大黄素改善KKAy胰岛素抵抗糖尿病小鼠作用机制的研究
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摘要
目的：通过对KKAy糖尿病小鼠进行为期8周的大黄素灌胃治疗,利用生化、RT-PCR、免疫组织化学及免疫印迹法等检验方法,探讨大黄素改善KKAy糖尿病小鼠肝脏、肌肉、脂肪组织胰岛素敏感性及降血糖的作用机制及对PI3K-AKt胰岛素信号转导通路的影响,为中药大黄素治疗糖尿病提供实验依据。
材料与方法：将SPF级健康雌性KKAy小鼠32只按血糖值随机分为模型组(DM组),大黄素低治疗组(EL组),大黄素按12.5mg/kg·d灌胃,大黄素高治疗组(EH组),大黄素按50mg/kg·d灌胃,.吡格列酮治疗组(PI组),吡格列酮按1.95mg/(kg·d)剂量灌胃,并选10只C57BL/6J小鼠为正常对照组(NC组),连续灌胃给药8周。8周后测定各组小鼠空腹血糖(FPG)、空腹胰岛素(Fins)并计算胰岛素敏感指数(ISI)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、(?)低密度脂蛋白胆固醇(LDL-C),游离脂肪酸(FFA),超敏C反应蛋白(hs-CRP)及肿瘤坏死因子-a (TNF-a);应用RT-PCR法测定各组小鼠肝脏过氧化物酶体增殖物激活受体γmRNA (PPARγ mRNA)及葡萄糖转运蛋白2mRNA (GluT-2mRNA)的表达；应用免疫组织化学法测定各组小鼠肝脏过氧化物酶体增殖物激活受体Y (PPAR Y)及葡萄糖转运蛋白2(GluT-2)蛋白的表达；应用RT-PCR法测定各组小鼠骨骼肌、脂肪组织过氧化物酶体增殖物激活受体γmRNA (PPAR γ mRNA)及葡萄糖转运蛋-4mRNA (GluT-4mRNA)的表达；应用免疫组织化学法测定各组小鼠骨骼肌、脂肪组织过氧化物酶体增殖物激活受体γ (PPAR γ)及葡萄糖转运蛋-4(GluT-4)蛋白的表达；应用免疫印迹法(western-blot)测定各组小鼠肝脏、骨骼肌和脂肪组织IRS-1,PI3K, AktSer473, Fox01的蛋白表达。实验结果以均数±标准差(X±s)表示,应用SPSS11.5统计软件进行分析,组间比较用单因素方差分析(One-Way ANOVE),组间两两显著性比较采用LSD法,P<0.05为统计学具有显著性差异。
结果：
各组小鼠喂养8周实验结束后,禁食8小时后留取血清进行生化检验,处死各组小鼠,速取部分肝脏、股四头肌和肾周脂肪组织,置入液氮中以备RT-PCR法及western-blot法检测,另取一部分用4%的多聚甲醛固定,石蜡包埋,以备免疫组织化学检测。
1.与NC组比较,DM组FBG、TG、TC、FFA、hs-CRP及TNF-α明显升高(P<0.05), ISI明显降低(P<0.05)；与DM组比较EL、EH、PI组FBG、TG、TC、FFA、hs-CRP及TNF-α明显降低(P<0.05),且成剂量依赖性,ISI明显升高(P<0.05)。
2.通过对RT-PCR产物电泳结果的观察以及凝胶扫描系统进行吸光度积分分析,与NC组比较,DM组肝脏组织PPAR γ mRNA及GluT-2mRNA的表达丰度明显降低(P<0.05);肌肉、脂肪组织PPAR Y mRNA及GluT-4mRNA的丰度表达明显降低(P<0.05)；与DM组比较EL. EH、PI组肝脏组织PPAR γ mRNA及GluT-2mRNA的表达丰度明显升高(P<0.05)；骨骼肌、脂肪组织PPAR γ mRNA及GluT-4mRNA的丰度表达明显升高,(P<0.05)。免疫组化染色结果可见,与NC组比较,DM组肝脏组织PPAR γ及GluT-2的表达明显降低(P<0.05);肌肉、脂肪组织PPAR γ及GluT-4的表达明显降低(P<0.05)；与DM组比较EL、EH、PI组肝脏组织PPARγ及GluT-2的表达明显升高(P<0.05)；骨骼肌、脂肪组织PPARγ及GluT-4的表达明显升高(P<0.05)。
3.通过对免疫印迹的结果进行吸光度积分分析,胰岛素刺激后,DM组与NC组比较,IRS-1、PI3K、及AktSer473蛋白磷酸化升高倍数明显降低(P<0.05), Fox01明显升高(P<0.05)；与DM组比较EL、EH组IRS-1、PI3K及胰岛素刺激后Akt Ser473蛋白磷酸化升高倍数明显升高(P<0.05), Fox01明显降低(P<0.05)。
结论：
1.10周龄KKAγ小鼠已经出现血糖升高,经8周高脂高热量饮食喂养后,存在典型的胰岛素抵抗,空腹血糖、血清Fins、TG、TC、FFA、hs-CRP和TNF-α明显升高,血ISI明显降低。
2.大黄素能够降低KKAγ小鼠空腹血糖、血清Fins、TG、TC、FFA、hs-CRP和TNF-α,升高血ISI,减少炎症反应,高剂量大黄素干预对胰岛素敏感性及相关指标的改善作用优于低剂量组。
3.模型组小鼠肝脏PPARγ和GluT-2的mRNA和蛋白表达明显下降;大黄素能够上调KKAy小鼠肝脏PPAR γ和GluT-2的mRNA和蛋白表达,改善肝脏的葡萄糖利用不足和过度释放,增强胰岛素敏感性,改善胰岛素抵抗。
