小檗碱降血糖作用的分子机理研究
摘要
高血糖是引起2型糖尿病最主要的危险因素,临床上血糖升高先于糖尿病发病,因此降低血糖可明显降低糖尿病发病率、改善机体对胰岛素的敏感性和降低糖尿病并发症的危险。体内血糖主要由肝脏、肌肉和脂肪组织代谢,经葡萄糖转运体(GLUT)转运而被细胞吸收。胰岛素受体(InsR)是位于细胞表面的跨膜受体,其表达调控机制至今尚未阐明。胰岛素通过与其受体的结合而增加葡萄糖的吸收和糖原合成来降低血糖,因此上调InsR的表达具有重要意义。目前临床应用最广泛的治疗2型糖尿病的主要药物有磺酰脲类、双胍类、α-葡萄糖苷酶抑制剂、噻唑烷二酮类。总体来说这些药物一般具有较好的降血糖疗效,但也有部分患者因不良反应(如肝毒性、低血糖、浮肿等)不能耐受其治疗,而有的患者药效反应则不够明显。因此,新型降血糖药物的发现一直是糖尿病药物研究的重点。
天然药物小檗碱(Berberine,BBR)在体内外具有明确的降血糖疗效。BBR是从黄连和黄柏等中草药中提取出来的生物碱,是具有明确化学结构的天然化合物,已报道有多种药理作用。BBR在我国已有很长的临床应用历史,过去主要作为抗菌药物治疗细菌性腹泻,其疗效和安全性均得到普遍认可。
为了研究未来BBR作为新型降血糖药物的可能性,我们研究BBR降血糖作用的分子机制,设计了一系列体内外和临床实验。BBR作用于体外培养的人肝细胞系HepG2和Bel-7402细胞后能显著上调InsR mRNA的表达。BBR的作用呈时间和剂量依赖性,其上调InsR的表达在处理细胞4h后即可显现,并可至少维持24h。BBR还可增加周边组织如胰腺细胞SW1990、结肠细胞HCT116、人胚肾细胞293T、淋巴细胞CEM等InsRmRNA的表达。BBR也能使细胞表面InsR蛋白的表达水平明显增加。BBR对细胞中InsRmRNA的半衰期基本没有影响。用带有InsR基因启动子和Luc报告基因的质粒共转染HepG2细胞后再用BBR处理,结果显示BBR可使InsR基因启动子的转录活性明显增加。说明BBR主要在转录水平通过增加InsR基因启动子的活性来增加其表达。
BBR在体外能显著降低培养基中葡萄糖的浓度,并且其降葡萄糖作用依赖胰岛素信号途径,去除培养基中的胰岛素或抑制PI3K的激酶活性能使BBR的降葡萄糖效应消失或显著下降。
BBR在体外能迅速激活PKC信号转导途径,并通过PKC通路激活InsR基因的启动子。PKC的激活在时间上提前于InsR表达的增加。BBR对PKC的激活也呈时间及剂量依赖性。PKC的激活是BBR上调InsR表达所必需的,用PKC抑制剂Calphostin C阻断PKC信号转导能使BBR上调InsR的表达作用显著降低,进一步的PKC亚型研究证明,BBR通过PKC中的PKCμ发挥作用。
BBR 75mg/kg/d和150mg/kg/d口服治疗15天后即可使高血糖Wistar大鼠的血糖浓度显著下降,肝脏及肌肉细胞中InsR mRNA的表达水平分别提高1.8倍和2.25倍;胰岛素敏感性增加2倍,并且显著提高肝组织中PKC的活性。BBR在2型糖尿病KK-Ay小鼠体内能显著降低血糖浓度及血液中胰岛素含量,增加InsR的表达。血液中胰岛素含量的降低与InsR表达的增加直接相关。BBR体内降血糖作用也依赖胰岛素信号途径,在缺失血液胰岛素的NOD/LtJ小鼠体内BBR降血糖作用消失,说明BBR主要应用于2型糖尿病的治疗。
BBR 0.5g每天2次口服给药治疗2个月后,使50例2型糖尿病患者禁食血糖、糖化血红蛋白、甘油三脂浓度分别下降25.9%、18.1%和17.6%。经BBR治疗后患者血液胰岛素浓度也明显下降,对患者外周血液淋巴细胞的检测也表明BBR能够上调其InsR的表达。所有患者在BBR治疗后未出现明显不良反应。BBR还能使患者的肝功能得到改善。
综上所述,我们的研究包括了从分子水平到细胞水平,从动物水平到临床试验等一系列工作,所有实验结论都说明BBR是一种安全可靠的新型降血糖药物,其作用机制不同于其他糖尿病治疗药物。我们认为BBR可单独应用或与其他类药物联合应用于2型糖尿病的临床治疗。
Blood glucose elevates in clinic before diabetic conditions and is by far one of the most important risk factors for the onset of diabetes.Lowering blood glucose significantly improves insulin sensitivity and decreases the mortality of diabetes.Insulin receptor(InsR) is a transmembrane receptor located on cell surface.Binding of insulin to InsR increases glucose uptake and glycogen synthesis.Up-regulation of InsR expression is considered to be one of the most effective means to lower blood glucose.Currently,the drugs widely-used to treat type 2 diabetes in clinic are Sulfonylureas,biguanide,α-Glucosidase Inhibitor and Thiazolidinedione. Although these drugs have good effects in blood glucose,a small portion of patients does not tolerate the adverse effects such as hepatotoxicity,hypoglycemia and edema et al,and the therapeutic effects are not satisfactory in some of the patients.Therefore,finding of new mechanism drugs to treat diabetes is highly desirable.
