小檗碱促进胰岛素分泌改善胰岛素抵抗的分子机制
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摘要
第一部分小檗碱对NIT-1细胞胰岛素分泌及葡萄糖激酶活性的影响
【目的】
观察小檗碱对NIT-1细胞在不同浓度葡萄糖刺激下胰岛素分泌的影响，检测小檗碱对葡萄糖激酶活性及表达的影响，以初步阐明小檗碱在体外促进胰岛素分泌的可能机制。
【方法】
将NIT-1细胞在含不同浓度葡萄糖(高浓度(16.5 mM)，低浓度(5.5 mM))的培养基中培养，并用不同浓度小檗碱干预，选用生物素作为阳性对照药。用放免法检测胰岛素浓度，液体闪烁计数法检测葡萄糖利用，生物发光技术检测ATP含量，酶法分析检测葡萄糖激酶活性，Western blot检测葡萄糖激酶(GK)和葡萄糖激酶调节蛋白(GKRP)在蛋白水平表达的变化，并用免疫荧光技术检测葡萄糖激酶在细胞核内外转移。
【结果】
在高浓度葡萄糖刺激下，与空白对照组相比较，小檗碱能使葡萄糖刺激下NIT-1细胞胰岛素分泌水平升高，葡萄糖利用增强，ATP含量增加，GK活性提高；同时，小檗碱能使细胞内GK表达增加而GKRP表达减少，还能使GK在细胞浆内的表达增加，小檗碱的这些生物学效应与已被证实的葡萄激酶激活剂生物素相比较无显著差异。在低浓度葡萄糖刺激，小檗碱和生物素的上述活性与空白对照组比较无显著差异。
【结论】
小檗碱能促进NIT-1细胞在高浓度葡萄糖刺激下的胰岛素分泌；这种效应的可能机制是：小檗碱作为GK激活剂，使GK表达增强而GKRP表达减少，促进GK向细胞核外转运，从而使GK活性增强，最终使胰岛素分泌增强。
第二部分小檗碱改善高糖高脂饮食加小剂量STZ诱导的2型糖尿病大鼠靶组织内质网应激的研究
【目的】
建立高糖高脂饮食加小剂量STZ诱导的2型糖尿病大鼠模型，观察小檗碱对2型糖尿病大鼠糖脂代谢的影响，同时检测肝脏和脂肪组织中内质网应激相关分子和胰岛素信号转导相关蛋白表达的影响，以探讨小檗碱改善胰岛素抵抗、治疗2型糖尿病的分子机制。
【方法】
采用高糖高脂饮食喂养加尾静脉注射小剂量链脲佐菌素(streptozotocin，STZ，15mg／kg)的方法建立2型糖尿病大鼠模型，将造模动物随机分为模型组、小檗碱组、4-苯基丁酸组，另设正常对照组。药物干预治疗6周后，进行口服糖耐量试验(oralglucose tolerance test，OGTT)并检测各组动物空腹血糖(fasting blood glucose，FBG)、空腹血清胰岛素(fasting serum insulin，FINS)、总胆固醇、甘油三酯、低密度脂蛋白和高密度脂蛋白值，并用Western blot检测各组大鼠肝脏和脂肪组织中总JNK和c-Jun-磷酸化水平、总IRS-1和AKT蛋白及磷酸化的水平，用RT-PCR检测GRP78和ORP150基因转录水平。
【结果】
与模型组比较，小檗碱能显著改善大鼠OGTT，降低FBG，升高FIN，使总胆固醇、甘油三酯、低密度脂蛋白显著降低，而高密度脂蛋白升高；同时，大鼠肝脏和脂肪组织中JNK活性降低，而GRP78和ORP150基因转录水平显著下调，小檗碱还能使外周组织胰岛素刺激后IRS-1 Ser307磷酸化水平下调，而AKT Ser473磷酸化水平升高；小檗碱的上述效应与已被证实的具有改善内质网应激的4-苯基丁酸治疗组相比无显著差异。
【结论】
小檗碱通过减缓2型糖尿病大鼠肝脏和脂肪组织内质网应激并改善胰岛素信号转导从而发挥降糖降脂的生物学活性。
第三部分小檗碱对衣霉素诱导的肝细胞内质网应激和胰岛素信号转导的影响
【目的】
建立衣霉素诱导肝细胞内质网应激的细胞模型，研究小檗碱对肝细胞葡萄糖代谢的效应，并检测小檗碱对内质网应激标志物JNK活性和胰岛素信号转导相关蛋白的影响，探讨小檗碱改善胰岛素抵抗的分子机制。
【方法】
分别以0.5μg／ml或2.0μg／ml衣霉素作用于Hep G2肝细胞诱导产生内质网应激，并予以小檗碱预处理，同时选用4-苯基丁酸作为阳性对照药，分别用葡萄糖氧化酶法检测培养液中葡萄糖消耗和葡萄糖合成水平，Western blot检测JNK和c-Jun-磷酸化表达水平，总IRS-1和AKT蛋白表达及其磷酸化水平；并用real time-PCR检测小檗碱对HepG2细胞内质网应激状态下GRP78和ORP150基因表达的影响。
【结果】
与模型组比较，小檗碱能显著改善Hep G2细胞胰岛素刺激下葡萄糖消耗，抑制肝细胞葡萄糖合成，并使JNK活性降低、而使GRP78和ORP150基因表达显著降低，同时，小檗碱能使IRS-1 Ser307磷酸化水平减少，而使AKT Ser473磷酸化水平增加；小檗碱的上述生物学效应与4-苯基丁酸治疗组相比无显著差异。
【结论】
小檗碱可以明显改善衣霉素诱导的Hep G2细胞内质网应激和胰岛素抵抗，其分子机制可能与小檗碱阻断JNK的激活，抑制内质网应激伴侣分子GRP78和ORP150基因转录，从而增强内质网折叠功能，减少IRS-1 Ser307磷酸化水平，进一步使AKT Ser473磷酸化水平升高；因此我们推测小檗碱增强胰岛素敏感性，改善糖代谢效应可能与其减轻内质网应激有关。
