背景:肝硬化患者中糖耐量受损和糖尿病的患病率远高于普通人群。然而,这些患者的糖尿病管理缺乏具体的指导方针,特别是在早期阶段。已发现胆汁辅助(BA)在控制脂质和葡萄糖代谢中发挥激素样功能。我们研究了熊去氧胆酸(UDCA)对胆管结扎(BDL)引起的肝硬化大鼠葡萄糖水平的影响。
方法:SD大鼠分为3组:假手术组(A组);BDL组(B组),和UDCA加BDL(C组)。4周后,进行口服葡萄糖耐量试验.血清生化指标和葡萄糖水平,胰岛素,并测定胰高血糖素样肽1(GLP-1)。观察肝脏和胰岛的组织病理学。胆固醇7α-水解酶(CYP7A1)基因表达,肝脏中的微粒体氧固醇7a-羟化酶(CYP7B1),通过实时PCR测定肠道中的武田G蛋白偶联受体5(TGR5)。
结果:与A组相比,空腹血糖和餐后1h和2h血糖水平略有升高(均P>0.05),餐后2h胰岛素水平显著升高(P<0.05),B组餐后15minGLP-1水平下降(P<0.05),与B组相比,空腹血糖和餐后1小时血糖水平下降(均P<0.05),餐后2h胰岛素水平下降(P<0.01),C组餐后15分钟GLP-1水平升高(P<0.05)。BDL诱导的肝纤维化得到缓解,胰岛面积增加(P<0.05)。与A组相比,CYP7A1和CYP7B1mRNA在肝脏中的表达增加,B组肠组织中TGR5的mRNA表达降低(均P<0.05)。与B组相比,肝脏CYP7A1和CYP7B1的mRNA表达降低,C组肠道TGR5升高(P<0.05)。
结论:BDL4周后,大鼠出现肝纤维化和糖代谢异常。UDCA给药改善肝纤维化,增加胰岛面积,降低葡萄糖水平,抑制BA合成中的基因,增强TGR5基因在肠道中的表达,进一步改善了胰岛功能。
BACKGROUND: The prevalence of impaired glucose tolerance and diabetes is much higher in people with cirrhosis than that in the general population. However, there are inadequate concrete guidelines for the management of diabetes in these patients, particularly in the early stage. Bile aids (BAs) have been found to exert hormone-like functions in the control of lipid and glucose metabolism. We studied the effect of ursodeoxycholic acid (UDCA) on glucose levels in rats with cirrhosis induced by bile duct ligation (BDL).
METHODS: SD rats were divided into three groups: sham operation (Group A); BDL (Group B), and UDCA plus BDL (Group C). After 4 weeks, oral glucose tolerance tests were performed. Serum biochemical parameters and the levels of glucose, insulin, and glucagon-like peptide 1 (GLP-1) were measured. Histopathology of the liver and islet was observed. The gene expression of cholesterol 7α-hydroylase (CYP7A1), microsomal oxysterol 7a-hydroxylase (CYP7B1) in the liver, and Takeda G-protein-coupled receptor-5 (TGR5) in the intestine was determined by real-time PCR.
RESULTS: Compared with Group A, fasting glucose and 1-h and 2-h postprandial glucose levels increased slightly (all P > 0.05), 2-h postprandial insulin levels increased significantly (P < 0.05), 15 min postprandial GLP-1 levels decreased (P < 0.05) in Group B. Compared with Group B, fasting glucose and 1-h postprandial glucose levels decreased (all P < 0.05), 2-h postprandial insulin levels decreased (P < 0.01), and 15 min postprandial GLP-1 levels increased (P < 0.05) in Group C. After UDCA intervention, liver fibrosis induced by BDL was alleviated, and the islet areas were increased (P < 0.05). Compared with Group A, the mRNA expression of CYP7A1 and CYP7B1 in the liver increased, and the mRNA expression of TGR5 in the intestine decreased in Group B (all P < 0.05). Compared with Group B, the mRNA expression of CYP7A1 and CYP7B1 in the liver decreased, and TGR5 in the intestine increased in Group C (P < 0.05).
CONCLUSIONS: After 4 weeks of BDL, the rats developed liver fibrosis and abnormal glucose metabolism. UDCA administration improved liver fibrosis, increased islet area, decreased glucose levels, inhibited genes in BA synthesis, enhanced TGR5 gene expression in the intestine, and further improved islet function.