降糖消渴颗粒对DM大鼠的作用及AMPK信号通路的影响研究
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摘要
研究背景：
糖尿病是一个多因素参与的胰岛素相对不足和／或绝对不足导致的以高血糖为基本病生理改变的糖、脂肪、蛋白质代谢紊乱综合征,目前尚无特效疗法。中医药对糖尿病的防治具有独特的优势,可以在降低血糖的同时调整机体阴阳失衡状态,对糖尿病的慢性并发症亦有较好的预防和治疗作用。导师高思华教授依据多年临床经验,以中西医结合理论为指导,提出了立足肝脾肾三脏同治辨证治疗2型糖尿病的脏腑辨证新模式和系列方药。降糖消渴颗粒便是其中的最常用的方剂之一,系针对2型糖尿病最常见的“肝脾肾气阴两虚,挟热挟瘀”的证型而立,经多年临床证实安全有效,前期临床观察及文献分析均证实其组方的合理性。该方被列入国家重大新药创制专项中的治疗糖尿病的备选药物立题研究。本论文就是该课题研究的内容之一。
研究目的：
本课题组采用2型糖尿病大鼠模型,通过观察降糖消渴颗粒对糖尿病(DM)大鼠的糖脂代谢的一般指标(血糖、血脂、糖化血红蛋白、血清胰岛素、糖耐量、胰岛素耐量)、氧化应激指标、肝脏与胰腺组织病理,及腺苷酸活化蛋白激酶(AMPK)信号通路中相关成分的mRNA及蛋白表达的影响,探讨降糖消渴颗粒对糖尿病大鼠的降糖降脂作用,并初步探讨其作用的机制,为中医药治疗糖尿病提供实验依据。研究方法：
将50只体重180-200g的雄性SD大鼠,按体重大小编号,随机抽取10只作为正常对照组,予普通饲料喂养。其余40只大鼠高脂饲料喂养4周后,腹腔注射链脲佐菌素(STZ)30mg/kg BW.3天后检测禁食16h后血糖水平,以空腹血糖>16.7mmol/L为糖尿病造模成功标准。
造模成功后按血糖值随机分为糖尿病模型组11只,降糖消渴颗粒组11只,吡格列酮组10只。给药组分别给予降糖消渴颗粒(9g生药/kg BW),吡格列酮片(1.5mg/kgBW),模型组及正常组等量纯净水灌胃。药物干预4周。
每周记录大鼠体重,观察一般症状、记录饮水量、摄食量、尿量,以及给药前后大鼠空腹血糖(FBG)、随机血糖(RBG),实验结束前各组进行口服葡萄糖耐量试验((OGTT)及胰岛素耐量试验(ITT)实验。实验结束时,腹主动脉采血,取血清测定各组大鼠血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、肌酐(Cr)、尿素氮(BUN)、糖化血红蛋白(HbAlc)、FINS(空腹胰岛素),超氧化物歧化酶(SOD)、丙二醛(MDA)、一氧化氮(NO)水平,计算胰岛素敏感指数(ISI)。并取出大鼠胰腺、肝脏组织固定进行切片观测其病理改变。
检测大鼠肌肉组织AMPK a、葡萄糖转运子4(GLUT4)、胰岛素受体底物1(IRS-1) mRNA表达,以及AMPK a、p-AMPKα、GLUT4、IRS-1蛋白表达；肝脏组织AMPK a mRNA表达,以及AMPKα、 p-AMPKα、磷酸化乙酰辅酶A羧化酶(p-ACC)蛋白表达；脂肪组织瘦素mRNA表达。
研究结果：
一般症状：降糖消渴颗粒能缓解DM大鼠多饮、多食、多尿、消瘦的症状。
糖代谢指标：降糖消渴颗粒组大鼠FBC、RBG水平均明显低于模型组大鼠(P<0.05),且降低FBG效果存在时-效关系。降糖消渴颗粒对DM大鼠HbAlc、血清INS水平无显著影响(P>0.05),但能显著提高DM大鼠ISI(P<0.05),改善DM大鼠糖耐量及胰岛素耐量。
血脂指标：降糖消渴颗粒能够使DM大鼠血清TC、TG、LDL-C水平分别下降33%、57%、44%,同时使HDL-C水平提高69%,与模型组比较差异具有统计学意义(P<0.05)。
肝肾功能：降糖消渴颗粒能够使DM大鼠ALT降低50%(P<0.05),但对AST、 BUN、Cr的水平未见显著改变(P>0.05)。
病理改变：降糖消渴颗粒能够保护DM大鼠胰腺组织、肝脏组织的病理改变。
氧化应激指标：与模型组比较,降糖消渴颗粒能够明显增加DM大鼠SOD活性(提高60%),降低血清MDA和NO水平(分别降低34%、52%),组间差异具有统计学意义(P<0.01)。
AMPK信号通路：降糖消渴颗粒能上调DM大鼠肝脏、骨骼肌组织AMPK a mRNA及蛋白表达,且p-AMPK蛋白量亦明显增加(P<0.01)。降糖消渴颗粒能够提高DM大鼠骨骼肌组织GLUT4、IRS-1mRNA及蛋白表达量(P<0.01)。降糖消渴颗粒显著增加DM大鼠肝组织p-ACC蛋白表达(P<0.01),显著提高DM大鼠脂肪组织瘦素mRNA的表达(P<0.01)。
结论：
1.降糖消渴颗粒能降低DM大鼠血糖水平,调节糖代谢,改善胰岛素抵抗,维持体内葡萄糖稳态。
2.降糖消渴颗粒可以降低DM大鼠血脂水平,纠正脂代谢紊乱。
3.降糖消渴颗粒能够提高大鼠抗氧化应激能力,调整DM大鼠氧化应激状态。
4.降糖消渴能够调节AMPK-GLUT4和AMPK-IRS1-GLUT4信号通路,改善DM大鼠骨骼肌胰岛素抵抗,可能为其抗糖尿病的机制之一。
5.降糖消渴能够调节肝脏AMPK-ACC信号通路,促进脂肪酸氧化,调节脂肪代谢,可能为其抗糖尿病的机制之一。
6.立足肝脾肾三脏同治辨证治疗糖尿病的理论是有实验数据支持的。
本论文的创新之处在于首次将中医脏腑相关理论与AMPK能量代谢通路联系起来,应用高脂饮食联合STZ诱导的DM大鼠模型,观察肝脾肾三脏同调之组方“降糖消渴颗粒”在糖脂代谢等方面的药学作用,及其对机体氧化应激状态的影响。并在此基础上,通过研究降糖消渴颗粒对能量代谢关键分子AMPK及其上下游元件的基因及蛋白的影响,探讨降糖消渴颗粒对AMPK信号转导通路的影响,从而揭示其可能的作用机制,并为立足肝脾肾三脏同治辨证治疗糖尿病的理论提供新的实验数据支持。
Background