Part 1 Berberine as a novel glucokinase activator modulatesinsulinoma cell function
【Objective】
To explore the effect of berberine on insulin secretion on NIT-1 cells line stimulatedwith different concentration of glucose, and to detect the effects of berberine on the activityand expression of glucokinase to reveal the potential mechanism of promoting insulinsecretion of berberine in vitro.
【Methods】
NIT-1 cells were stimulated with different concentration of glucose (high concentrationat 16.5 mM and low concentration at 5.5 mM) and were treated with different concentrarionof berberine, while biotin was used as positive control. The concentration of insulin wasmeasured with radioimmunoassay. The glucose utilization of NIT-1 cells was detected withliquid scintillation counting, while cellular ATP content with bioluminescence technique,glucokinase (GK) activity with enzymatic analysis respectively. GK and Glucokinaseregulatory protein (GKRP) expression were determined with Western blot, and GKtranslocation from nucleus to cytoplasm were measured with immunofluorescenece.
【Results】
Compared to blank group, berberine could promote GSIS, fercilitate glucose utilization,increase ATP content and GK activity, it could can improve GK expression, whereas theGKRP expression was inhibited, GK translocation from nucleus to cytoplasm was enhancedwhen cells were stimulated with high concentration of glucose, there were no significantdeviation for these effects when compared to biotin-a reagent which was been confirmed asGK activator. However, when NIT-1 cells were stimulated with low concentration ofglucose, all these activities of berberine or biotin were not been detected in comparison with blank group.
【Conclusion】
Berberine could promote GSIS, this action may be closely related to that berberineworked as GK activator, thus increasing the expression of GK but decreasing the expressionof GKRP, improving GK translocation from nucleus to cytoplasm thereby augmente GKactivity and promote insulin secretion ultimately when cells were stimulated with highconcentration of glucose.
