中药糖耐康干预KKAy小鼠胰岛素抵抗信号转导的作用机制研究
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摘要
目的:观察中药复方糖耐康颗粒对自发性2型糖尿病KKAy小鼠和3T3-L1脂肪细胞的胰岛素抵抗及胰岛素信号转导途径的影响及作用机理。方法:动物实验中,将SPF级KKAy小鼠40只按血糖值随机分为模型组、糖耐康高剂量组、糖耐康低剂量组、吡咯列酮组,并选C57b1/6J小鼠为正常对照组,连续灌喂给药60天。每周测量随机血糖,60d后测定空腹血糖(FPG)、空腹胰岛素(Fins)以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)及肿瘤坏死因子-a(TNF-a),并对胰岛进行HE染色。实验结束后,用实时定量RT-PCR法测定小鼠骨骼肌和脂肪组织中P13-K及GluT4的mRNA的表达,免疫印迹杂交法(Weatern-blot)检测糖原合成激酶3(GSK3β)及蛋白激酶B(PKB/Akt 1αSer473)的蛋白表达及磷酸化水平。细胞实验中,将3T3-L1前脂肪细胞诱导分化为成熟脂肪细胞,油红“O”染色鉴定。用胰岛素联合地塞米松造成胰岛素抵抗模型。同时制备糖耐康、罗格列酮及空白含药血清,对细胞进行分组,分为正常组(3T3-L1脂肪细胞)、模型组、空白血清组、罗格列酮含药血清组(含8%罗格列酮血清)、中药高(含12%中药血清)、中(含8%中药血清)、低(含4%中药血清)七个剂量组。作用48h。后提取蛋白和RNA以检测。用半定量RT-PCR法测定抗性3T3-L1脂肪细胞中InsR及GluT-4的mRNA的表达。免疫印迹杂交法(Westernblot)测定IRS-1、P13-Kp85、PKB/Akt1αSer473磷酸化及GSK-3β的蛋白表达含量。结果:动物实验中,糖耐康组动物一般状况、体重较模型组有一定改善,但无明显差异,中药高剂量组动物饮水量较模型组明显减少。糖耐康高剂量组的FPG、Fins、TNF-a水平较模型组显著降低(p＜0.05),PI3-K及GluT4 mRNA表达及PKB/Akt 1αSer 473蛋白表达及磷酸化水平较模型组明显升高(p＜0.05或p＜0.01),且糖耐康在一定程度上能够保护胰岛β细胞,延缓β细胞衰竭,对GSK3β蛋白表达、血脂及FFA有降低趋势,但无显著性差异。细胞实验中,与模型组比较,各给药组中InsR、IRS-1、PI3-Kp85及GluT-4的蛋白及基因表达量均有一定程度上调,GSK-3β的蛋白表达有一定程度的下调,且随着中药含药血清浓度升高上调/下调程度亦升高,西药血清组作用接近中药高组或中组。结论:中药复方糖耐康具有改善KKAy小鼠胰岛素抵抗状态,保护胰岛β细胞功能,防治2型糖尿病发生发展的作用。其作用可能通过以下环节实现:①恢复胰岛素信号转导途径的异常、调节靶蛋白或基因的表达及活性而达到降低FPG及Fins等指标的水平;②通过降低TNF-α含量而减少对胰岛素信号传递的干扰因素,从受体后水平改善胰岛素抵抗状态,从而改善GluT-4的转位。
Objective:To study the effection of Tangnai-Kang concoction for insulin resistance and Insulin signal-transduction pathway in spontaneous diabetic animal model KKAy mouse and 3T3-L1 adipocytes,then explaining the mechanism of it.
Methods:In vivo,Specific pathogen free(SPF)KKAy mice 40 were divided randomly according to plasma glucose level into Models、TNK-low dosage、TNK-high dosage、Pioglitazone and normal C57BL/6J mice(normal control group).Each group was tested randomly plasma glucodelevel every week.60 days later,all animals were tested Fasting plasma glucose(FPG)、Fasting insulin level for caculating Insulin Sensitivity Index(ISI)、Total Cholesterol(TC)、Total triacylglycerol(TG)、High-density Lipoprotein Cholesterol (HDL-C)、Low- density Lipoprotein Cholesterol(LDL-C)、Floating fatty acid(FFA)、Tumor necrosis factor-a(TNF-a)and dying islet by HE.At the end,tested the muscle and adipose expression of PI3-K and GluT4 mRNA by reverse transcriptase PCR(RT-PCR),tested the expression of GSK 3βprotein level and PKB/AktlαSer 473 phosphorating level.In vitro, 3T3-L1 preadipocytes were cultured in vitro and differentiated into the matured adipocytes, dyed oil red "O" to authenticate.Then using dexamethasone and isulin induced insulin resistance in 3T3-L1 adipocyte.Divied cells into seven groups,such as Models、TNK-low dosage(4%serum)、TNK-middle dosage(8%serum)、TNK-high dosage(12%serum)、Rosiglitazone dosage(8%serum)、blank serum dosage and normal control group(3T3-L1 adipocytes).Treated the cells 48h,then extracted the total RNA and protein.At the end,tested the expression of InsR mRNA、IRS-1、PI-3K、GSK-3 protein and GluT-4 mRNA by reverse transcriptase PCR(RT-PCR)and Western blot.
