Mao Xian-qing, Yu Feng, Wang Nian, Wu Yong, Zou Feng, Wu Ke, Liu Min, Ouyang Jing-ping
Department of Pathophysiology, Medical College of Wuhan University, Hubei Provincial Key Laboratory of Allergy and Immune-Related Diseases, Wuhan, China.
Phytomedicine. 2009 May;16(5):416-25. doi: 10.1016/j.phymed.2008.12.011. Epub 2009 Feb 6.
Our previous studies found that Astragalus polysaccharide (APS) exerts insulin-sensitizing and hypoglycemic activities in type 2 diabetic (T2DM) rats. The present study was designed to further confirm the hypoglycemic effect of APS and to investigate its possible mechanism underlying the improvement of insulin resistance in vivo and in vitro. Diet-induced insulin resistant C57BL/6J mice treated with or without APS (orally, 700 mg/kg/d) for 8 weeks were analyzed and compared. Simultaneously, an insulin resistant C(2)C(12) cell model and an ER stressed HepG2 cell model were established and incubated with or without APS (200 microg/ml) for 24h respectively. Systematic insulin sensitivity was measured with an insulin-tolerance test (ITT) and an homeostasis model assessment (HOMA IR) index. Metabolic stress variation was analyzed for biochemical parameters and pathological variations. The expression and activity of protein tyrosine phosphatase 1B (PTP1B), which plays a very important role in insulin signaling and in the ER stress response, was measured by immunoprecipitation and Western blot. The ER stress response was analyzed through XBP1 transcription and splicing by real-time PCR. APS could alleviate insulin resistance and ER stress induced by high glucose in vivo and in vitro, respectively. The hyperglycemia, hypolipemia, and hyperinsulinemia status were controlled with APS therapy. Insulin action in the liver of insulin resistant mice was restored significantly with APS administration. APS enhanced adaptive capacity of the ER and promoted insulin signaling by the inhibition of the expression and activity of PTP1B. Furthermore, the anti-obesity effect and hypolipidemia effects of APS were probably due partly to decreasing the leptin resistance of mice, which would positively couple with the normalization of plasma insulin levels. We have shown that APS has beneficial effects on insulin resistance and hyperglycemia. The mechanism is related to the alleviation of ER stress and insulin resistance under hyperglycemia conditions.
我们之前的研究发现，黄芪多糖（APS）对2型糖尿病（T2DM）大鼠具有胰岛素增敏和降血糖活性。本研究旨在进一步证实APS的降血糖作用，并探讨其在体内和体外改善胰岛素抵抗的可能机制。对饮食诱导的胰岛素抵抗C57BL/6J小鼠进行分析和比较，这些小鼠接受或未接受APS（口服，700mg/kg/d）治疗8周。同时，建立胰岛素抵抗的C(2)C(12)细胞模型和内质网应激的HepG2细胞模型，并分别用或不用APS（200μg/ml）孵育24小时。通过胰岛素耐量试验（ITT）和稳态模型评估（HOMA IR）指数测量系统胰岛素敏感性。分析代谢应激变化的生化参数和病理变化。通过免疫沉淀和蛋白质印迹法测量在胰岛素信号传导和内质网应激反应中起非常重要作用的蛋白酪氨酸磷酸酶1B（PTP1B）的表达和活性。通过实时PCR分析XBP1转录和剪接来分析内质网应激反应。APS可分别在体内和体外减轻高糖诱导的胰岛素抵抗和内质网应激。APS治疗可控制高血糖症、低脂血症和高胰岛素血症状态。给予APS可显著恢复胰岛素抵抗小鼠肝脏中的胰岛素作用。APS通过抑制PTP1B的表达和活性增强内质网的适应能力并促进胰岛素信号传导。此外，APS的抗肥胖作用和降血脂作用可能部分归因于降低小鼠的瘦素抵抗，这与血浆胰岛素水平的正常化呈正相关。我们已经表明，APS对胰岛素抵抗和高血糖症具有有益作用。其机制与高血糖条件下内质网应激和胰岛素抵抗的减轻有关。