Part 2 Ameliorative Effect of berberine on endoplasmicreticulum stress in periphery organs of T2DM rats induced byhigh sucrose-fat diet and low-dose STZ
【Objective】
To observe the effects of berberine on glycolipids metabolism in rat with type 2diabetes mellitus (T2DM) induced by high sucrose-fat diet and low-dose STZ, and to detectthe effects of berberine on the expression of markers of endoplasmic reticulum stress andproteins related with insulin signal transduction in liver and adipose tissue to reveal themechanism of berberine on the therapeutic mechanism of type 2 diabetes mellitus.
【METHODS】
The rats with T2DM were induced by high sucrose-fat diet and the intravenousinjection of low-dose streptozotocin (STZ, 15mg/kg). Then modeled diabetic animals weredivided into model, berberine and 4-phenyl butyric acid (PBA) group, normal rats fed withcommon chow were designated as normal group. Six weeks later, the oral glucose tolerancetest (OGTT) was performed in all animals, the changes of routine body weight, fastingblood glucose (FBG), fasting serum insulin (FINS), total cholesterol (TC), triglyceride(TG), low density lipoprotein (LDL) and high density lipoprotein (HDL) were measuredrespectively, the expression of JNK and c-Jun-phosphorylation,total IRS-I and AKT, IRS-1ser307 and AKT phosphorylation were detected with Western blot, the expression ofGRP78和ORP150 were measured with RT-PCR.
【RESULTS】
Compared with the model group, the result of OGTT was improved, the levels of thebody weights and FBG was decreased, FIN was increased, while TC, TG, LDL weredecreased and HDL was enhanced, meanwhile, the activity of JNK was reduced, GRP78and ORP150 transduction were down-regulated significantly after treated with berberine.Berberine could inhibite IRS-1 Ser307 after stimulation with insulin. It also enhanced the expression of AKT Ser473 obviously; there were no significant difference of these effectsas compared to PBA group.
[CONCLUSION]
It is suggested that the therapeutic effects of berberine on T2DM might be related to itsability of alleviating endoplasmic reticulum stress and improve insulin resistance.
Part 3 Berberine reduces endoplasmic reticulum stress andimproves insulin signal transduction in Hep G2 cells
【Objective】
This study was carried out to investigate the effect of berberine on glucose metabolismon Hep G2 cells on the condition of endoplasmic reticulum stress induced withtunicamycine, and to detect the effects of berberine on markers of endoplasmic reticulumstress and insulin resistance to reveal the possible molecular mechanism of berberine onimprove insulin resistance.
【Methods】
Hep G2 cells were exposed to tumicamycin to induce tthe endoplasmic reticulum stress,the cells were pretreated with berberine or PBA. Glucose metabolism were measured withglucose oxidase method, the markers of ER stress-JNK were assessed with Western blot.The chaperones of ER stress -GRP78, ORP150 were detected with real time-PCR.Moreover, Ser~(307) phosphorylations of IRS-1, Ser473 phosphorylation of AKT weredetermined with Western blot.
【Results】
Berberine could enhance glucose uptake and inhibit glucose production when Hep G2cells were stimulated with insulin after the cells were exposed to tunicamycineo Meanwhile,the activity of JNK was blocked, Ser~(307) phosphorylations of IRS-1 was decreased whileasSer473 phosphorylation of AKT were increased, while GRP78 and ORP150 transductionwere down-regulated when cells wre treated with berberine.
【Conelution】
Berberine could alleviate the endoplasmic reticulum stress and insulin resistance inHep G2 cells induced with tunicamycine, the potential therapeutic mechanism of berberinemight be related with its inhibiting the activity of JNK and the transduction of GRP78 and ORP150. Therefore, it is suggested that berberine might improve ER folding capacity, andreduce IRS-1 Ser~(307) phosphorylation and enhance AKT Ser~(473) phosphorylation. Thus wepresume that the antidiabetic effect of berberine may be related to the reduction of ERstress and improvement of insulin signal transduction in Hep G2 cells.