Berberine(BBR),an alkaloid from herbs(such as Coptis chinensis),is known to lower blood glucose and has a well-defined chemical structure.It has been used in China to treat diarrhea for decades.The clinical effectiveness and safety of BBR has been widely accepted.
To learn the glucose-lowering mechanism of BBR and explore the possibility of using BBR as a new drug to treat diabetes in the future,we have designed a series of experiments and the results are presented in the report.BBR up-regulates the expression of InsR mRNA in the human liver cell lines Bel-7402 and HepG2.The effect of BBR is in a time-and dose-dependent fashion.We found that InsR expression was up-regulated 4 hrs after BBR treatment and lasted for at least 24 hrs.BBR also up-regulates InsR mRNA expression in other types of human cells,such as pancreas cell SW1990,colon cell HCT116,human embryo kidney cell 293T and lymphocyte CEM.The InsR protein level on the cell surface was accordingly increased.BBR treatment didn't alter the half life of InsR mRNA.To learn if BBR enhances the transcriptional activity of InsR promoter,we used a plasmid containing the InsR promoter sequence and Luc reporter to transfect HepG2 cells,followed by BBR treatment.We found that BBR largely increased the activity of InsR gene promoter.These results indicated that BBR up-regulates InsR expression at the transcriptional level by promoting the transcriptional activity of InsR gene promoter.
Glucose concentration in the culture medium was largely decreased after BBR treatment in vitro.The increase of glucose consumption by BBR is mediated through the insulin signal way,because remove of insulin in the culture circumstances or blockage of the activity of PI3K abolishes or decreases the hypoglycemic effect of BBR.
BBR activates cellular PKC activity in a time- and dose-dependent manner,and increases the activity of InsR promoter through a PKC-mediated mechanism.Activation of PKC by BBR occurs before the increase of InsR expression.PKC activation is essential,because blocking PKC pathway by Calphostin C abolishes the effect of BBR on InsR up-regulation. Furthermore,PKCμ(PKD1),one of the subtypes of PKCs,was identified to be responsible for BBR's activity on InsR.
We have then studied the hypoglycemic effect of BBR in hyperglycaemia Wistar rats. Treating the rats with 75 mg/kg/d and 150 mg/kg/d of BBR(orally) for 15 days reduced blood glucose and up-regulated InsR mRNA in liver and muscle by 1.8 and 2.25 folds,respectively. The insulin sensitivity increased by 2 folds and the activity of PKC in the rat livers also elevated.BBR effectively reduced blood glucose in the type 2 diabetic KK-Ay mice.The hypoglycemic effect of BBR required the presence of insulin in the blood,because the therapeutic effect of BBR vanished in the NOD/LtJ mice that were null of blood insulin.
Fifty type 2 diabetic patients were then orally treated with BBR(0.5g,bid,for 2 months,). The treatment effectively lowered fasting blood glucose,haemoglobin A1c and triglyceride by 25.9%,18.1%and 17.6%,respectively.BBR also lowered blood insulin in these patients.InsR expressed on the peripheral blood lymphocytes elevated after BBR treatment.Liver function was improved.Side-effects in the BBR treated patients were not observed.
In conclusion,we consider BBR to be a promising glucose-lowering agent,with good safety and a new mechanism distinctive from that of the known diabetes drugs.