Diabetes mellitus (DM) is a multi-factorial metabolic disorder characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion and/or insulin action. Far from now, there is not an effective method for diabetes control. Traditional Chinese medicine (TCM) has played a significant role in treatment of diabetes for centuries. It acts on reducing blood glucose, as well as adjusting the balance between Yin and Yang, so it can also prevent and control the chronic complications besides DM. Based on the ample clinical experience and comprehensive understanding of TCM and western medicine theories, we proposed the novel theory based on zang-fu differentiation for treatment of DM. The root of the theory is diabetes should be treated based on regulating the function of liver, spleen and kidneys. And we also constructed a series of formula according to the above theory, of which Jiang Tang Xiao Ke Granule (JTXKG) was one of them. Function of JTXKG is to deal with the qi and yin deficiency of liver, spleen and kidney, as well as excessive heat and blood stasis. JTXKG has been proved to be effect and safe in clinic, so that it has been chosen as the important drugs for diabetes treatment for study by New Drug Development Program. This researches in this dissertation is part of the above program.
Objectives:
In the present study, we intended to study the pharmacological action of JTXKG in experimental diabetic rats. The observed indictors includes blood glucose, serum lipid profiles, serum glycosylated hemoglobin, fasting serum insulin, glucose tolerance and insulin tolerance, oxidative stress, liver and pancreatic pathological changes, and AMPK signal pathway. So that to investigate the hypoglycemic effect of JTXKG and the related mechanisms, and to provide experimental proofs for treatment of diabetes with TCM methods.
Methods:
50male Sprague Dawley rats, weighing180-200g, were numbered according to the body weight.10of them were randomly selected as the normal control rats, which were fed with normal diet. The other40rats were fed with high fat diet for4weeks, and then a single intraperitoneal injection of a prepared solution of STZ (30mg/kg suspended in0.1mol/L citrate buffer at pH4.5) was applied to induce diabetic models. If volume of fasting blood glucose (FBG) was not less than16.7mmol/L after72hours of STZ injection, the diabetic models were successful. The32diabetic rats were randomly divided into three groups.(1) drug-untreated diabetic rats;(2) and (3) diabetic rats treated with pioglitazone1.5mg/kg and JTXKG9g/kg, respectively. Both pioglitazone and JTXKG were dissolved in distilled water and given to the rats via gastrogavage once a day. The normal and drug-untreated DM rats were administrated with the same volume of vehicle. Drug intervention lasted for4weeks.
