摘要
目的①了解长期高脂喂养的伴胰岛素抵抗糖尿病(diabetes mellitus,DM)大鼠肝脏的病理改变;②了解糖尿病大鼠肝脏c-Jun氨基末端激酶(c-Jun N–terminal kinase,JNK)表达的变化;③了解胰岛素增敏剂对伴胰岛素抵抗的糖尿病大鼠肝脏JNK信号通路的影响。
方法将长期高脂喂养、伴胰岛素抵抗(insulin resistance,IR)的DM大鼠随机分为模型组,吡格列酮组(PIO,10mg/kg/d)和二甲双胍组(MET,160mg/kg/d),治疗6周后颈椎脱臼处死大鼠。留取肝脏标本。对肝脏进行HE染色,免疫组化检测JNK及磷酸化c-Jun氨基末端激酶(c-JunN–terminal kinase phosphorylation, p-JNK)分布及表达;逆转录聚合酶链反应(reverse transcription-polymerase chain raction RT-PCR)测定JNK-mRNA在肝脏中的表达。Western免疫印迹方法定量分析肝脏JNK,p-JNK蛋白的表达。
结果①肝脏HE染色显示:模型组肝细胞肿胀、脂肪变性,存在炎细胞浸润,部分出现点、灶状坏死。二甲双胍组和吡格列酮组肝细胞病理改变明显减轻。②免疫组化:对照组肝脏JNK及p-JNK表达甚微。在肝脏中JNK,p-JNK蛋白表达量以及p-JNK/JNK,模型组显著高于对照组,高于吡格列酮组和二甲双胍组;吡格列酮组和二甲双胍组高于对照组,差异有显著性(P<0.05)。吡格列酮组和二甲双胍组相比,差异无显著性(P>0.05)。③RT-PCR:在对照组中肝脏JNK-mRNA几乎不表达。肝脏JNK-mRNA在模型组表达显著高于对照组,高于吡格列酮组和二甲双胍组;吡格列酮组和二甲双胍组高于对照组。④Werstrn Blot:对照组肝脏JNK,p-JNK蛋白表达量较低。肝脏JNK,p-JNK蛋白表达量及p-JNK/JNK,模型组显著高于对照组,高于吡格列酮组和二甲双胍组;吡格列酮组和二甲双胍组高于对照组,差异有显著性(P<0.05)。吡格列酮组和二甲双胍组相比,差异无显著性(P>0.05)。
结论长期高脂饮食伴IR的糖尿病大鼠可出现肝细胞肿胀,脂肪变性,炎细胞浸润及局灶性坏死,且肝脏免疫组化JNK-mRNA,JNK及p-JNK蛋白表达量均明显增加。二甲双胍和吡格列酮治疗可改善2型糖尿病引起的早期肝脏损害,该作用可能是通过抑制JNK信号通路的活性,减少JNK,p-JNK表达来实现的。
Objective :①.To analyse pathologic changes in the liver of experimental diabetic rats;②.To study activation of JNK and transcription of JNK signalling pathway in hepatic of diabetic rat;③.To investigate the effects of insulin-sensitizing agent on JNK signalling pathway in hepatic ,induced by diabetic concomitancy insulin resistance.
Methods :T2DM with insulin resistance rat model was established by high fat/ high glucose diet. Four groups of diabetic rat included normal control (NC, n = 12) ,models(DM,n=9),models with Pioglitazone (Pioglitazone,10mg/kg/d,PIO,n=10) and with Metformin(Metformin,160mg/kg/d,MET,n=11) treatment for 6 weeks, then sacrificed by dislocating the cervical vertebrae.The liver specimens were harvested. Hematoxylin and eosin-staining, and expression of JNK, p-JNK protein was measured by immunohistochemical technique.Reverse transcription polymerase chain reaction (RT-PCR) were used to evaluate JNK mRNA of liver expression. The level of JNK, p-JNK proteins of liver was analyzed by Western blot.
Results:①Pathological changes of liver structure:We observed the pathological changes of rat liver tissue in the diabetes mellitus group (DM), and found that,compared with normal control group(NC), hepatic cells were swollen and developed granular degeneration, fatty degeneration;hepatic cells appeared many necrotic areas, inflammatory cell infiltration. Compared with DM group, in the PIO and MET groups , liver cell cords were clear, liver antrum almost recovered to normal, hepatic cells developed slightly granular degeneration.②Immunol histochemistry(IHC):There was was little JNK and P-JNK expression in the liver of NC group. JNK, p-JNK proteins expression and the ratio of p-JNK protein expression level to JNK protein expression level (p-JNK /JNK) of liver in DM group increased dramatically when compared with that in NC group, increased when compared with that in PIO group and MET group;that in PIO group and MET group increased in contrast to that of NC group ,with statistical significance(P<0.05). That in PIO group compared with MET group had no statistical significance(P> 0.05).③RT-PCR: There was almost no JNK mRNA expression in NC group.The JNK mRNA expression in DM group increased dramatically when compared with that in NC group.JNK mRNA expression level of PIO group and MET group decreased remarkably in contrast to that of DM group ,but increased in contrast to that of NC group..④Western Blot: P-JNK and JNK protein expression of DM group increased dramatically when compared to that of NC group,and the difference was statistically significant(P<0.05),increased when compared with that of PIO group and MET group,with statistical significance (P<0.05).The ratio of JNK protein expression level to P-JNK protein expression level in DM group increased dramatically when compared to that of NC group,and the difference was statistically significant(P<0.05),increased when compared with that of PIO group and MET group,with statistical significance(P<0.05).JNK and P-JNK protein expression level and their ratio in PIO group and MET group increased when compared with that of NC group,and there was statistical significance(P>0.05).
Conclusions :High fat/ high glucose diet and T2DM would induce that hepatic cells were swollen and developed granular degeneration, fatty degeneration;hepatic cells appeared many necrotic areas,inflammatory cell infiltration.Treatment of PIO and MET can decrease the liver damage induced by T2DM in rats. This effect may be attributed to the inhibition of the JNK signalling pathway activation to decrease JNK , p-JNK expression.
引文
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