开郁清热方改善2型糖尿病β细胞功能的临床和实验研究
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摘要
胰岛素抵抗、β细胞功能不全是2型糖尿病发病(T2DM)的根本原因,胰岛素抵抗只有在β细胞功能不全的基础上才引起发病。近年来对β细胞分泌功能的研究越来越受到重视。胰岛素生成、胰岛素分泌和2型糖尿病的核心问题:β细胞。β细胞的数量和质量决定了β细胞的功能状况,而β细胞的功能既体现在胰岛素分泌的时相变化上,又表现在所分泌的胰岛素的数量和质量上。在T2DM的发生过程中,由于胰岛β细胞凋亡增加,使其功能降低,可能是导致糖尿病发病的机制之一。
导师多年从事糖尿病的临床与科研工作,特别关注现代糖尿病的研究进展,应用开郁清热法治疗肥胖T2DM是导师治疗2型糖尿病的重要学术思想之一。开郁清热方是在开郁清热法的指导下,针对肥胖T2DM的主要证型肝(胆)胃郁热证化裁大柴胡汤加减而来,前期研究初步证实此方可以改善2型糖尿病β细胞功能,本研究为阐明其作用机理做深入研究,从临床观察和动物实验两方面研究开郁清热方对T2DM胰岛素分泌的时相、分泌胰岛素的数量和质量的影响。
为了深入学习导师治疗2性糖尿病的学术思想,探讨开郁清热方治疗肥胖2型糖尿病的科学内涵,作者对β细胞功能的研究进展及中医药对β细胞功能保护的研究成果与问题进行了系统梳理,在全面整理导师治疗2型糖尿病的学术经验的基础上,设计了本课题临床研究和实验研究两部分内容。
临床研究部分以肥胖T2DM辨证为肝胃郁热证型患者为研究对象,与西药二甲双胍随机对照,采用OGTT方法研究肥胖T2DM胰岛素分泌的特点,观察药物干预治疗后体重、腰臀围比、血糖、胰岛素、胰岛素分泌指数、胰岛素敏感指数等指标变化,初步探讨了开郁清热方改善肥胖T2DM胰岛β细胞功能的作用机理。研究结果得出如下结论:1、肥胖T2DM胰岛素分泌在分泌时相、分泌数量和质量上较正常组有较大不同,应用真胰岛素评估β细胞结果更真实;2、开郁清热方有良好的减肥降脂功效,特别是可以显著降低WHR,对内脏脂肪的减少、改善腹型肥胖有较好的作用;3、开郁清热方可明显降低肥胖T2DM患者的空腹、糖负荷后血糖和糖化血红蛋白;4、开郁清热方通过改善β细胞后相分泌使得血糖整体水平下降,糖毒性的减少使得胰岛β细胞功能改善,胰岛素抵抗程度减轻。
动物实验研究部分以高脂饲养的SD大鼠腹腔注射小剂量的STZ造成的实验性糖尿病大鼠为模型,在疗效观察的基础上,通过免疫组化的方法观察胰岛细胞内胰岛素和β细胞凋亡的表达,初步揭示开郁清热方改善2型糖尿病胰岛β细胞功能的作用机制。研究结果得出如下结论:1、开郁清热方可明显降低实验性糖尿病大鼠的血糖,改善糖代谢紊乱,减轻糖毒性对胰岛β细胞功能的损害;开郁清热方可减肥调脂,改善脂代谢紊乱,减轻脂毒性对胰岛β细胞功能的损害;开郁清热方可增加实验性糖尿病大鼠静脉葡萄糖刺激的胰岛素分泌量及曲线下面积,增加胰岛素分泌指数,改善胰岛素分泌曲线,提高胰岛β细胞功能;开郁清热方可增加实验性糖尿病大鼠胰岛细胞内胰岛素表达阳性的β细胞数量,增加胰岛素的表达,促进胰岛素的合成及分泌;开郁清热方改善β细胞功能可能同其减少β细胞凋亡的作用有关,作用途径之一可能为增加Bcl-2蛋白表达,提高Bcl-2/Bax比率。
本研究从理论、临床、实验三方面系统研究了开郁清热方治疗2型糖尿病的因机证治、功能疗效及作用机理,拓展了经方的临床应用范围,为中医药治疗2型糖尿病胰岛功能受损的研究开拓了新的思路,同时本研究将现代科学研究技术与方法与传统方药有机结合,用现代语言诠释中医方药的作用机理,为中药走向世界进行了有益探索。
The main pathological mechanism of type 2 diabetes(T2DM) are insulin resistance(IR)and impairedβ-cell function,and now we think only if IR can't cause diabetes,it must have impairedβ-cell function simultaneously.In recent years,β-cell secretion function research has drawn more and more attention.β-cell is the core of insulin-production,insulin-secretion and T2DM.β-cell function is decided by the quality and quantity ofβ-cell,β-cell function is indicated not only by time phase fluctuation of insulin secretion but also by quality and quantity of insulin.In the course of T2DM,apoptosis increase cause disfunction ofβ-cells is the direct inducement to T2DM.
Professor Tong xiao-lin has make a great contribution to the research and cure of T2DM.The method of Kaiyuqingre to cure obese T2DM is his significant scientific attainments.Kaiyuqingre formula is evolved from Dachaihu dedoction, whose curative effect has been proved by former research.Our research observes the Kaiyuqingre formula' effect on quality,quantity and phase ofβ-cell in order to deeply explain its mechanism by clinical research and experiment research.