The body weight of the rats was record weekly. The fasting blood glucose (FBG) and the random blood glucose (RBG) before and after the treatment were detected. The oral glucose tolerance test (OGTT) and insulin tolerence test (ITT) were performed at the end of the study. We also measured the serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr), urea nitrogen (BUN), fasting insulin (FINS), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) and calculated the insulin sensitivity index (ISI). The pancreas and liver were removed and fixed for pathological observation.
The mRNA levels of AMPKa, GLUT4and IRS-1and the protein expression levels of AMPKa, p-AMPKa, GLUT4and IRS-1in muscle tissues were detected. The mRNA levels of AMPKa and the protein expression levels of AMPKa, p-AMPKa, p-ACC in liver tissues were determined. The mRNA of leptin in adipose tissue was also measured.
Results:
Improvement of the symptoms:The typical symptoms of DM, such as polydipsia, polyphagia, polyuria, and emaciation of rats were relieved by JTXKG.
Indicators of glucose metabolism:JTXKG reduced the FBG and RBG levels of the diabetic rats (P<0.05), and effect on reducing FBS was dose-dependent. The HbAlc and the serum insulin levels of the diabetic rats were not improved by JTXKG (P>0.05). JTXKG increased the ISI (P<0.05), and improved the glucose tolerance and the insulin tolerance of the diabetic rats.
Indicators of lipid metabolism:Compared with the model group, serum TC, TG, LDL-C levels of the rats in JTXKG group decreased by33%,57%and44%, respectively, and the serum HDL level increased by69%. And the difference between groups was significant (P0.05).
Liver and kidney function:JTXKG reduced the ALT level by50%(P<0.05), but it did not change the AST, BUN and Cr levels (P>0.05).
Pathological changes:JTXKG protected the pathological changes of the pancreatic and liver tissue of the diabetic rats.
Oxidative stress indicators:Compared with the model group, JTXKG increased the SOD activity by60%in diabetic rats, and it lowered serum MDA and NO levels by34%and52%, respectively. The difference between the groups was statistical significance (P<0.05).
Influence on AMPK signal pathway:The AMPK-a mRNA and protein expression in liver and skeletal muscle of the diabetic rats were lower than the normal rats. However, JTXKG increased the AMPK-a mRNA level, as well as the AMPKa and p-AMPKa protein expression in liver and muscle tissues. JTXKG up-regulated the mRNA level of GLUT4and IRS-1in the muscular tissues of diabetic rats. It enhanced the protein expression of GLUT4and IRS-1in the muscular tissues of diabetic rats. JTXKG significantly increased p-ACC protein expression in the liver tissue of diabetic rats. The mRNA expression of leptin in adipose tissue of diabetic rats was also increased by JTXKG.
Conclusion:
1JTXKG can reduce the blood glucose levels, regulate glucose metabolism, improve the insulin sensitivity, and maintain glucose homeostasis of the diabetic rats.
2JTXKG can decrease serum lipid profiles and regulate lipid metabolism of the diabetic
3JTXKG can improve the ability of anti-oxidative stress, adjust the oxidative stress state of the diabetic rats.
4JTXKG can regulate the AMPK-GLUT4-ISR-1signal pathway, so that it relieved insulin resistance in the muscle tissue of the diabetic rats, which may be one of the mechanism of JTXKG treating diabetes.
5JTXKG can regulate the AMPK-ACC signal pathway in the liver, through which it can promote fatty acid oxidation and regulate lipid metabolism. This may be another mechanism of JTXKG on diabetes.
6Theory of controlling DM by regulating the function of liver, spleen and kidney together is not only theoretically scientific but also supported by experimental data.
The innovation of the study is to research on the pharmacological and anti-oxidative effect of JTXKG on diabetic rats, which was induced by high fat diet combined with streptozotozin. The constructed principal of JTXKG, which is controlling DM by regulating the function of liver, spleen and kidney together, was innovated. And we further studied the influence of JTXKG on AMPK signal pathway, which is one of the most important pathway in glucose and lipid metabolism, so as to reveal the possible working mechanisms of JTXKG and provide the experimental data proof for the novel theory in DM treatment.