【目的】
观察小檗碱对NIT-1细胞在不同浓度葡萄糖刺激下胰岛素分泌的影响，检测小檗碱对葡萄糖激酶活性及表达的影响，以初步阐明小檗碱在体外促进胰岛素分泌的可能机制。
【方法】
将NIT-1细胞在含不同浓度葡萄糖(高浓度(16.5 mM)，低浓度(5.5 mM))的培养基中培养，并用不同浓度小檗碱干预，选用生物素作为阳性对照药。用放免法检测胰岛素浓度，液体闪烁计数法检测葡萄糖利用，生物发光技术检测ATP含量，酶法分析检测葡萄糖激酶活性，Western blot检测葡萄糖激酶(GK)和葡萄糖激酶调节蛋白(GKRP)在蛋白水平表达的变化，并用免疫荧光技术检测葡萄糖激酶在细胞核内外转移。
【结果】
在高浓度葡萄糖刺激下，与空白对照组相比较，小檗碱能使葡萄糖刺激下NIT-1细胞胰岛素分泌水平升高，葡萄糖利用增强，ATP含量增加，GK活性提高；同时，小檗碱能使细胞内GK表达增加而GKRP表达减少，还能使GK在细胞浆内的表达增加，小檗碱的这些生物学效应与已被证实的葡萄激酶激活剂生物素相比较无显著差异。在低浓度葡萄糖刺激，小檗碱和生物素的上述活性与空白对照组比较无显著差异。
【结论】
小檗碱能促进NIT-1细胞在高浓度葡萄糖刺激下的胰岛素分泌；这种效应的可能机制是：小檗碱作为GK激活剂，使GK表达增强而GKRP表达减少，促进GK向细胞核外转运，从而使GK活性增强，最终使胰岛素分泌增强。
第二部分小檗碱改善高糖高脂饮食加小剂量STZ诱导的2型糖尿病大鼠靶组织内质网应激的研究
【目的】
建立高糖高脂饮食加小剂量STZ诱导的2型糖尿病大鼠模型，观察小檗碱对2型糖尿病大鼠糖脂代谢的影响，同时检测肝脏和脂肪组织中内质网应激相关分子和胰岛素信号转导相关蛋白表达的影响，以探讨小檗碱改善胰岛素抵抗、治疗2型糖尿病的分子机制。
【方法】
采用高糖高脂饮食喂养加尾静脉注射小剂量链脲佐菌素(streptozotocin，STZ，15mg／kg)的方法建立2型糖尿病大鼠模型，将造模动物随机分为模型组、小檗碱组、4-苯基丁酸组，另设正常对照组。药物干预治疗6周后，进行口服糖耐量试验(oralglucose tolerance test，OGTT)并检测各组动物空腹血糖(fasting blood glucose，FBG)、空腹血清胰岛素(fasting serum insulin，FINS)、总胆固醇、甘油三酯、低密度脂蛋白和高密度脂蛋白值，并用Western blot检测各组大鼠肝脏和脂肪组织中总JNK和c-Jun-磷酸化水平、总IRS-1和AKT蛋白及磷酸化的水平，用RT-PCR检测GRP78和ORP150基因转录水平。
【结果】
与模型组比较，小檗碱能显著改善大鼠OGTT，降低FBG，升高FIN，使总胆固醇、甘油三酯、低密度脂蛋白显著降低，而高密度脂蛋白升高；同时，大鼠肝脏和脂肪组织中JNK活性降低，而GRP78和ORP150基因转录水平显著下调，小檗碱还能使外周组织胰岛素刺激后IRS-1 Ser307磷酸化水平下调，而AKT Ser473磷酸化水平升高；小檗碱的上述效应与已被证实的具有改善内质网应激的4-苯基丁酸治疗组相比无显著差异。
【结论】
小檗碱通过减缓2型糖尿病大鼠肝脏和脂肪组织内质网应激并改善胰岛素信号转导从而发挥降糖降脂的生物学活性。
第三部分小檗碱对衣霉素诱导的肝细胞内质网应激和胰岛素信号转导的影响
【目的】
建立衣霉素诱导肝细胞内质网应激的细胞模型，研究小檗碱对肝细胞葡萄糖代谢的效应，并检测小檗碱对内质网应激标志物JNK活性和胰岛素信号转导相关蛋白的影响，探讨小檗碱改善胰岛素抵抗的分子机制。
【方法】
分别以0.5μg／ml或2.0μg／ml衣霉素作用于Hep G2肝细胞诱导产生内质网应激，并予以小檗碱预处理，同时选用4-苯基丁酸作为阳性对照药，分别用葡萄糖氧化酶法检测培养液中葡萄糖消耗和葡萄糖合成水平，Western blot检测JNK和c-Jun-磷酸化表达水平，总IRS-1和AKT蛋白表达及其磷酸化水平；并用real time-PCR检测小檗碱对HepG2细胞内质网应激状态下GRP78和ORP150基因表达的影响。
【结果】
与模型组比较，小檗碱能显著改善Hep G2细胞胰岛素刺激下葡萄糖消耗，抑制肝细胞葡萄糖合成，并使JNK活性降低、而使GRP78和ORP150基因表达显著降低，同时，小檗碱能使IRS-1 Ser307磷酸化水平减少，而使AKT Ser473磷酸化水平增加；小檗碱的上述生物学效应与4-苯基丁酸治疗组相比无显著差异。
【结论】
小檗碱可以明显改善衣霉素诱导的Hep G2细胞内质网应激和胰岛素抵抗，其分子机制可能与小檗碱阻断JNK的激活，抑制内质网应激伴侣分子GRP78和ORP150基因转录，从而增强内质网折叠功能，减少IRS-1 Ser307磷酸化水平，进一步使AKT Ser473磷酸化水平升高；因此我们推测小檗碱增强胰岛素敏感性，改善糖代谢效应可能与其减轻内质网应激有关。