In the part of clinical study,We selected the patients of obese T2DM as subjects,observes the features of insulin-secretion through OGTT by random contrast with Metformin,observe the change of weight,BMI,WHR,blood sugar, insulin secretion,insulin secretion index,insulin sensitivity index and symptoms, and discuss initially the mechanism of Kaiyuqingre formula.We can draw the conclusions from the clinical results:First,Distinctive difference exists in the quality,quantity of insulin-secretion between the patients of obese T2DM and normal contrast group,it's the right way to evaluatedβ-cell function only by trueinsulin(TI).Second,Kaiyuqingre formula can produce a good curative effect on blood fat disorder obviously.Third,Kaiyuqingre formula can decrease FBG, PG2h and HBAIc obviously.Fourth,Kaiyuqingre formula can improve the later-phase secretion.
Experimental part selected the experiment DM rats by 8 weeks high fat feeding and injecting small dose STZ.We observe the expression of insulin, apoptosis ofβ-cells based on observing effect.We can draw the conclusions from the experimental results:Kaiyuqingre formula can decrease experiment DM rats's blood sugar,improve the disorder of fat metabolism,and then can lighten the damage of glucotoxicity and lipotoxicity toβ-cell function;increase insulin secretion,area,index;improve the insulin secretion and insulin secretion index curve and protectingβ-cell function;increase the expression of insulin in pancreatic islet and decrease theβ-cell apoptosis by increasing the expression of Blc-2 protein and ratio of Blc-2/Bax.
In our research,we discuss the pathological mechanism,curative effect of Kaiyuqingre formula through theoretical,clinical and experimental research. develop the extension of clinical range after the modification of Dachaihu dedoction.It will be a new train of thought for the research of impairedβ-cell function of T2DM by Chinese medicine.At the same time,it also establishes a firm foundation for the new Chinese medicine exploration of improvingβ-cell function.The Traditional Chinese Medicine's pathological mechanism is further revealed in modern language,by comprehensive application of modern scientific technology and method.