天然药物小檗碱(Berberine,BBR)在体内外具有明确的降血糖疗效。BBR是从黄连和黄柏等中草药中提取出来的生物碱,是具有明确化学结构的天然化合物,已报道有多种药理作用。BBR在我国已有很长的临床应用历史,过去主要作为抗菌药物治疗细菌性腹泻,其疗效和安全性均得到普遍认可。
为了研究未来BBR作为新型降血糖药物的可能性,我们研究BBR降血糖作用的分子机制,设计了一系列体内外和临床实验。BBR作用于体外培养的人肝细胞系HepG2和Bel-7402细胞后能显著上调InsR mRNA的表达。BBR的作用呈时间和剂量依赖性,其上调InsR的表达在处理细胞4h后即可显现,并可至少维持24h。BBR还可增加周边组织如胰腺细胞SW1990、结肠细胞HCT116、人胚肾细胞293T、淋巴细胞CEM等InsRmRNA的表达。BBR也能使细胞表面InsR蛋白的表达水平明显增加。BBR对细胞中InsRmRNA的半衰期基本没有影响。用带有InsR基因启动子和Luc报告基因的质粒共转染HepG2细胞后再用BBR处理,结果显示BBR可使InsR基因启动子的转录活性明显增加。说明BBR主要在转录水平通过增加InsR基因启动子的活性来增加其表达。
BBR在体外能显著降低培养基中葡萄糖的浓度,并且其降葡萄糖作用依赖胰岛素信号途径,去除培养基中的胰岛素或抑制PI3K的激酶活性能使BBR的降葡萄糖效应消失或显著下降。
BBR在体外能迅速激活PKC信号转导途径,并通过PKC通路激活InsR基因的启动子。PKC的激活在时间上提前于InsR表达的增加。BBR对PKC的激活也呈时间及剂量依赖性。PKC的激活是BBR上调InsR表达所必需的,用PKC抑制剂Calphostin C阻断PKC信号转导能使BBR上调InsR的表达作用显著降低,进一步的PKC亚型研究证明,BBR通过PKC中的PKCμ发挥作用。
BBR 75mg/kg/d和150mg/kg/d口服治疗15天后即可使高血糖Wistar大鼠的血糖浓度显著下降,肝脏及肌肉细胞中InsR mRNA的表达水平分别提高1.8倍和2.25倍;胰岛素敏感性增加2倍,并且显著提高肝组织中PKC的活性。BBR在2型糖尿病KK-Ay小鼠体内能显著降低血糖浓度及血液中胰岛素含量,增加InsR的表达。血液中胰岛素含量的降低与InsR表达的增加直接相关。BBR体内降血糖作用也依赖胰岛素信号途径,在缺失血液胰岛素的NOD/LtJ小鼠体内BBR降血糖作用消失,说明BBR主要应用于2型糖尿病的治疗。
BBR 0.5g每天2次口服给药治疗2个月后,使50例2型糖尿病患者禁食血糖、糖化血红蛋白、甘油三脂浓度分别下降25.9%、18.1%和17.6%。经BBR治疗后患者血液胰岛素浓度也明显下降,对患者外周血液淋巴细胞的检测也表明BBR能够上调其InsR的表达。所有患者在BBR治疗后未出现明显不良反应。BBR还能使患者的肝功能得到改善。
综上所述,我们的研究包括了从分子水平到细胞水平,从动物水平到临床试验等一系列工作,所有实验结论都说明BBR是一种安全可靠的新型降血糖药物,其作用机制不同于其他糖尿病治疗药物。我们认为BBR可单独应用或与其他类药物联合应用于2型糖尿病的临床治疗。
Blood glucose elevates in clinic before diabetic conditions and is by far one of the most important risk factors for the onset of diabetes.Lowering blood glucose significantly improves insulin sensitivity and decreases the mortality of diabetes.Insulin receptor(InsR) is a transmembrane receptor located on cell surface.Binding of insulin to InsR increases glucose uptake and glycogen synthesis.Up-regulation of InsR expression is considered to be one of the most effective means to lower blood glucose.Currently,the drugs widely-used to treat type 2 diabetes in clinic are Sulfonylureas,biguanide,α-Glucosidase Inhibitor and Thiazolidinedione. Although these drugs have good effects in blood glucose,a small portion of patients does not tolerate the adverse effects such as hepatotoxicity,hypoglycemia and edema et al,and the therapeutic effects are not satisfactory in some of the patients.Therefore,finding of new mechanism drugs to treat diabetes is highly desirable.
Berberine(BBR),an alkaloid from herbs(such as Coptis chinensis),is known to lower blood glucose and has a well-defined chemical structure.It has been used in China to treat diarrhea for decades.The clinical effectiveness and safety of BBR has been widely accepted.
To learn the glucose-lowering mechanism of BBR and explore the possibility of using BBR as a new drug to treat diabetes in the future,we have designed a series of experiments and the results are presented in the report.BBR up-regulates the expression of InsR mRNA in the human liver cell lines Bel-7402 and HepG2.The effect of BBR is in a time-and dose-dependent fashion.We found that InsR expression was up-regulated 4 hrs after BBR treatment and lasted for at least 24 hrs.BBR also up-regulates InsR mRNA expression in other types of human cells,such as pancreas cell SW1990,colon cell HCT116,human embryo kidney cell 293T and lymphocyte CEM.The InsR protein level on the cell surface was accordingly increased.BBR treatment didn't alter the half life of InsR mRNA.To learn if BBR enhances the transcriptional activity of InsR promoter,we used a plasmid containing the InsR promoter sequence and Luc reporter to transfect HepG2 cells,followed by BBR treatment.We found that BBR largely increased the activity of InsR gene promoter.These results indicated that BBR up-regulates InsR expression at the transcriptional level by promoting the transcriptional activity of InsR gene promoter.