糖尿病是一个多因素参与的胰岛素相对不足和／或绝对不足导致的以高血糖为基本病生理改变的糖、脂肪、蛋白质代谢紊乱综合征,目前尚无特效疗法。中医药对糖尿病的防治具有独特的优势,可以在降低血糖的同时调整机体阴阳失衡状态,对糖尿病的慢性并发症亦有较好的预防和治疗作用。导师高思华教授依据多年临床经验,以中西医结合理论为指导,提出了立足肝脾肾三脏同治辨证治疗2型糖尿病的脏腑辨证新模式和系列方药。降糖消渴颗粒便是其中的最常用的方剂之一,系针对2型糖尿病最常见的“肝脾肾气阴两虚,挟热挟瘀”的证型而立,经多年临床证实安全有效,前期临床观察及文献分析均证实其组方的合理性。该方被列入国家重大新药创制专项中的治疗糖尿病的备选药物立题研究。本论文就是该课题研究的内容之一。
研究目的：
本课题组采用2型糖尿病大鼠模型,通过观察降糖消渴颗粒对糖尿病(DM)大鼠的糖脂代谢的一般指标(血糖、血脂、糖化血红蛋白、血清胰岛素、糖耐量、胰岛素耐量)、氧化应激指标、肝脏与胰腺组织病理,及腺苷酸活化蛋白激酶(AMPK)信号通路中相关成分的mRNA及蛋白表达的影响,探讨降糖消渴颗粒对糖尿病大鼠的降糖降脂作用,并初步探讨其作用的机制,为中医药治疗糖尿病提供实验依据。研究方法：
将50只体重180-200g的雄性SD大鼠,按体重大小编号,随机抽取10只作为正常对照组,予普通饲料喂养。其余40只大鼠高脂饲料喂养4周后,腹腔注射链脲佐菌素(STZ)30mg/kg BW.3天后检测禁食16h后血糖水平,以空腹血糖>16.7mmol/L为糖尿病造模成功标准。
造模成功后按血糖值随机分为糖尿病模型组11只,降糖消渴颗粒组11只,吡格列酮组10只。给药组分别给予降糖消渴颗粒(9g生药/kg BW),吡格列酮片(1.5mg/kgBW),模型组及正常组等量纯净水灌胃。药物干预4周。
每周记录大鼠体重,观察一般症状、记录饮水量、摄食量、尿量,以及给药前后大鼠空腹血糖(FBG)、随机血糖(RBG),实验结束前各组进行口服葡萄糖耐量试验((OGTT)及胰岛素耐量试验(ITT)实验。实验结束时,腹主动脉采血,取血清测定各组大鼠血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、肌酐(Cr)、尿素氮(BUN)、糖化血红蛋白(HbAlc)、FINS(空腹胰岛素),超氧化物歧化酶(SOD)、丙二醛(MDA)、一氧化氮(NO)水平,计算胰岛素敏感指数(ISI)。并取出大鼠胰腺、肝脏组织固定进行切片观测其病理改变。
检测大鼠肌肉组织AMPK a、葡萄糖转运子4(GLUT4)、胰岛素受体底物1(IRS-1) mRNA表达,以及AMPK a、p-AMPKα、GLUT4、IRS-1蛋白表达；肝脏组织AMPK a mRNA表达,以及AMPKα、 p-AMPKα、磷酸化乙酰辅酶A羧化酶(p-ACC)蛋白表达；脂肪组织瘦素mRNA表达。
研究结果：
一般症状：降糖消渴颗粒能缓解DM大鼠多饮、多食、多尿、消瘦的症状。
糖代谢指标：降糖消渴颗粒组大鼠FBC、RBG水平均明显低于模型组大鼠(P<0.05),且降低FBG效果存在时-效关系。降糖消渴颗粒对DM大鼠HbAlc、血清INS水平无显著影响(P>0.05),但能显著提高DM大鼠ISI(P<0.05),改善DM大鼠糖耐量及胰岛素耐量。
血脂指标：降糖消渴颗粒能够使DM大鼠血清TC、TG、LDL-C水平分别下降33%、57%、44%,同时使HDL-C水平提高69%,与模型组比较差异具有统计学意义(P<0.05)。
肝肾功能：降糖消渴颗粒能够使DM大鼠ALT降低50%(P<0.05),但对AST、 BUN、Cr的水平未见显著改变(P>0.05)。
病理改变：降糖消渴颗粒能够保护DM大鼠胰腺组织、肝脏组织的病理改变。
氧化应激指标：与模型组比较,降糖消渴颗粒能够明显增加DM大鼠SOD活性(提高60%),降低血清MDA和NO水平(分别降低34%、52%),组间差异具有统计学意义(P<0.01)。
AMPK信号通路：降糖消渴颗粒能上调DM大鼠肝脏、骨骼肌组织AMPK a mRNA及蛋白表达,且p-AMPK蛋白量亦明显增加(P<0.01)。降糖消渴颗粒能够提高DM大鼠骨骼肌组织GLUT4、IRS-1mRNA及蛋白表达量(P<0.01)。降糖消渴颗粒显著增加DM大鼠肝组织p-ACC蛋白表达(P<0.01),显著提高DM大鼠脂肪组织瘦素mRNA的表达(P<0.01)。
结论：
1.降糖消渴颗粒能降低DM大鼠血糖水平,调节糖代谢,改善胰岛素抵抗,维持体内葡萄糖稳态。
2.降糖消渴颗粒可以降低DM大鼠血脂水平,纠正脂代谢紊乱。
3.降糖消渴颗粒能够提高大鼠抗氧化应激能力,调整DM大鼠氧化应激状态。
4.降糖消渴能够调节AMPK-GLUT4和AMPK-IRS1-GLUT4信号通路,改善DM大鼠骨骼肌胰岛素抵抗,可能为其抗糖尿病的机制之一。
5.降糖消渴能够调节肝脏AMPK-ACC信号通路,促进脂肪酸氧化,调节脂肪代谢,可能为其抗糖尿病的机制之一。
6.立足肝脾肾三脏同治辨证治疗糖尿病的理论是有实验数据支持的。
本论文的创新之处在于首次将中医脏腑相关理论与AMPK能量代谢通路联系起来,应用高脂饮食联合STZ诱导的DM大鼠模型,观察肝脾肾三脏同调之组方“降糖消渴颗粒”在糖脂代谢等方面的药学作用,及其对机体氧化应激状态的影响。并在此基础上,通过研究降糖消渴颗粒对能量代谢关键分子AMPK及其上下游元件的基因及蛋白的影响,探讨降糖消渴颗粒对AMPK信号转导通路的影响,从而揭示其可能的作用机制,并为立足肝脾肾三脏同治辨证治疗糖尿病的理论提供新的实验数据支持。
Background