4.模型组小鼠骨骼肌和脂肪组织PPAR y及GluT-4的mRNA和蛋白表达明显下降；大黄素能够上调KKAy小鼠骨骼肌和脂肪组织PPAR γ及GluT-4的mRNA和蛋白表达,从而促进骨骼肌和脂肪组织对葡萄糖的摄取,从而增强胰岛素敏感性,改善胰岛素抵抗。
5.胰岛素刺激后,模型组与正常对照组比较,小鼠肝脏、骨骼肌及脂肪组织中IRS-1、PI3K、AktSer473蛋白磷酸化表达明显下降,Fox01蛋白表达明显升高；大黄素可以上调KKAy小鼠肝脏、骨骼肌及脂肪组织中IRS-1、PI3K、AktSer473蛋白磷酸化表达,下调Fox01蛋白表达,从PI3K-AKt胰岛素信号传导通路改善胰岛素抵抗。
Purpose:After emodin was given to the type2diabetic KKAy mice for8weeks, we use biochemical method, RT-PCR method, immunohistocemistry method and Western-blot method to test the mechanism of how can emodin improve KKAy diabetes mouse liver, muscle and adipose ti ssue insulin sensitivity and lowering blood sugar. And we study how can emodin affect PI3K/AKt insulin signal transduction pathway. In order to provide the experimental basis of emodin in treatment of diabetes mellitus.
Materials and Methods:32female KKAy mice of Specific pathogen free (SPF) were divided randomly into four groups:model(DM) group, emodin-low dose group(EL), emodin-high dose group (EH), and pioglitazone group (PI) according to plasma glucose level. We selected10C57BL/6J mice as normal control group(NC)8weeks later, all animals were tested fasting plasma glucose, fasting insulin level for caculating Insulin Sensitivity Index, total cholesterol, total triacylglycerol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, floating fatty acid, high sensitive creaetor protein, tumor necrosis factor-α. The expression of PPARγ and GluT-2in hepatic tissue were determined by immunohistochemistry and RT-PCR. The expression of PPARγ and GluT-4in musle and adipose tissue were determined by immunohistochemistry and RT-PCR. The expressions of IRS-1, PI3K, AktSer473and Fox01in hepatic tissue, musle tissue and adipose tissue were determined by Western-blot. The experimental results were analyzed by statistical software
Results:
8weeks later, the experiment was over. The mice were fasting for8hours, and then we used the serum to test biochemical datas. The mice were put to death, we take out partial liver, musle and adipose speedly into the liquid nitrogen for RT-PCR and Western-blot.The other partial liver,musle and adipose wre fixed by paraformaldehyde. Paraffin embedding for Immunohistochemistry.
