格列齐特调节InsR/PI3K/GSK-3β通路改善2型糖尿病小鼠肝脏胰岛素抵抗作用  

Gliclazide regulates InsR/PI3K/GSK-3β pathway to improve hepatic insulin resistance of type 2 diabetic mice

作　　者：赵天娇 黄琼[1] 魏伟[1] Zhao Tianjiao;Huang Qiong;Wei Wei(Institute of Clinical Pharmacology,Anhui Medical University,Key Laboratory of Anti-inflammatory and lmmune Medicine(Anhui Medical University),Ministry of Education,Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine,Hefei230032)

机构地区：[1]安徽医科大学临床药理研究所,抗炎免疫药物教育部重点实验室,抗炎免疫药物安徽省协同创新中心,合肥230032

出　　处：《安徽医科大学学报》2020年第11期1655-1661,共7页Acta Universitatis Medicinalis Anhui

基　　金：国家自然科学基金(编号:81673492、81974508)。

摘　　要：目的探讨格列齐特改善2型糖尿病(T2DM)肝脏胰岛素抵抗的作用及机制。方法采用高脂联合链脲佐菌素构建T2DM小鼠模型,观察格列齐特对T2DM小鼠空腹血糖、血清胰岛素、葡萄糖耐量、胰岛素敏感性及肝脏病理的影响。观察格列齐特对胰岛素抵抗HepG2细胞葡萄糖消耗,糖原含量的影响;并采用免疫印迹法检测肝组织和HepG2细胞中胰岛素受体、磷脂酰肌醇3-激酶、葡萄糖转运蛋白4的表达以及糖原合成激酶3β、胰岛素受体底物1的磷酸化水平。结果与T2DM组比较,格列齐特组小鼠空腹血糖下降、血清胰岛素升高、葡萄糖耐量和胰岛素敏感性增加、肝细胞坏死和空泡化现象减轻。格列齐特增加胰岛素抵抗HepG2细胞的葡萄糖消耗和糖原含量,增加胰岛素受体、磷脂酰肌醇3-激酶和葡萄糖转运蛋白4的表达,促进胰岛素受体底物1酪氨酸磷酸化,抑制糖原合成激酶3β酪氨酸磷酸化。结论格列齐特可以改善T2DM小鼠糖代谢紊乱和胰岛素抵抗,缓解肝脏损伤,增加HepG2细胞胰岛素抵抗模型的葡萄糖消耗和糖原含量,其作用机制可能与上调胰岛素信号通路有关。Objective To investigate the mechanism of gliclazide in improving hepatic insulin resistance of type 2 diabetes mellitus(T2 DM).Methods We established T2 DM animal model by high fat diet combined with intraperitoneal injection of streptozotocin.Fasting blood glucose,serum insulin,glucose tolerance,insulin sensitivity and liver pathology in T2 DM mice were detected.Glucose consumption and glycogen content were measured.The expression of insulin signaling pathway proteins(insulin receptor,insulin receptor substrate1,phosphatidylinositol 3-kinase,glycogen synthesis kinase 3βand glucose transporter 4)in liver tissues and HepG2 cells were detected by WB.Results Compared with T2 DM group,the mice in gliclazide groups showed decreased blood glucose,increased serum insulin,significantly improved glucose tolerance and insulin sensitivity,and reduced hepatocyte necrosis and vacuolation.Gliclazide significantly increased glucose consumption and glycogen content in insulin resistant HepG2 cells.Gliclazide increased insulin receptor,phosphatidylinositol 3-kinase and glucose transporter 4 expression and insulin receptor substrate1 tyrosine phosphorylation.Gliclazide inhibited glycogen synthesis kinase 3βtyrosine phosphorylation.Conclusion Gliclazide can improve glucose metabolism disorder,insulin sensitivity and liver injury in T2 DM mice.Gliclazide can increase glucose consumption and glycogen content in insulin resistant HepG2 cells.The mechanism may be related to the up-regulated insulin signaling pathway.

关 键 词：格列齐特 T2DM 胰岛素抵抗 胰岛素信号通路 

分 类 号：R965[医药卫生—药理学]