导师多年从事糖尿病的临床与科研工作,特别关注现代糖尿病的研究进展,应用开郁清热法治疗肥胖T2DM是导师治疗2型糖尿病的重要学术思想之一。开郁清热方是在开郁清热法的指导下,针对肥胖T2DM的主要证型肝(胆)胃郁热证化裁大柴胡汤加减而来,前期研究初步证实此方可以改善2型糖尿病β细胞功能,本研究为阐明其作用机理做深入研究,从临床观察和动物实验两方面研究开郁清热方对T2DM胰岛素分泌的时相、分泌胰岛素的数量和质量的影响。
为了深入学习导师治疗2性糖尿病的学术思想,探讨开郁清热方治疗肥胖2型糖尿病的科学内涵,作者对β细胞功能的研究进展及中医药对β细胞功能保护的研究成果与问题进行了系统梳理,在全面整理导师治疗2型糖尿病的学术经验的基础上,设计了本课题临床研究和实验研究两部分内容。
临床研究部分以肥胖T2DM辨证为肝胃郁热证型患者为研究对象,与西药二甲双胍随机对照,采用OGTT方法研究肥胖T2DM胰岛素分泌的特点,观察药物干预治疗后体重、腰臀围比、血糖、胰岛素、胰岛素分泌指数、胰岛素敏感指数等指标变化,初步探讨了开郁清热方改善肥胖T2DM胰岛β细胞功能的作用机理。研究结果得出如下结论:1、肥胖T2DM胰岛素分泌在分泌时相、分泌数量和质量上较正常组有较大不同,应用真胰岛素评估β细胞结果更真实;2、开郁清热方有良好的减肥降脂功效,特别是可以显著降低WHR,对内脏脂肪的减少、改善腹型肥胖有较好的作用;3、开郁清热方可明显降低肥胖T2DM患者的空腹、糖负荷后血糖和糖化血红蛋白;4、开郁清热方通过改善β细胞后相分泌使得血糖整体水平下降,糖毒性的减少使得胰岛β细胞功能改善,胰岛素抵抗程度减轻。
动物实验研究部分以高脂饲养的SD大鼠腹腔注射小剂量的STZ造成的实验性糖尿病大鼠为模型,在疗效观察的基础上,通过免疫组化的方法观察胰岛细胞内胰岛素和β细胞凋亡的表达,初步揭示开郁清热方改善2型糖尿病胰岛β细胞功能的作用机制。研究结果得出如下结论:1、开郁清热方可明显降低实验性糖尿病大鼠的血糖,改善糖代谢紊乱,减轻糖毒性对胰岛β细胞功能的损害;开郁清热方可减肥调脂,改善脂代谢紊乱,减轻脂毒性对胰岛β细胞功能的损害;开郁清热方可增加实验性糖尿病大鼠静脉葡萄糖刺激的胰岛素分泌量及曲线下面积,增加胰岛素分泌指数,改善胰岛素分泌曲线,提高胰岛β细胞功能;开郁清热方可增加实验性糖尿病大鼠胰岛细胞内胰岛素表达阳性的β细胞数量,增加胰岛素的表达,促进胰岛素的合成及分泌;开郁清热方改善β细胞功能可能同其减少β细胞凋亡的作用有关,作用途径之一可能为增加Bcl-2蛋白表达,提高Bcl-2/Bax比率。
本研究从理论、临床、实验三方面系统研究了开郁清热方治疗2型糖尿病的因机证治、功能疗效及作用机理,拓展了经方的临床应用范围,为中医药治疗2型糖尿病胰岛功能受损的研究开拓了新的思路,同时本研究将现代科学研究技术与方法与传统方药有机结合,用现代语言诠释中医方药的作用机理,为中药走向世界进行了有益探索。
The main pathological mechanism of type 2 diabetes(T2DM) are insulin resistance(IR)and impairedβ-cell function,and now we think only if IR can't cause diabetes,it must have impairedβ-cell function simultaneously.In recent years,β-cell secretion function research has drawn more and more attention.β-cell is the core of insulin-production,insulin-secretion and T2DM.β-cell function is decided by the quality and quantity ofβ-cell,β-cell function is indicated not only by time phase fluctuation of insulin secretion but also by quality and quantity of insulin.In the course of T2DM,apoptosis increase cause disfunction ofβ-cells is the direct inducement to T2DM.