1. Compared with normal control group, DM group showed higher fasting plasma glucose, total cholesterol, total triacylglycerol, low-density lipoprotein cholesterol, floating fatty acid, high sensitive creaetor protein, and tumor necrosis factor-α (P<0.05), lower ISI(P<0.05). Compared with DM group, emodin could reduce fasting plasma glucose, total cholesterol, total triacylglycerol, low-density lipoprotein cholesterol, floating fatty acid, high sensitive creaetor protein, and tumor necrosis factor-α (P<0.05). In addition, emodin could improve insulin sensitivity in KKAy diabetic mice(P<0.05). emodin showed dose dependent.
2. By RT-PCR products and gel electrophoresis results of the observation optical density scanning system integration analysis, the expression of PPARγmRNA and GluT-2mRNA in hepatic tissue of DM group was decreased as compared with NC group (p<0.05). The expression of PPAR y mRNA and GluT-4mRNA in musle tissue and adipose tissue of DM group was decreased too as compared with NC group (p<0.05). Compared with DM group, the expression of PPARγmRNA and GluT-2mRNA in hepatic tissue of EL、EH、PI group was up-regulated (p<0.05) the expression of PPARγmRNA and GluT-4mRNA in musle tissue and adipose tissue of EL、EH、PI group was also up-regulated(p<0.05). Immunohistochemical results showed lower protein expression of PPARγ and GluT-2in hepatic tissue of DM group as compared with normal control group (p<0.05), and showed lower protein expression of PPARγ and GluT-4in musle tissue and adipose tissue of DM group as compared with normal control group (p<0.05). Compared with DM group, the protein expression of PPAR Y and GluT-2in hepatic tissue of EL、EH、PI group was up-regulated (p<0.05); the protein expression of PPARγand GluT-4in musle tissue and adipose tissue of EL、EH、PI group was also up-regulated (p <0.05).
3.By the results of Western blot analysis of absorbance points, the expression of IRS-1、PI3K、AktSer473in hepatic tissue, musle tissue and adipose tissue of DM group was decreased; the protein expression of Fox01was up-regulated as compared with NC group (p<0.05). Compared with DM group, the protein expression of IRS-1、PI3K、AktSer473in hepatic tissue, musle tissue and adipose tissue of EL、EHgroup was up-regulated (p<0.05); the protein expression of Fox01was decreased (p<0.05).
Conclusion:
1.10weeks old KKAy mice have appeared high blood sugar. After8weeks high-fat diet feeding, KKAy mice existed typical insulin resistance. Fasting plasma Glucose, fasting insulin level, total cholesterol, total triacylglycerol, low-density lipoprotein cholesterol, floating fatty acid, high sensitive creaetor protein, tumor necrosis factor-α. increased significantly and the blood insulin sensitivity index. decreased significantly.
2. emodin can decrease fasting plasma glucose, fasting insulin level, total cholesterol, total triacylglycerol,, low-density lipoprotein cholesterol, floating fatty acid, high sensitive creaetor protein, tumor necrosis factor-α and increase insulin sensitivity.The role of high dose emodin outstripped low dose.
3. In model group mice, the expression of PPAR γ mRNA and GluT-2mRNA in hepatic tissue are decreased obviously.. Emodin can up-regulate the expression of PPAR γ mRNA and GluT-2mRNA in hepatic tissue of KKAy mice. Emodin can improve liver glucose utilization of inadequate and excessive release and enhance insulin sensitivity and improve insulin resistance.
4. In model group mice, the expression of PPARγ mRNA and GluT-4mRNA in skeletal muscle and adipose tissue are decreased obviously.Emodin can up-regulate the expression of PPARγ mRNA and GluT-4mRNA in skeletal muscle and adipose tissue of KKAy mice In order to promote skeletal muscle and adipose tissue uptake of glucose and enhance insulin sensitivity and improve insulin resistance.
