黄芪散干预2型糖尿病胰岛素抵抗机制及制剂基础研究
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摘要
胰岛素抵抗是2型糖尿病(T2DM)发生的重要因素和显著特征。因此针对胰岛素抵抗(IR)的治疗是防治糖尿病(DM)及代谢综合征的重中之重。中药防治疾病时主要采用复方的形式,体现了整体调节,综合治疗的特点。中药复方发挥其疗效的物质基础来自于其化学成分或活性部位,然而仅仅的几个单体化合物无法代表全方,应更重视化学成分群体或有效部位的作用。将复方有效部位进行配伍应用,则有可能使全方药效呈现增效协同的作用,同时降低不良反应的程度。因此,以中药有效部位进行组方,研制创新药物,创建在中医药理论指导下具有示范效应的创新中药的研究模式,提高中药产业的整体素质和竞争力。
黄芪散古方源自《圣济总录》,组方为:葛根、黄芪、桑白皮。三药相伍,益气健脾,益气清热,生津止渴,三消并治,共奏标本兼顾之效。大量研究表明三药对T2DM或IR具有良好的疗效,其药效物质基础及作用机制各有所不同,因此认为该方可能通过多途径、多靶点的综合效应来改善T2DM-IR。目前基于黄芪散整方的研究未见有报道,这使得该方的临床应用及开发具有一定的局限性。本研究首先立足于整方,试图阐明黄芪散干预T2DM-IR的作用及作用机制,并采用一系列现代中药制剂技术,富集各药有效部位,为黄芪散的进一步制剂开发奠定基础。
第一部分文献研究
文献研究方面全面查阅了近年来国内外T2DM-IR的现代医学研究进展,包括IR的流行病学研究、病因研究以及发病机制等相关文献资料,同时对DM的中医认识、黄芪散各药的化学成分和药理学研究进展进行文献研究。对目前现代医学和中医学对于T2DM-IR的发病机理、治疗用药,T2DM-IR分子机制的近期研究成果,以及动物模型的建立及研究方法等概况进行了较为系统的总结和综述,掌握了相关项目科研的前沿动态。
第二部分实验研究
1.黄芪散干预实验性2型糖尿病胰岛素抵抗的作用及机制研究
通过建立STZ所致DM小鼠模型、氢化可的松琥珀酸钠(HCSS)诱导的IR小鼠模型初步评价黄芪散对DM及IR的干预作用。结果表明黄芪散降低DM小鼠的空腹血糖(FBG),增加糖耐量,同时提高糖耐量异常而尚未形成DM的小鼠对胰岛素的敏感性,改善胰岛素抵抗。
采用STZ及高脂饮食建立T2DM-IR大鼠模型。通过对模型大鼠FBG、空腹胰岛素水平(FINS)、糖耐量、胰岛素耐量、胰岛素敏感指数(ISI)和抵抗指数(HOMA-IR)、血清和肝脏的脂质代谢及游离脂肪酸(FFA)水平测定、胰腺HE染色病理形态学检查,探讨黄芪散对T2DM-IR的糖脂代谢和IR的影响。结果表明黄芪散显著降低T2DM-IR大鼠的FBG,改善糖耐量,降低IR所形成的高FINS水平,提高胰岛素耐量,增加ISI指数和降低HOMA-IR指数,对胰腺组织结构的病变具有保护作用;同时黄芪散可调节血脂、肝脂、下调血清及肝脏中FFA的水平。提示黄芪散可改善糖脂代谢、提高胰岛素的敏感性发挥其治疗IR的作用。
在建立T2DM-IR模型大鼠的基础上,通过采用放免法测定血清中肿瘤坏死因子(TNF-α)、瘦素(leptin)水平,RT-PCR和免疫组化法测定肝脏、骨骼肌和脂肪组织中GLUT-4、IRS-1的mRNA和蛋白的表达,RT-PCR法测定脂肪组织中PPAR-γmRNA,探讨黄芪散改善IR的机制。结果表明黄芪散改善IR的机制表现在:①上调T2DM-IR大鼠骨骼肌和脂肪组织中GLUT-4的mRNA和蛋白的表达,提高肝脏、骨骼肌和脂肪组织中IRS-1的mRNA和蛋白的表达,从而调节胰岛素信号转导通路,促进葡萄糖的转运,增加外周组织对胰岛素的敏感性;②显著下调TNF-α,leptin的水平,改善胰岛素信号通路转导,减少脂肪分解,纠正脂肪-胰岛内分泌轴的反馈机制,改善机体对瘦素的敏感性,从而改善机体对胰岛素的敏感性;③促进脂肪组织中调控胰岛素敏感性的重要受体PPAR-γmRNA的表达,间接发挥其改善IR的作用。
2.黄芪散的制剂基础研究
对不同产地葛根、黄芪药材进行质量考察,筛选质量中等的药材进行工艺考察。对葛根总黄酮的提取纯化工艺进行了研究,考察不同乙醇浓度,溶媒倍量,提取时间、提取次数和提取温度对总黄酮转移率和纯度的影响,建立了四因素三水平的正交试验,最终确立了最佳的提取工艺为:10倍量70%乙醇加热回流提取2次,每次2小时。采用大孔吸附树脂对总黄酮粗提物进行了纯化处理,筛选了不同型号的树脂,考察树脂的静态、动态吸附性能,并对上样液浓度和流速,洗脱溶剂浓度和体积等相关因素进行优化,确立了最佳的纯化工艺为:AB-8型大孔吸附树脂,药材与干树脂重量比2:1,上样液浓度为0.10g生药/ml,依次用10BV蒸馏水、10BV50%乙醇以1～3ml/min的洗脱速度洗脱,收集50%乙醇部分,减压回收乙醇,冷冻干燥,得到的总黄酮纯度在62.0%以上。对10个批次的葛根药材进行总黄酮提取物的制备,建立薄层鉴别方法;确定提取物干燥失重限度;建立紫外—可见分光光度法以及高效液相色谱法对提取物中总黄酮和葛根素的含量测定方法,初步建立葛根总黄酮提取物的质量标准。