Part 1 Berberine as a novel glucokinase activator modulatesinsulinoma cell function
【Objective】
To explore the effect of berberine on insulin secretion on NIT-1 cells line stimulatedwith different concentration of glucose, and to detect the effects of berberine on the activityand expression of glucokinase to reveal the potential mechanism of promoting insulinsecretion of berberine in vitro.
【Methods】
NIT-1 cells were stimulated with different concentration of glucose (high concentrationat 16.5 mM and low concentration at 5.5 mM) and were treated with different concentrarionof berberine, while biotin was used as positive control. The concentration of insulin wasmeasured with radioimmunoassay. The glucose utilization of NIT-1 cells was detected withliquid scintillation counting, while cellular ATP content with bioluminescence technique,glucokinase (GK) activity with enzymatic analysis respectively. GK and Glucokinaseregulatory protein (GKRP) expression were determined with Western blot, and GKtranslocation from nucleus to cytoplasm were measured with immunofluorescenece.
【Results】
Compared to blank group, berberine could promote GSIS, fercilitate glucose utilization,increase ATP content and GK activity, it could can improve GK expression, whereas theGKRP expression was inhibited, GK translocation from nucleus to cytoplasm was enhancedwhen cells were stimulated with high concentration of glucose, there were no significantdeviation for these effects when compared to biotin-a reagent which was been confirmed asGK activator. However, when NIT-1 cells were stimulated with low concentration ofglucose, all these activities of berberine or biotin were not been detected in comparison with blank group.
【Conclusion】
Berberine could promote GSIS, this action may be closely related to that berberineworked as GK activator, thus increasing the expression of GK but decreasing the expressionof GKRP, improving GK translocation from nucleus to cytoplasm thereby augmente GKactivity and promote insulin secretion ultimately when cells were stimulated with highconcentration of glucose.