5. In model group mice, the protein expression of IRS-1, PI3K and Akt phosphorylation of Ser473in hepatic, skeletal muscle and adipose tissue are decreased obviously. Emodin can up-regulate the protein expression of IRS-1, PI3K and Akt phosphorylation of Ser473and down-regulate the protein expression of Fox01in hepatic, skeletal muscle and adipose tissue of KKAy mice. Emodin can improve insulin resistance from PI3K insulin signal transduction pathway.
材料与方法：将SPF级健康雌性KKAy小鼠32只按血糖值随机分为模型组(DM组),大黄素低治疗组(EL组),大黄素按12.5mg/kg·d灌胃,大黄素高治疗组(EH组),大黄素按50mg/kg·d灌胃,.吡格列酮治疗组(PI组),吡格列酮按1.95mg/(kg·d)剂量灌胃,并选10只C57BL/6J小鼠为正常对照组(NC组),连续灌胃给药8周。8周后测定各组小鼠空腹血糖(FPG)、空腹胰岛素(Fins)并计算胰岛素敏感指数(ISI)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、(?)低密度脂蛋白胆固醇(LDL-C),游离脂肪酸(FFA),超敏C反应蛋白(hs-CRP)及肿瘤坏死因子-a (TNF-a);应用RT-PCR法测定各组小鼠肝脏过氧化物酶体增殖物激活受体γmRNA (PPARγ mRNA)及葡萄糖转运蛋白2mRNA (GluT-2mRNA)的表达；应用免疫组织化学法测定各组小鼠肝脏过氧化物酶体增殖物激活受体Y (PPAR Y)及葡萄糖转运蛋白2(GluT-2)蛋白的表达；应用RT-PCR法测定各组小鼠骨骼肌、脂肪组织过氧化物酶体增殖物激活受体γmRNA (PPAR γ mRNA)及葡萄糖转运蛋-4mRNA (GluT-4mRNA)的表达；应用免疫组织化学法测定各组小鼠骨骼肌、脂肪组织过氧化物酶体增殖物激活受体γ (PPAR γ)及葡萄糖转运蛋-4(GluT-4)蛋白的表达；应用免疫印迹法(western-blot)测定各组小鼠肝脏、骨骼肌和脂肪组织IRS-1,PI3K, AktSer473, Fox01的蛋白表达。实验结果以均数±标准差(X±s)表示,应用SPSS11.5统计软件进行分析,组间比较用单因素方差分析(One-Way ANOVE),组间两两显著性比较采用LSD法,P<0.05为统计学具有显著性差异。
结果：
各组小鼠喂养8周实验结束后,禁食8小时后留取血清进行生化检验,处死各组小鼠,速取部分肝脏、股四头肌和肾周脂肪组织,置入液氮中以备RT-PCR法及western-blot法检测,另取一部分用4%的多聚甲醛固定,石蜡包埋,以备免疫组织化学检测。
1.与NC组比较,DM组FBG、TG、TC、FFA、hs-CRP及TNF-α明显升高(P<0.05), ISI明显降低(P<0.05)；与DM组比较EL、EH、PI组FBG、TG、TC、FFA、hs-CRP及TNF-α明显降低(P<0.05),且成剂量依赖性,ISI明显升高(P<0.05)。
2.通过对RT-PCR产物电泳结果的观察以及凝胶扫描系统进行吸光度积分分析,与NC组比较,DM组肝脏组织PPAR γ mRNA及GluT-2mRNA的表达丰度明显降低(P<0.05);肌肉、脂肪组织PPAR Y mRNA及GluT-4mRNA的丰度表达明显降低(P<0.05)；与DM组比较EL. EH、PI组肝脏组织PPAR γ mRNA及GluT-2mRNA的表达丰度明显升高(P<0.05)；骨骼肌、脂肪组织PPAR γ mRNA及GluT-4mRNA的丰度表达明显升高,(P<0.05)。免疫组化染色结果可见,与NC组比较,DM组肝脏组织PPAR γ及GluT-2的表达明显降低(P<0.05);肌肉、脂肪组织PPAR γ及GluT-4的表达明显降低(P<0.05)；与DM组比较EL、EH、PI组肝脏组织PPARγ及GluT-2的表达明显升高(P<0.05)；骨骼肌、脂肪组织PPARγ及GluT-4的表达明显升高(P<0.05)。
3.通过对免疫印迹的结果进行吸光度积分分析,胰岛素刺激后,DM组与NC组比较,IRS-1、PI3K、及AktSer473蛋白磷酸化升高倍数明显降低(P<0.05), Fox01明显升高(P<0.05)；与DM组比较EL、EH组IRS-1、PI3K及胰岛素刺激后Akt Ser473蛋白磷酸化升高倍数明显升高(P<0.05), Fox01明显降低(P<0.05)。
结论：
1.10周龄KKAγ小鼠已经出现血糖升高,经8周高脂高热量饮食喂养后,存在典型的胰岛素抵抗,空腹血糖、血清Fins、TG、TC、FFA、hs-CRP和TNF-α明显升高,血ISI明显降低。
2.大黄素能够降低KKAγ小鼠空腹血糖、血清Fins、TG、TC、FFA、hs-CRP和TNF-α,升高血ISI,减少炎症反应,高剂量大黄素干预对胰岛素敏感性及相关指标的改善作用优于低剂量组。