Diabetes mellitus (DM) is a multi-factorial metabolic disorder characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion and/or insulin action. Far from now, there is not an effective method for diabetes control. Traditional Chinese medicine (TCM) has played a significant role in treatment of diabetes for centuries. It acts on reducing blood glucose, as well as adjusting the balance between Yin and Yang, so it can also prevent and control the chronic complications besides DM. Based on the ample clinical experience and comprehensive understanding of TCM and western medicine theories, we proposed the novel theory based on zang-fu differentiation for treatment of DM. The root of the theory is diabetes should be treated based on regulating the function of liver, spleen and kidneys. And we also constructed a series of formula according to the above theory, of which Jiang Tang Xiao Ke Granule (JTXKG) was one of them. Function of JTXKG is to deal with the qi and yin deficiency of liver, spleen and kidney, as well as excessive heat and blood stasis. JTXKG has been proved to be effect and safe in clinic, so that it has been chosen as the important drugs for diabetes treatment for study by New Drug Development Program. This researches in this dissertation is part of the above program.
Objectives:
In the present study, we intended to study the pharmacological action of JTXKG in experimental diabetic rats. The observed indictors includes blood glucose, serum lipid profiles, serum glycosylated hemoglobin, fasting serum insulin, glucose tolerance and insulin tolerance, oxidative stress, liver and pancreatic pathological changes, and AMPK signal pathway. So that to investigate the hypoglycemic effect of JTXKG and the related mechanisms, and to provide experimental proofs for treatment of diabetes with TCM methods.
Methods:
50male Sprague Dawley rats, weighing180-200g, were numbered according to the body weight.10of them were randomly selected as the normal control rats, which were fed with normal diet. The other40rats were fed with high fat diet for4weeks, and then a single intraperitoneal injection of a prepared solution of STZ (30mg/kg suspended in0.1mol/L citrate buffer at pH4.5) was applied to induce diabetic models. If volume of fasting blood glucose (FBG) was not less than16.7mmol/L after72hours of STZ injection, the diabetic models were successful. The32diabetic rats were randomly divided into three groups.(1) drug-untreated diabetic rats;(2) and (3) diabetic rats treated with pioglitazone1.5mg/kg and JTXKG9g/kg, respectively. Both pioglitazone and JTXKG were dissolved in distilled water and given to the rats via gastrogavage once a day. The normal and drug-untreated DM rats were administrated with the same volume of vehicle. Drug intervention lasted for4weeks.
