0.05).[结论]二甲双胍及塞来昔布对非糖尿病患者的直肠ACF均具有抑制作用,且二甲双胍的作用优于塞来昔布,其机制可能是通过直接作用(非胰岛素依赖)来抑制组织细胞的增殖.

Inhibitory effect of metformin on rectal aberrant crypt foci

[Objctive]To investigate inhibitory efects of metformin on rectal aberrant crypt foci(ACF)and its possible mechanism.[Methods]We prospectively enrolled 90 nondiabetic patients with ACF which had been treated with metformin(500 mg bid,n=30),celecoxib(200 mg bid,n=30)or without any treatment(control,n=30).The lower rectal region from the middle Houston valve to the dentate line was sprayed with 0.4%methylene blue,the number of rectal ACF and its formation were counted by a magnifying colonoscopy in every patients at a baseline and after 2 months'treatment.Normal rectal epithelium samples were obtained from the same trial patients by biopsy before and after treatment.Proliferation of normal rectal epithelium was detected by proliferating cell nuclear antigen(PCNA)labeling index and apoptosis was detected by terminal deoxynucleotidyl dUTP nick-end labeling(TUNEL).[Results]The mean number of ACF and other baseline clinical characteristics in three groups were similar at baseline(P>0.05).After 2 months,the mean number of ACF was significantly suppressed in the metformin group and celecoxib group,whereas,no such difference was observed in the control group.In the metformin group,the mean number of ACF was significantly lower,respectively,in comparison with celecoxib group(P<0.05).The proliferating cell nuclear antigen index of normal rectal epithelium was significantly decreased in metformin and celecoxib groups,but not in control group.Furthermore,the proliferating cell nuclear antigen index in metformin group was even markedly lower compared with that in celecoxib group.However,the apoptosis index(AI)remained unaltered in all groups before and after treatment.[Conclusion]Metformin and celecoxib can suppress rectal ACF in nondiabetic patients.Moreover,the chemoprevention of metformin is more effective than celecoxib.Its mechanism may be related to the inhibition of cell proliferation,suggesting that metformin exerts an insulin-independent direct mechanism of action.