Hypoglycemic effect of deoxynojirimycin-polysaccharide on high fat diet and streptozotocin-induced diabetic mice via regulation of hepatic glucose metabolism
Hypoglycemic effect of deoxynojirimycin-polysaccharide on high fat diet and streptozotocin-induced diabetic mice via regulation of hepatic glucose metabolism
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脱氧野尻霉素多糖通过调节肝糖代谢对高脂饮食和链脲佐菌素诱导的糖尿病小鼠的降血糖作用
DOI：
10.1016/j.cbi.2014.11.003
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发表时间：
2015-01-05
影响因子：
5.1
通讯作者：
Lv, Zhi-qiang
中科院分区：
文献类型：
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作者：
Li, You-gui;Ji, Dong-feng;Lv, Zhi-qiang
2型糖尿病(T2 DM)目前被认为是一种世界性的流行病，寻找有效的治疗策略是非常重要的。脱氧诺吉霉素-多糖混合物(DPM)此前已被证明对四氧嘧啶或链脲佐菌素(STZ)诱导的糖尿病小鼠具有降血糖作用。本研究旨在探讨丹参对小鼠低剂量链脲佐菌素诱导的高脂饮食诱导的2型糖尿病的治疗作用及其作用机制(S)。糖尿病小鼠每日口服DPM(150 mg/kg bw)。90d后血糖、丙酮酸、甘油三酯(TG)、天冬氨酸转氨酶(AST)、丙氨酸氨基转移酶(ALT)、肌酐(Cr)、过氧化脂质(LPO)和丙二醛(MDA)水平明显下降，高密度脂蛋白(HDLc)和肝糖原浓度明显升高。在服用DPM 60d的第一阶段，血胰岛素水平没有发生显著变化，但HOMA-IR指数显著下降。相比之下，T2 MD对照组的HOMA-IR指数显著增加。在第二阶段，DPM治疗再持续30天，与T2 DM对照组相比，DPM治疗组小鼠的胰岛素水平显著升高。这些结果表明，DPM治疗可以改善糖尿病前期的胰岛素抵抗和胰岛β细胞功能障碍。DPM还下调外周组织(肝脏和/或肌肉)中胰岛素受体(IR)和糖异生酶(丙酮酸羧基酶、果糖-1，6-二磷酸酶、磷酸烯醇式丙酮酸羧基酶和葡萄糖-6-磷酸酶)的蛋白水平，但增强胰腺中胰岛素、脂蛋白脂酶(LPL)和肝脏糖酵解酶(葡萄糖激酶、磷酸果糖激酶、专用激酶和丙酮酸脱羧酶E1)的表达。此外，体外实验还发现脱氧野生霉素(DNJ)和多糖(P)能促进肝LO-2细胞的增殖和清除自由基。这些结果支持我们的生化分析结果，并强调了DPM对STZ诱导的胰腺和肝脏损伤的保护作用的可能机制。综上所述，我们的研究结果表明，DPM可能被开发为一种治疗糖尿病的降血糖药物。(C)2014爱思唯尔爱尔兰有限公司。保留所有权利。
Type 2 diabetes mellitus (T2DM) is currently considered a worldwide epidemic and finding effective therapeutic strategies against this disease is highly important. A deoxynojirimycin-polysaccharide mixture (DPM) has previously been shown to exert hypoglycemic effects on alloxan- or streptozotocin (STZ)-induced diabetic mice. The purpose of the present study was to evaluate the therapeutic effects and underlying mechanism(s) of DPM on T2DM induced by high fat diet following low-dose STZ treatment in mice. After daily oral treatment of diabetic mice with DPM (150 mg/kg b.w.) for 90 d, significant decline in blood glucose, pyruvate, triglyceride (TG), aspartate transaminase (AST), alanine transaminase (ALT), creatinine (Cr), lipid peroxide (LPO) and malondialdehyde (MDA) levels as well as evident increases in high density lipoprotein (HDL-c) and hepatic glycogen concentrations were observed. In the first stage, in which DPM was administered for 60 d, blood insulin levels did not undergo significant change but a significant decrease in the HOMA-IR index was detected. By contrast, the HOMA-IR index increased significantly in T2MD controls. In the second stage, in which DPM treatment was continued for another 30 d, insulin levels significantly increased in DPM-treated mice in comparison with T2DM controls. These results indicate that insulin resistance in the pre-diabetic period and the dysfunction of pancreatic beta-cells are ameliorated by DPM treatment. DPM also down-regulated protein levels of insulin receptor (IR) and gluconeogenic enzymes (pyruvate carboxylase, fructose-1, 6-bisphosphatase, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) in peripheral tissues (liver and/or muscle), but enhanced the expressions of insulin in pancreas, lipoprotein lipase (LPL) and glycolysis enzymes (glucokinase, phosphofructokinase, private kinase and pyruvate decarboxylase E1) in the liver. Furthermore, deoxynojirimycin (DNJ) and polysaccharide (P) were found to increase proliferation of hepatic LO-2 cells and scavenging of radicals in vitro. These results support the results of our biochemical analyses and underscore possible mechanisms underlying the protective effects of DPM on STZ-induced damage to the pancreas and the liver. Taken together, our findings suggest that DPM may be developed as an antihyperglycemic agent for the treatment of diabetes mellitus. (C) 2014 Elsevier Ireland Ltd. All rights reserved.