中药糖耐康干预炎症介导的胰岛素抵抗作用机制研究
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摘要
目的:探讨中药糖耐康对炎症介导的胰岛素抵抗的作用机制研究。
方法:实验分两部分进行:
1细胞实验
本实验采用3T3-L1脂肪细胞作为胰岛素抵抗细胞模型,首先将3T3-L1前脂肪细胞分化为成熟的脂肪细胞,通过油红“O”鉴定。然后通过地塞米松联合胰岛素建立胰岛素抵抗细胞模型,同时,制备中药糖耐康、西药吡格列酮、空白含药血清,通过MTT实验,确立含药血清浓度。将细胞分组,共计7组,分别为正常脂肪细胞组、模型组、空白血清(含空白血清浓度为6.4%)组、糖耐康低(含中药血清浓度为2.56%)、中(含中药血清浓度为6.4%)、高(含中药血清浓度为16%)剂量组、吡格列酮(含西药血清浓度为6.4%)组,作用72h后,收集细胞上清液进行TNF-α、IL-6、CRP、FFA的ELISA及比色法检测;Western blot法测定InsR蛋白、IRS-1 Tyr蛋白、IRS-1 Ser307蛋白及GLUT-4蛋白的表达含量;Real-time PCR测定PPAR-γ及IKKβ的mRNA表达;EMSA方法检测NF-κB蛋白及AP-1蛋白的活性。
2动物实验
本实验采用自发性GK大鼠配合高脂饲料复制2型糖尿病IR动物模型,将12周龄雄性SPF级GK大鼠55只按照随机血糖值≥11.1mmol/L的入组,并随机分为模型组(同体积蒸馏水)、吡格列酮组(每日灌服0.405mg/ml/100g)、糖耐康低(每日灌服0.116g/ml/100g)、中(每日灌服0.232g/ml/100g)、高(0.464g/ml/100g)剂量5组,并另设Wistar大鼠作为正常对照组(同体积蒸馏水),每日1次,连续给药8周,在第4周末、第8周末检测OGTT;8周后麻醉后取材检测FBG、Fins、HOMA-IR、TC、TG、LDL-C、HDL-C、TNF-α、CRP、IL-6水平,观察胰腺组织形态学改变。
结果:
1细胞实验
与模型组比较,中药糖耐康可显著降低胰岛素抵抗3T3-L1脂肪细胞中TNF-α、IL-6、CRP及FFA水平(P＜0.01);可降低IKKβmRNA表达量,并且使NF-κB及AP-1蛋白与DNA复合物的量也下降,同时增加脂肪细胞中PPAR-γmRNA表达;可升高InsR蛋白、p-IRS-1 Tyr941蛋白、GLUT-4蛋白水平,同时降低p-IRS-1 Ser307蛋白水平。
2动物实验
与模型组比较,中药糖耐康可降低GK大鼠血糖、胰岛素水平及HOMA-IR指数(P＜0.05或P＜0.01);可降低GK大鼠TG、LDL-C、FFA水平(P＜0.01),TC虽有一定下降,但无统计学意义(P＞0.05),同时升高HDL-C水平(P＜0.01);可降低GK大鼠TNF-α、CRP、IL-6水平(P＜0.01);可改善胰脏的病理损伤,对胰岛细胞有一定的保护作用。
结论:
中药糖耐康可降低血糖,改善IR状态,保护胰岛细胞,其机制主要为:
1.通过上调PPAR-γ表达、抑制炎症信号通路,从而降低炎症因子的产生,减少对胰岛素信号传导通路的干扰。
2.通过恢复胰岛素信号传导通路中异常的信号蛋白,从受体后水平改善胰岛素抵抗。
Objective:To study the mechanism of action of Tang Naikang about inflammation mediating insulin resistance
Methods:Experiment was divided two parts
1 Experiment in vitro
To Apply 3T3-L1 adipocytes as cellular model of insulin resistance.First,3T3-L1 pre -adipocytes were differentiated into mature adipocytes and dyed by oil red "O" to identi -fy.Then make use of dexamethasone and insulin to induce insulin resistance in 3T3-L1 adipocytes.At the same time,prepared the drug serum containing TNK,Pioglitazone and blank and established serum concentration with MTT method.Divided adipocytes into seven groups,such as normal adipocyte group,model group,blank serum group(6.4% serum),TNK-low dosage group(2.56%serum),TNK-middle dosage group(6.4%serum), TNK-high dosage group(16%serum),Pioglitazone group(6.4%group).Treated the cells in 72th and collected supernates to test the levels of tumor necrosis-alpha(TNF-α), interleukin-6(IL-6),C-reactive protein(CRP),floating fatty acid(FFA) by enzyme linked immunosorbent assay(ELISA) and colorimetric method.To detect the expression contents of InsR,p-IRS-1 Tyr,p-IRS-1 Ser307,GLUT-4 protein and PPAR-γmRNA,IKKβmRNA by western blot and Real-time PCR.Tested the acitivity of NF-κB and AP-1 protein by electrophoretic bobility shift assay(EMSA).