3.模型组小鼠肝脏PPARγ和GluT-2的mRNA和蛋白表达明显下降;大黄素能够上调KKAy小鼠肝脏PPAR γ和GluT-2的mRNA和蛋白表达,改善肝脏的葡萄糖利用不足和过度释放,增强胰岛素敏感性,改善胰岛素抵抗。
4.模型组小鼠骨骼肌和脂肪组织PPAR y及GluT-4的mRNA和蛋白表达明显下降；大黄素能够上调KKAy小鼠骨骼肌和脂肪组织PPAR γ及GluT-4的mRNA和蛋白表达,从而促进骨骼肌和脂肪组织对葡萄糖的摄取,从而增强胰岛素敏感性,改善胰岛素抵抗。
5.胰岛素刺激后,模型组与正常对照组比较,小鼠肝脏、骨骼肌及脂肪组织中IRS-1、PI3K、AktSer473蛋白磷酸化表达明显下降,Fox01蛋白表达明显升高；大黄素可以上调KKAy小鼠肝脏、骨骼肌及脂肪组织中IRS-1、PI3K、AktSer473蛋白磷酸化表达,下调Fox01蛋白表达,从PI3K-AKt胰岛素信号传导通路改善胰岛素抵抗。
Purpose:After emodin was given to the type2diabetic KKAy mice for8weeks, we use biochemical method, RT-PCR method, immunohistocemistry method and Western-blot method to test the mechanism of how can emodin improve KKAy diabetes mouse liver, muscle and adipose ti ssue insulin sensitivity and lowering blood sugar. And we study how can emodin affect PI3K/AKt insulin signal transduction pathway. In order to provide the experimental basis of emodin in treatment of diabetes mellitus.
Materials and Methods:32female KKAy mice of Specific pathogen free (SPF) were divided randomly into four groups:model(DM) group, emodin-low dose group(EL), emodin-high dose group (EH), and pioglitazone group (PI) according to plasma glucose level. We selected10C57BL/6J mice as normal control group(NC)8weeks later, all animals were tested fasting plasma glucose, fasting insulin level for caculating Insulin Sensitivity Index, total cholesterol, total triacylglycerol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, floating fatty acid, high sensitive creaetor protein, tumor necrosis factor-α. The expression of PPARγ and GluT-2in hepatic tissue were determined by immunohistochemistry and RT-PCR. The expression of PPARγ and GluT-4in musle and adipose tissue were determined by immunohistochemistry and RT-PCR. The expressions of IRS-1, PI3K, AktSer473and Fox01in hepatic tissue, musle tissue and adipose tissue were determined by Western-blot. The experimental results were analyzed by statistical software
Results:
8weeks later, the experiment was over. The mice were fasting for8hours, and then we used the serum to test biochemical datas. The mice were put to death, we take out partial liver, musle and adipose speedly into the liquid nitrogen for RT-PCR and Western-blot.The other partial liver,musle and adipose wre fixed by paraformaldehyde. Paraffin embedding for Immunohistochemistry.