The body weight of the rats was record weekly. The fasting blood glucose (FBG) and the random blood glucose (RBG) before and after the treatment were detected. The oral glucose tolerance test (OGTT) and insulin tolerence test (ITT) were performed at the end of the study. We also measured the serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr), urea nitrogen (BUN), fasting insulin (FINS), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) and calculated the insulin sensitivity index (ISI). The pancreas and liver were removed and fixed for pathological observation.
The mRNA levels of AMPKa, GLUT4and IRS-1and the protein expression levels of AMPKa, p-AMPKa, GLUT4and IRS-1in muscle tissues were detected. The mRNA levels of AMPKa and the protein expression levels of AMPKa, p-AMPKa, p-ACC in liver tissues were determined. The mRNA of leptin in adipose tissue was also measured.
Results:
Improvement of the symptoms:The typical symptoms of DM, such as polydipsia, polyphagia, polyuria, and emaciation of rats were relieved by JTXKG.
Indicators of glucose metabolism:JTXKG reduced the FBG and RBG levels of the diabetic rats (P<0.05), and effect on reducing FBS was dose-dependent. The HbAlc and the serum insulin levels of the diabetic rats were not improved by JTXKG (P>0.05). JTXKG increased the ISI (P<0.05), and improved the glucose tolerance and the insulin tolerance of the diabetic rats.
Indicators of lipid metabolism:Compared with the model group, serum TC, TG, LDL-C levels of the rats in JTXKG group decreased by33%,57%and44%, respectively, and the serum HDL level increased by69%. And the difference between groups was significant (P0.05).
Liver and kidney function:JTXKG reduced the ALT level by50%(P<0.05), but it did not change the AST, BUN and Cr levels (P>0.05).
Pathological changes:JTXKG protected the pathological changes of the pancreatic and liver tissue of the diabetic rats.
Oxidative stress indicators:Compared with the model group, JTXKG increased the SOD activity by60%in diabetic rats, and it lowered serum MDA and NO levels by34%and52%, respectively. The difference between the groups was statistical significance (P<0.05).
Influence on AMPK signal pathway:The AMPK-a mRNA and protein expression in liver and skeletal muscle of the diabetic rats were lower than the normal rats. However, JTXKG increased the AMPK-a mRNA level, as well as the AMPKa and p-AMPKa protein expression in liver and muscle tissues. JTXKG up-regulated the mRNA level of GLUT4and IRS-1in the muscular tissues of diabetic rats. It enhanced the protein expression of GLUT4and IRS-1in the muscular tissues of diabetic rats. JTXKG significantly increased p-ACC protein expression in the liver tissue of diabetic rats. The mRNA expression of leptin in adipose tissue of diabetic rats was also increased by JTXKG.
Conclusion:
1JTXKG can reduce the blood glucose levels, regulate glucose metabolism, improve the insulin sensitivity, and maintain glucose homeostasis of the diabetic rats.
2JTXKG can decrease serum lipid profiles and regulate lipid metabolism of the diabetic
3JTXKG can improve the ability of anti-oxidative stress, adjust the oxidative stress state of the diabetic rats.
4JTXKG can regulate the AMPK-GLUT4-ISR-1signal pathway, so that it relieved insulin resistance in the muscle tissue of the diabetic rats, which may be one of the mechanism of JTXKG treating diabetes.
5JTXKG can regulate the AMPK-ACC signal pathway in the liver, through which it can promote fatty acid oxidation and regulate lipid metabolism. This may be another mechanism of JTXKG on diabetes.
6Theory of controlling DM by regulating the function of liver, spleen and kidney together is not only theoretically scientific but also supported by experimental data.
The innovation of the study is to research on the pharmacological and anti-oxidative effect of JTXKG on diabetic rats, which was induced by high fat diet combined with streptozotozin. The constructed principal of JTXKG, which is controlling DM by regulating the function of liver, spleen and kidney together, was innovated. And we further studied the influence of JTXKG on AMPK signal pathway, which is one of the most important pathway in glucose and lipid metabolism, so as to reveal the possible working mechanisms of JTXKG and provide the experimental data proof for the novel theory in DM treatment.
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