对黄芪总皂苷的提取纯化工艺进行了研究,考察不同乙醇浓度,溶媒倍量,提取时间、提取次数和提取温度对总皂苷转移率和纯度的影响,建立了四因素三水平的正交试验,最终确立最佳提取工艺为:8倍量70%乙醇加热回流提取3次,每次1.5小时。采用大孔吸附树脂对总皂苷粗提物进行了纯化处理,筛选了不同型号的树脂,考察了树脂的静态、动态吸附性能,并对上样液浓度和流速,洗脱溶剂浓度和体积等相关因素进行了优化,确立了最佳的纯化工艺为:药材与干树脂重量比3:1,上样液浓度为0.075g生药/ml,依次用10BV蒸馏水、10BV0.5%NaOH、10BV10%乙醇、10BV70%乙醇以1～3ml/min的洗脱速度洗脱,收集70%乙醇部分,减压回收乙醇,冷冻干燥,得到的总皂苷纯度在68.0%以上。对10个批次的黄芪药材进行总皂苷提取物的制备,建立薄层鉴别方法;确定提取物干燥失重限度;建立紫外—可见分光光度法以及高效液相色谱法对提取物中总皂苷和黄芪甲苷的含量测定方法,初步建立黄芪总皂苷提取物的质量标准。
Insulin resistance(IR) is important factor and dominant feature in type 2 diabetes mellitus pathogenesis.Therefore IR treatment is the most important in prevention and treating diabetes mellitus and metabolic syndrome.Chinese medicine mainly apply compound recipe to treat disease,displaying features of integral regulation and combined therapy.Chinese herbal compound effective material basis are its chemical compositions or active sites,however just a few monomer compounds cannot be representing the whole recipe,should attach more important to the role of of chemical constituents group or active sites.Active sites effective application compatibility,there maybe present synergy,while reducing theextent of adverse reactions.Therefore,under the guidance of TCM theory,compatibility apply Chinese medicine active sites to develop innovative drugs,set up innovative Chinese medicine studying mode with demonstration effects,to improve the overall quality and competitiveness of Chinese medicine industry.
Huang QI San ancient recipe origin from《Shengji Zonglu》,composed by radix Pueraria,Radix Astragali,Cortex Mori.rhe three medicines compatible application,could be nourishing qi to invigorate spleen,benefiting vital energy and clean fever,nourishing qi to invigorate spleen,treating triple diabetes together,to play the role of treating appearance and substance together.Much research indicate that the three medicines have the good curative effect to T2DM or IR,which active material and mechanism of effect are all different,therefore the recipe is presumed be through multi-ways, and multi-target targets comprehensive effect improve T2DM-IR.At present, the study based on Huang Qi San has not been reported,so its clinical application and development has certain limitation.The research firstly based on the whole recipe,attempted to interpret the effect and mechanism of Huang Qi San intervention in T2DM-IR,then apply a series of modern Chinese medicine purification and pharmaceutical production technology,to gather each medicine active sites,to make foundation for further preparations development.