Results:In vivo,compared with Model groups,FPG、TNF-a levels were all decreased significantly(p＜0.05);the expression of PI3-K and GluT4 mRNA were all up-regulated(p＜0.05 or p＜0.01);and PKB/Akt1αSer 473 phosphorating level were up-regulated at some degree(p＜0.05);the recipe could protectedβ-cells in some degree and postpontedβ-cells failure in islet,displayed decreasing tendency to the expression of GSK 3βprotein level and plasma lipocy and FFA levels.In vitro,compared with Model groups,the expression of everyone were upregulated in some degree following the serum concentration of Tangnai-Kang Compound.such as InsR and GluT-4 mRNA、IRS-1 and PI3-K p85 protein level, the expression of GSK-3βprotein level were down-regulated.The effecting of Rosiglitazone dosage group were similar with TNK-high dosage or TNK-middle dosage.
Conclusion:Tang-nai Kang Concoction have the effection of improving the insulin resistance and protecting the isletβcells function,prevented the T2DM development,which may realized through these links as follows:①Recovery the abnormal of insulin signal-transduction,controlled the goal proteins or genes expression level,increasing the activity of the goal points in insulin signal-transduction pathway for which decreasing the FPG、Fins levels and so on.②Through decreasing the TNF-αlevel to relief the interference factors on insulin signal-transduction pathwy.On the other hand,the mechanism of the serum containing Tangnai-Kang Compound improving insulin resistance might be up/down-regulated the expression of key points in post-receptor of insulin signal-transduetion roads,so increased GluT-4 translocation.
Objective:To study the effection of Tangnai-Kang concoction for insulin resistance and Insulin signal-transduction pathway in spontaneous diabetic animal model KKAy mouse and 3T3-L1 adipocytes,then explaining the mechanism of it.
Methods:In vivo,Specific pathogen free(SPF)KKAy mice 40 were divided randomly according to plasma glucose level into Models、TNK-low dosage、TNK-high dosage、Pioglitazone and normal C57BL/6J mice(normal control group).Each group was tested randomly plasma glucodelevel every week.60 days later,all animals were tested Fasting plasma glucose(FPG)、Fasting insulin level for caculating Insulin Sensitivity Index(ISI)、Total Cholesterol(TC)、Total triacylglycerol(TG)、High-density Lipoprotein Cholesterol (HDL-C)、Low- density Lipoprotein Cholesterol(LDL-C)、Floating fatty acid(FFA)、Tumor necrosis factor-a(TNF-a)and dying islet by HE.At the end,tested the muscle and adipose expression of PI3-K and GluT4 mRNA by reverse transcriptase PCR(RT-PCR),tested the expression of GSK 3βprotein level and PKB/AktlαSer 473 phosphorating level.In vitro, 3T3-L1 preadipocytes were cultured in vitro and differentiated into the matured adipocytes, dyed oil red "O" to authenticate.Then using dexamethasone and isulin induced insulin resistance in 3T3-L1 adipocyte.Divied cells into seven groups,such as Models、TNK-low dosage(4%serum)、TNK-middle dosage(8%serum)、TNK-high dosage(12%serum)、Rosiglitazone dosage(8%serum)、blank serum dosage and normal control group(3T3-L1 adipocytes).Treated the cells 48h,then extracted the total RNA and protein.At the end,tested the expression of InsR mRNA、IRS-1、PI-3K、GSK-3 protein and GluT-4 mRNA by reverse transcriptase PCR(RT-PCR)and Western blot.
Results:In vivo,compared with Model groups,FPG、TNF-a levels were all decreased significantly(p＜0.05);the expression of PI3-K and GluT4 mRNA were all up-regulated(p＜0.05 or p＜0.01);and PKB/Akt1αSer 473 phosphorating level were up-regulated at some degree(p＜0.05);the recipe could protectedβ-cells in some degree and postpontedβ-cells failure in islet,displayed decreasing tendency to the expression of GSK 3βprotein level and plasma lipocy and FFA levels.In vitro,compared with Model groups,the expression of everyone were upregulated in some degree following the serum concentration of Tangnai-Kang Compound.such as InsR and GluT-4 mRNA、IRS-1 and PI3-K p85 protein level, the expression of GSK-3βprotein level were down-regulated.The effecting of Rosiglitazone dosage group were similar with TNK-high dosage or TNK-middle dosage.
Conclusion:Tang-nai Kang Concoction have the effection of improving the insulin resistance and protecting the isletβcells function,prevented the T2DM development,which may realized through these links as follows:①Recovery the abnormal of insulin signal-transduction,controlled the goal proteins or genes expression level,increasing the activity of the goal points in insulin signal-transduction pathway for which decreasing the FPG、Fins levels and so on.②Through decreasing the TNF-αlevel to relief the interference factors on insulin signal-transduction pathwy.On the other hand,the mechanism of the serum containing Tangnai-Kang Compound improving insulin resistance might be up/down-regulated the expression of key points in post-receptor of insulin signal-transduetion roads,so increased GluT-4 translocation.
引文
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