Glucose concentration in the culture medium was largely decreased after BBR treatment in vitro.The increase of glucose consumption by BBR is mediated through the insulin signal way,because remove of insulin in the culture circumstances or blockage of the activity of PI3K abolishes or decreases the hypoglycemic effect of BBR.
BBR activates cellular PKC activity in a time- and dose-dependent manner,and increases the activity of InsR promoter through a PKC-mediated mechanism.Activation of PKC by BBR occurs before the increase of InsR expression.PKC activation is essential,because blocking PKC pathway by Calphostin C abolishes the effect of BBR on InsR up-regulation. Furthermore,PKCμ(PKD1),one of the subtypes of PKCs,was identified to be responsible for BBR's activity on InsR.
We have then studied the hypoglycemic effect of BBR in hyperglycaemia Wistar rats. Treating the rats with 75 mg/kg/d and 150 mg/kg/d of BBR(orally) for 15 days reduced blood glucose and up-regulated InsR mRNA in liver and muscle by 1.8 and 2.25 folds,respectively. The insulin sensitivity increased by 2 folds and the activity of PKC in the rat livers also elevated.BBR effectively reduced blood glucose in the type 2 diabetic KK-Ay mice.The hypoglycemic effect of BBR required the presence of insulin in the blood,because the therapeutic effect of BBR vanished in the NOD/LtJ mice that were null of blood insulin.
Fifty type 2 diabetic patients were then orally treated with BBR(0.5g,bid,for 2 months,). The treatment effectively lowered fasting blood glucose,haemoglobin A1c and triglyceride by 25.9%,18.1%and 17.6%,respectively.BBR also lowered blood insulin in these patients.InsR expressed on the peripheral blood lymphocytes elevated after BBR treatment.Liver function was improved.Side-effects in the BBR treated patients were not observed.
In conclusion,we consider BBR to be a promising glucose-lowering agent,with good safety and a new mechanism distinctive from that of the known diabetes drugs.
引文
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63.Kim SH,Shin EJ,Kim ED,Bayaraa T,Frost SC,Hyun CK.Berberine activates GLUT1-mediated glucose uptake in 3T3-L1 adipocytes.Biol Pharm Bull.2007,30(11):2120-2125.
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69.Barbara B Kahn.Type 2 diabetes:when insulin secretion fails to compensate for insulin resistance.Cell.1998,92:593-596.
70.盛美萍,孙淇,王宏.盐酸小檗碱在Beagle狗静脉注射和口服药动学研究.中国药理学通报.1993,9(1):64-67.
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74.Nakamaru K,Matsumoto K,Taguchi T,et al.AICAR,an activator of AMP-activated protein kinase,down-regulates the insulin receptor expression in HepG2 cells.Biochem Biophys Res Commun.2005,328 (2):449-54.
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70.盛美萍,孙淇,王宏.盐酸小檗碱在Beagle狗静脉注射和口服药动学研究.中国药理学通报.1993,9(1):64-67.
71.Kemp BE,Stapleton D,et al.AMP-activated protein kinase,super metabolic regulator.Biochem Soc Trans.2003,31 (Pt 1):162-8.
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73.Kazuhiko Nakamaru,Kazuya Matsumoto,et al.AICAR,an AMP-activated protein kinase,down-regulates the insulin receptor expression in HepG2 cells.Biochemical and Biophysical Research Communication.2005,328:449-454.
74.Nakamaru K,Matsumoto K,Taguchi T,et al.AICAR,an activator of AMP-activated protein kinase,down-regulates the insulin receptor expression in HepG2 cells.Biochem Biophys Res Commun.2005,328 (2):449-54.
1.Bandyopadhyay G,Standaert ML,Sajan MP,Karnitz L,Quon MJ,Farese RV.Dependence of insulin-stimulated glucose transporter 4 translocation on phosphoinositide-dependent protein kinase-1 and its target threonine-410 in the activation loop of protein kinase C-ζ.Mol Endocrinol.1999,13:1766-1771.
2.Standaert ML,Bandyopadhyay G,Kanoh Y,Sajan MP,Farese RV.Insulin and PIP3 PKC-ζby mechanisms that are both dependent and independent of phosphorylation of activation loop (T410)and autophosphorylation (T560)sites.Biochemistry.2001,40:249-255.
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