2 Experiment in vivo
To apply spontaneous GK rats accompanied high fat forages to duplicate insulin resistance animal model of T2DM.Specific pathogen free(SPF) and male GK rats 55 were entered into the experiment according to random blood sugar value≥11.1mmol/L and divided randomly into five group,such as model group(same volum distilled water), Pioglitazone group(0.405mg/ml/100g.d),TNK-low dosage group(0.116mg/ml/100g.d), TNK-middle dosage group((0.232mg/ml/100g.d),TNK-high dosage group(0.464mg/ml/ 100g.d),and Wistar rats 10 were normal control group(same volum distilled water).The rats were administrated successivly for 8 weeks and observed separately oral glucose tolerance test(OGTT) after 4 and 8 weeks.To dectect fasting blood glucose(FBG),fasing insulin level(Fins),calculating insulin resistance index(HOMA-IR),total cholesterol(TC), triacylglycerol(TG),low density lipoprotein cholesterol(LDL-C),high density lipoprotein cholesterol(HDL-C),floating fatty acid(FFA),tumor necrosis-alpha(TNF-α),interleukin -6(IL-6) and C-reactive protein(CRP),and observe pathological changes of pancreas after 8 weeks.
Results:
1 Experiment in vitro
Compared with model group,TNK could decrease significantly the levels of TNF-α、IL-6、CRP and FFA in 3T3-L1 adipocytes of insulin resistance(P＜0.01).To reduce the expression contents of IKKβmRNA and the acitivity of NF-κB and AP-1 protein,at the same time,and increase the expression of PPAR-γmRNA.Increased the expression contents of InsR,p-IRS-1 Tyr,GLUT-4 protein and decreased the expresion of p-IRS-1 Ser307.
2 Experiment in vivo
Compared with model group,TNK could decrease blood sugar,Fins,HOMA-IR in GK rats(P＜0.05 or P＜0.01).To reduce the levels of TG、LDL-C、FFA(P＜0.01) and increase the levels of HDL-C(P＜0.01).To decrease the levels of TNF-α、CRP、IL-6 (P＜0.01).To improve pathological damages of pancreas and protect islet cells.
Conclusion:
TNK could decrease blood sugar,inprove insulin resistance condition and protect islet cells.Its mechanisms are as follow:
(1)TNK could up-regulate the expression of PPAR-γ,inhibit the inflammatory signaling pathways,decrease the generation of inflammatory factors and reduced interfering with the insuiln signaling transduction pathway.
(2)TNK can recovery the abnormal signaling proteins in insulin signaling transduction pathway and improve insulin resistance in post-receptor level.
方法:实验分两部分进行:
1细胞实验
本实验采用3T3-L1脂肪细胞作为胰岛素抵抗细胞模型,首先将3T3-L1前脂肪细胞分化为成熟的脂肪细胞,通过油红“O”鉴定。然后通过地塞米松联合胰岛素建立胰岛素抵抗细胞模型,同时,制备中药糖耐康、西药吡格列酮、空白含药血清,通过MTT实验,确立含药血清浓度。将细胞分组,共计7组,分别为正常脂肪细胞组、模型组、空白血清(含空白血清浓度为6.4%)组、糖耐康低(含中药血清浓度为2.56%)、中(含中药血清浓度为6.4%)、高(含中药血清浓度为16%)剂量组、吡格列酮(含西药血清浓度为6.4%)组,作用72h后,收集细胞上清液进行TNF-α、IL-6、CRP、FFA的ELISA及比色法检测;Western blot法测定InsR蛋白、IRS-1 Tyr蛋白、IRS-1 Ser307蛋白及GLUT-4蛋白的表达含量;Real-time PCR测定PPAR-γ及IKKβ的mRNA表达;EMSA方法检测NF-κB蛋白及AP-1蛋白的活性。
2动物实验
本实验采用自发性GK大鼠配合高脂饲料复制2型糖尿病IR动物模型,将12周龄雄性SPF级GK大鼠55只按照随机血糖值≥11.1mmol/L的入组,并随机分为模型组(同体积蒸馏水)、吡格列酮组(每日灌服0.405mg/ml/100g)、糖耐康低(每日灌服0.116g/ml/100g)、中(每日灌服0.232g/ml/100g)、高(0.464g/ml/100g)剂量5组,并另设Wistar大鼠作为正常对照组(同体积蒸馏水),每日1次,连续给药8周,在第4周末、第8周末检测OGTT;8周后麻醉后取材检测FBG、Fins、HOMA-IR、TC、TG、LDL-C、HDL-C、TNF-α、CRP、IL-6水平,观察胰腺组织形态学改变。
结果:
1细胞实验
与模型组比较,中药糖耐康可显著降低胰岛素抵抗3T3-L1脂肪细胞中TNF-α、IL-6、CRP及FFA水平(P＜0.01);可降低IKKβmRNA表达量,并且使NF-κB及AP-1蛋白与DNA复合物的量也下降,同时增加脂肪细胞中PPAR-γmRNA表达;可升高InsR蛋白、p-IRS-1 Tyr941蛋白、GLUT-4蛋白水平,同时降低p-IRS-1 Ser307蛋白水平。
2动物实验
与模型组比较,中药糖耐康可降低GK大鼠血糖、胰岛素水平及HOMA-IR指数(P＜0.05或P＜0.01);可降低GK大鼠TG、LDL-C、FFA水平(P＜0.01),TC虽有一定下降,但无统计学意义(P＞0.05),同时升高HDL-C水平(P＜0.01);可降低GK大鼠TNF-α、CRP、IL-6水平(P＜0.01);可改善胰脏的病理损伤,对胰岛细胞有一定的保护作用。
结论:
中药糖耐康可降低血糖,改善IR状态,保护胰岛细胞,其机制主要为:
1.通过上调PPAR-γ表达、抑制炎症信号通路,从而降低炎症因子的产生,减少对胰岛素信号传导通路的干扰。
2.通过恢复胰岛素信号传导通路中异常的信号蛋白,从受体后水平改善胰岛素抵抗。