1. Compared with normal control group, DM group showed higher fasting plasma glucose, total cholesterol, total triacylglycerol, low-density lipoprotein cholesterol, floating fatty acid, high sensitive creaetor protein, and tumor necrosis factor-α (P<0.05), lower ISI(P<0.05). Compared with DM group, emodin could reduce fasting plasma glucose, total cholesterol, total triacylglycerol, low-density lipoprotein cholesterol, floating fatty acid, high sensitive creaetor protein, and tumor necrosis factor-α (P<0.05). In addition, emodin could improve insulin sensitivity in KKAy diabetic mice(P<0.05). emodin showed dose dependent.
2. By RT-PCR products and gel electrophoresis results of the observation optical density scanning system integration analysis, the expression of PPARγmRNA and GluT-2mRNA in hepatic tissue of DM group was decreased as compared with NC group (p<0.05). The expression of PPAR y mRNA and GluT-4mRNA in musle tissue and adipose tissue of DM group was decreased too as compared with NC group (p<0.05). Compared with DM group, the expression of PPARγmRNA and GluT-2mRNA in hepatic tissue of EL、EH、PI group was up-regulated (p<0.05) the expression of PPARγmRNA and GluT-4mRNA in musle tissue and adipose tissue of EL、EH、PI group was also up-regulated(p<0.05). Immunohistochemical results showed lower protein expression of PPARγ and GluT-2in hepatic tissue of DM group as compared with normal control group (p<0.05), and showed lower protein expression of PPARγ and GluT-4in musle tissue and adipose tissue of DM group as compared with normal control group (p<0.05). Compared with DM group, the protein expression of PPAR Y and GluT-2in hepatic tissue of EL、EH、PI group was up-regulated (p<0.05); the protein expression of PPARγand GluT-4in musle tissue and adipose tissue of EL、EH、PI group was also up-regulated (p <0.05).
3.By the results of Western blot analysis of absorbance points, the expression of IRS-1、PI3K、AktSer473in hepatic tissue, musle tissue and adipose tissue of DM group was decreased; the protein expression of Fox01was up-regulated as compared with NC group (p<0.05). Compared with DM group, the protein expression of IRS-1、PI3K、AktSer473in hepatic tissue, musle tissue and adipose tissue of EL、EHgroup was up-regulated (p<0.05); the protein expression of Fox01was decreased (p<0.05).
Conclusion:
1.10weeks old KKAy mice have appeared high blood sugar. After8weeks high-fat diet feeding, KKAy mice existed typical insulin resistance. Fasting plasma Glucose, fasting insulin level, total cholesterol, total triacylglycerol, low-density lipoprotein cholesterol, floating fatty acid, high sensitive creaetor protein, tumor necrosis factor-α. increased significantly and the blood insulin sensitivity index. decreased significantly.
2. emodin can decrease fasting plasma glucose, fasting insulin level, total cholesterol, total triacylglycerol,, low-density lipoprotein cholesterol, floating fatty acid, high sensitive creaetor protein, tumor necrosis factor-α and increase insulin sensitivity.The role of high dose emodin outstripped low dose.
3. In model group mice, the expression of PPAR γ mRNA and GluT-2mRNA in hepatic tissue are decreased obviously.. Emodin can up-regulate the expression of PPAR γ mRNA and GluT-2mRNA in hepatic tissue of KKAy mice. Emodin can improve liver glucose utilization of inadequate and excessive release and enhance insulin sensitivity and improve insulin resistance.
4. In model group mice, the expression of PPARγ mRNA and GluT-4mRNA in skeletal muscle and adipose tissue are decreased obviously.Emodin can up-regulate the expression of PPARγ mRNA and GluT-4mRNA in skeletal muscle and adipose tissue of KKAy mice In order to promote skeletal muscle and adipose tissue uptake of glucose and enhance insulin sensitivity and improve insulin resistance.
5. In model group mice, the protein expression of IRS-1, PI3K and Akt phosphorylation of Ser473in hepatic, skeletal muscle and adipose tissue are decreased obviously. Emodin can up-regulate the protein expression of IRS-1, PI3K and Akt phosphorylation of Ser473and down-regulate the protein expression of Fox01in hepatic, skeletal muscle and adipose tissue of KKAy mice. Emodin can improve insulin resistance from PI3K insulin signal transduction pathway.
引文
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