Professor Tong xiao-lin has make a great contribution to the research and cure of T2DM.The method of Kaiyuqingre to cure obese T2DM is his significant scientific attainments.Kaiyuqingre formula is evolved from Dachaihu dedoction, whose curative effect has been proved by former research.Our research observes the Kaiyuqingre formula' effect on quality,quantity and phase ofβ-cell in order to deeply explain its mechanism by clinical research and experiment research.
In the part of clinical study,We selected the patients of obese T2DM as subjects,observes the features of insulin-secretion through OGTT by random contrast with Metformin,observe the change of weight,BMI,WHR,blood sugar, insulin secretion,insulin secretion index,insulin sensitivity index and symptoms, and discuss initially the mechanism of Kaiyuqingre formula.We can draw the conclusions from the clinical results:First,Distinctive difference exists in the quality,quantity of insulin-secretion between the patients of obese T2DM and normal contrast group,it's the right way to evaluatedβ-cell function only by trueinsulin(TI).Second,Kaiyuqingre formula can produce a good curative effect on blood fat disorder obviously.Third,Kaiyuqingre formula can decrease FBG, PG2h and HBAIc obviously.Fourth,Kaiyuqingre formula can improve the later-phase secretion.
Experimental part selected the experiment DM rats by 8 weeks high fat feeding and injecting small dose STZ.We observe the expression of insulin, apoptosis ofβ-cells based on observing effect.We can draw the conclusions from the experimental results:Kaiyuqingre formula can decrease experiment DM rats's blood sugar,improve the disorder of fat metabolism,and then can lighten the damage of glucotoxicity and lipotoxicity toβ-cell function;increase insulin secretion,area,index;improve the insulin secretion and insulin secretion index curve and protectingβ-cell function;increase the expression of insulin in pancreatic islet and decrease theβ-cell apoptosis by increasing the expression of Blc-2 protein and ratio of Blc-2/Bax.
In our research,we discuss the pathological mechanism,curative effect of Kaiyuqingre formula through theoretical,clinical and experimental research. develop the extension of clinical range after the modification of Dachaihu dedoction.It will be a new train of thought for the research of impairedβ-cell function of T2DM by Chinese medicine.At the same time,it also establishes a firm foundation for the new Chinese medicine exploration of improvingβ-cell function.The Traditional Chinese Medicine's pathological mechanism is further revealed in modern language,by comprehensive application of modern scientific technology and method.
引文
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[1]仝小林,消渴六论,中医杂志 2001.04:17;42(4):252-253
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[1]仝小林,消渴六论,中医杂志2001.04.17;42(4):252-253
[2]仝小林.降糖心悟,中国医药学报,2004;19(1):36
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[4]柳红芳,仝小林,朴信映肝胃郁热证在消渴病治疗中的辨识 中国中医基础医学杂志,2002年第8卷第3期65-67页
[5]谢杜红,仝小林,徐远 糖尿病从肝胃辨治论,中国中医药信息杂志 2003年2月第10卷第2期7-8页
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[1]赵昱,仝小林,刘素宾.开郁清热颗粒对2型糖尿病β细胞功能的影响.中华实用中 西医杂志,2005,18(16):712-715
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[8]Del-Prato,S;Tiengo,A.The importance of First-phase insulin:implications for the therapy 2 type diabetes mellitus.Diabetese/metabolism research and reviews 2001.Vol.17 P:164-174.
[9]仝小林、毕桂芝、甄仲.2518例肥胖2型糖尿病中医证型分类研究.世界中西医结合杂志.2008,3(1):26-28
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[1]Zahra Fatehi-Hassanabadl,Catherine B Chan.Transcriptional regulation of lipid metabolism by fatty acids:a key determinant of pancreatic β-cell function..Nutr Metab(Lond).2005;2:1.