Objective:To study the mechanism of action of Tang Naikang about inflammation mediating insulin resistance
Methods:Experiment was divided two parts
1 Experiment in vitro
To Apply 3T3-L1 adipocytes as cellular model of insulin resistance.First,3T3-L1 pre -adipocytes were differentiated into mature adipocytes and dyed by oil red "O" to identi -fy.Then make use of dexamethasone and insulin to induce insulin resistance in 3T3-L1 adipocytes.At the same time,prepared the drug serum containing TNK,Pioglitazone and blank and established serum concentration with MTT method.Divided adipocytes into seven groups,such as normal adipocyte group,model group,blank serum group(6.4% serum),TNK-low dosage group(2.56%serum),TNK-middle dosage group(6.4%serum), TNK-high dosage group(16%serum),Pioglitazone group(6.4%group).Treated the cells in 72th and collected supernates to test the levels of tumor necrosis-alpha(TNF-α), interleukin-6(IL-6),C-reactive protein(CRP),floating fatty acid(FFA) by enzyme linked immunosorbent assay(ELISA) and colorimetric method.To detect the expression contents of InsR,p-IRS-1 Tyr,p-IRS-1 Ser307,GLUT-4 protein and PPAR-γmRNA,IKKβmRNA by western blot and Real-time PCR.Tested the acitivity of NF-κB and AP-1 protein by electrophoretic bobility shift assay(EMSA).
2 Experiment in vivo
To apply spontaneous GK rats accompanied high fat forages to duplicate insulin resistance animal model of T2DM.Specific pathogen free(SPF) and male GK rats 55 were entered into the experiment according to random blood sugar value≥11.1mmol/L and divided randomly into five group,such as model group(same volum distilled water), Pioglitazone group(0.405mg/ml/100g.d),TNK-low dosage group(0.116mg/ml/100g.d), TNK-middle dosage group((0.232mg/ml/100g.d),TNK-high dosage group(0.464mg/ml/ 100g.d),and Wistar rats 10 were normal control group(same volum distilled water).The rats were administrated successivly for 8 weeks and observed separately oral glucose tolerance test(OGTT) after 4 and 8 weeks.To dectect fasting blood glucose(FBG),fasing insulin level(Fins),calculating insulin resistance index(HOMA-IR),total cholesterol(TC), triacylglycerol(TG),low density lipoprotein cholesterol(LDL-C),high density lipoprotein cholesterol(HDL-C),floating fatty acid(FFA),tumor necrosis-alpha(TNF-α),interleukin -6(IL-6) and C-reactive protein(CRP),and observe pathological changes of pancreas after 8 weeks.
Results:
1 Experiment in vitro
Compared with model group,TNK could decrease significantly the levels of TNF-α、IL-6、CRP and FFA in 3T3-L1 adipocytes of insulin resistance(P＜0.01).To reduce the expression contents of IKKβmRNA and the acitivity of NF-κB and AP-1 protein,at the same time,and increase the expression of PPAR-γmRNA.Increased the expression contents of InsR,p-IRS-1 Tyr,GLUT-4 protein and decreased the expresion of p-IRS-1 Ser307.
2 Experiment in vivo
Compared with model group,TNK could decrease blood sugar,Fins,HOMA-IR in GK rats(P＜0.05 or P＜0.01).To reduce the levels of TG、LDL-C、FFA(P＜0.01) and increase the levels of HDL-C(P＜0.01).To decrease the levels of TNF-α、CRP、IL-6 (P＜0.01).To improve pathological damages of pancreas and protect islet cells.
Conclusion:
TNK could decrease blood sugar,inprove insulin resistance condition and protect islet cells.Its mechanisms are as follow:
(1)TNK could up-regulate the expression of PPAR-γ,inhibit the inflammatory signaling pathways,decrease the generation of inflammatory factors and reduced interfering with the insuiln signaling transduction pathway.
(2)TNK can recovery the abnormal signaling proteins in insulin signaling transduction pathway and improve insulin resistance in post-receptor level.
引文
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