Part 2 Ameliorative Effect of berberine on endoplasmicreticulum stress in periphery organs of T2DM rats induced byhigh sucrose-fat diet and low-dose STZ
【Objective】
To observe the effects of berberine on glycolipids metabolism in rat with type 2diabetes mellitus (T2DM) induced by high sucrose-fat diet and low-dose STZ, and to detectthe effects of berberine on the expression of markers of endoplasmic reticulum stress andproteins related with insulin signal transduction in liver and adipose tissue to reveal themechanism of berberine on the therapeutic mechanism of type 2 diabetes mellitus.
【METHODS】
The rats with T2DM were induced by high sucrose-fat diet and the intravenousinjection of low-dose streptozotocin (STZ, 15mg/kg). Then modeled diabetic animals weredivided into model, berberine and 4-phenyl butyric acid (PBA) group, normal rats fed withcommon chow were designated as normal group. Six weeks later, the oral glucose tolerancetest (OGTT) was performed in all animals, the changes of routine body weight, fastingblood glucose (FBG), fasting serum insulin (FINS), total cholesterol (TC), triglyceride(TG), low density lipoprotein (LDL) and high density lipoprotein (HDL) were measuredrespectively, the expression of JNK and c-Jun-phosphorylation,total IRS-I and AKT, IRS-1ser307 and AKT phosphorylation were detected with Western blot, the expression ofGRP78和ORP150 were measured with RT-PCR.
【RESULTS】
Compared with the model group, the result of OGTT was improved, the levels of thebody weights and FBG was decreased, FIN was increased, while TC, TG, LDL weredecreased and HDL was enhanced, meanwhile, the activity of JNK was reduced, GRP78and ORP150 transduction were down-regulated significantly after treated with berberine.Berberine could inhibite IRS-1 Ser307 after stimulation with insulin. It also enhanced the expression of AKT Ser473 obviously; there were no significant difference of these effectsas compared to PBA group.
[CONCLUSION]
It is suggested that the therapeutic effects of berberine on T2DM might be related to itsability of alleviating endoplasmic reticulum stress and improve insulin resistance.
Part 3 Berberine reduces endoplasmic reticulum stress andimproves insulin signal transduction in Hep G2 cells
【Objective】
This study was carried out to investigate the effect of berberine on glucose metabolismon Hep G2 cells on the condition of endoplasmic reticulum stress induced withtunicamycine, and to detect the effects of berberine on markers of endoplasmic reticulumstress and insulin resistance to reveal the possible molecular mechanism of berberine onimprove insulin resistance.
【Methods】
Hep G2 cells were exposed to tumicamycin to induce tthe endoplasmic reticulum stress,the cells were pretreated with berberine or PBA. Glucose metabolism were measured withglucose oxidase method, the markers of ER stress-JNK were assessed with Western blot.The chaperones of ER stress -GRP78, ORP150 were detected with real time-PCR.Moreover, Ser~(307) phosphorylations of IRS-1, Ser473 phosphorylation of AKT weredetermined with Western blot.
【Results】
Berberine could enhance glucose uptake and inhibit glucose production when Hep G2cells were stimulated with insulin after the cells were exposed to tunicamycineo Meanwhile,the activity of JNK was blocked, Ser~(307) phosphorylations of IRS-1 was decreased whileasSer473 phosphorylation of AKT were increased, while GRP78 and ORP150 transductionwere down-regulated when cells wre treated with berberine.
【Conelution】
Berberine could alleviate the endoplasmic reticulum stress and insulin resistance inHep G2 cells induced with tunicamycine, the potential therapeutic mechanism of berberinemight be related with its inhibiting the activity of JNK and the transduction of GRP78 and ORP150. Therefore, it is suggested that berberine might improve ER folding capacity, andreduce IRS-1 Ser~(307) phosphorylation and enhance AKT Ser~(473) phosphorylation. Thus wepresume that the antidiabetic effect of berberine may be related to the reduction of ERstress and improvement of insulin signal transduction in Hep G2 cells.
引文
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