[2]Kathrin Maedler,Pavel Sergeev,Fr(?)d(?)ric Ris,etc.Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets.J Clin Invest.2002 September 15;110(6):851-860.
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[6]赵昱,仝小林,刘素宾.糖脂灵对糖尿病前期患者β细胞-相分泌功能的影响.中国实验方剂学杂志.2006,(11):53-55
[7]LIU Hongfang(柳红芳),TONG Xiao--lin(仝小林),WANG Qingguo(王庆国) et al.Effect of Kaiyu Qingwei Granule(开郁清胃颗粒)on Insulin RecePtor in Liver and Skeletal Muscular Cell Membrane in Diabetes Mellitus Rats.CJIM,2003;9(2):132-135.
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[11]Gwenola Bougras,Pierre-Francois Cartron,Fabien Gautier etc.Opposite role of Bax and BCL-2 in the anti-tumoral responses of the immune system.BMC Cancer.2004;4:54.
[12]何庆、王保平、刘铭等。高浓度游离脂肪酸对胰岛细胞凋亡及相关基因表达的影响。天津医药2004 Vol.32,No.5 P:293-295.
[13]柳红芳,仝小林,朴信映肝胃郁热证在消渴病治疗中的辨识 中国中医基础医学杂志,2002年第8卷第3期65-67页
[14]谢杜红,仝小林,徐远 糖尿病从肝胃辨治论,中国中医药信息杂志 2003年2月第10卷第2期7-8页
[15]仝小林、段军,清泻肝郁胃热法在消渴病治疗中的地位和作用,中国实验方剂学杂志,2004 10(4):8
[2]年晓萍,孙改生,窦春梅,等.糖尿病患者胰岛素抵抗和β细胞功能与血糖水平的关系.中华医学杂志.2002,82(11):732.
[3]Zahra Fatehi-Hassanabadl,Catherine B Chan.Transcriptional regulation of lipid metabolism by fatty acids:a key determinant of pancreatic β-cell function..Nutr Metab(Lond).2005;2:1.
[4]Kathrin Maedler,Pavel Sergeev,Fr(?)d(?)ric Ris,etc.Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets.J Clin Invest.2002 September 15;110(6):851-860.
[5]Kathrin Maedler,Pavel Sergeev,Jan A.Ehses etc.Leptin modulates B cell expression of IL-1 receptor antagonist and release of IL-1β in human islets.Medical Sciences.2004 May 25;101(21):8138-8143.
[6]Ernesto Bernal-Mizrachi,Szabolcs Fatrai,James D etc..Defective insulin secretion and increased susceptibility to experimental diabetes are induced by reduced Akt activity in pancreatic islet β cells.J Clin Invest.2004 October 1;114(7):928-936.
[7]仝小林、毕桂芝、甄仲.2518例肥胖2型糖尿病中医证型分类研究.世界中西医结合杂志.2008,3(1):26-28
[8]赵昱,仝小林,刘素宾.开郁清热颗粒对2型糖尿病B细胞功能的影响.中华实用中西医杂志,2005,18(16):712-715
[9]赵昱,仝小林,刘素宾等.开郁清热颗粒对不同血糖水平患者β细胞功能的影响.北京中医药大学学报.2006,29(9);635-639
[10]赵昱,仝小林,刘素宾.糖脂灵对糖尿病前期患者β细胞-相分泌功能的影响.中国实验方剂学杂志.2006,(11):53-55
[11]LIU Hongfang(柳红芳),TONG Xiao-lin(仝小林),WANG Qingguo(王庆国)et al.Effect of Kaiyu Qingwei Granule(开郁清胃颗粒)on Insulin RecePtor in Liver and Skeletal Muscular Cell Membrane in Diabetes Mellitus Rats.CJIM,2003;9(2):132-135.
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