PartⅠ:Literature review
All recent relevant literature concerning T2DM-IR modern medicine research progression,concerning epidemiology,etiopathogenisis,and pathogenesis studies are documented.We also review the literature concerning TCM recognition in DM,chemical composition and Huang Qi San each medicine pharmacology research progression.So this study made a systematic review of mechanism,pathogenesis and allopathic medicine studies of IR in T2DM into consideration both TCM and modern medicine,latest molecule pathogenesis study achievement,and animal model establish and experiments study,to prehensile related advancing front research developments.
PartⅡ:Laboratory studies
1.The studies on effects and mechanisms of Huang Qi San interfere in laboratory IR in type 2 diabetes.
To assess the effects of Huang Qi San on streptozocin(STZ) inducing DM mouse model,Hydrocortisone Sodium Succinate(HSCC) inducing IR mouse model. The results showed that Hang Qi San can lower fasting blood sugar(FBG) and increase sugar tolerance,and increase insulin sensibility of mice with abnormal sugar tolerance but not DM,to improve insulin resistance.
Use STZ with high fat diet to set up T2DM-IR rat model.We determine model rat FBG,fasting insulin(FINS),sugar tolerance,insulin tolerance,insulin sensitivity index(ISI),and insulin resistance index(HOMA-IR),lipid metabolism and free fatty acids content of serum and hepatic,HE staining of pancreas,to observe the effects of Huang Qi San on glycolipid metabolism and insulin resistance in T2DM-IR.The results showed Huang Qi San can significant lower FBG,improve sugar tolerance,lower serum hyperinsulinism induced by IR,increase insulin tolerance,ISI,lower HOMA-IR index,and protect pancreatic tissue structure.Meanwhile,Huang Qi San can regulate blood fat, hepatic lipid,down regulate serum and hepatic FFA level.That indicate Huang Qi San can improve glycolipid metabolism,increase insulin sensitivity to cure IR.
On the basis of T2DM-IR model rats,apply radioimmunity(RI) method to determine TNF-α,leptin content in serum,apply RT-PCR method and immunohistochemical method to observe mRNA and protein expression of GLUT-4, IRS-lin liver,skeletal muscle and adipose tissue,apply RT-PCR method determine adipose tissue PPAR-γmRNA expression,to illuminate the mechanisms of Huang Qi San improve IR.The results showed the mechanisms of Huang Qi San improving IR followed as:①Up-regulate T2DM-IR rats skeletal muscle and adipose tissue GLUT-4 mRNA and protein expression,increase liver, skeletal muscle and adipose tissue IRS-1mRNA and protein expression,to regulate insulin signal transduction,promot glucose transportation,increase periphery tissue insulin sensitivity.②Down-regulate significantly TNF-α, leptin content in serum,improve organism leptin sensitivity,to improve organism insulin sensitivity.③Promote adipose tissue PPAR-γmRNA expressions,which are important receptor for controlling insulin sensitivity, improve indirectly IR.
2.The Preparation of Basic Research on Huang Qi San
Examine quality of radix puerariae and radix astragali from different habitats,to sieve mediocre quality medical material for technology study. Studies were carried on the extraction and purification process of total flavonoids by comparing total flavonoids extract yield and purity of the impact of ethanol concentration,ratio of herb to solvent,extraction time,extraction times and extraction temperature.Set up the L_9(3~4) orthogonal test and confirmed the best extraction process as 10BV 70%ethanol distilling two times, 2h per time.Extract of total flavonoids was purified with macroeticular resins. Different kinds of resins were applied to inspect the static and dynamic adsorption ability,to optimize the concentration,volume and flow rate of eluant.It was confirmed that the best purification process was AB-8 macroeticular resins,medical material dried resins being 2:1,sample fluid concentration being 0.10g dried medicinal herb per milliliter,eluted in order by 10BV distilled water,10BV 50%ethanol with flow rate of 1～3ml/min.50% ethanol part was collected,dried under vacuum and freeze drying resulting in the total flavonoids purity above 62.0%.Total flavonoids extract were prepared by 10 lots radix puerariae.The studies established TLC method. confirmed the limits of loss on drying,established quantitative analysis method of total flavonoids by ultra-voilet spectrophotometry and puerarin by RP-HPLC,for establishing the criteria of quality control of radix puerariae total flavonoids extract.
Studies were carried on the extraction and purification process of radix astragali total saponins by comparing total saponins extract yield and purity of the impact of ethanol concentration,ratio of herb to solvent,extraction time,extraction times and extraction temperature.Set up the L_9(3~4) orthogonal test and confirmed the best extraction process as 8BV 70%ethanol distilling three times,1.5h per time.Extract of total saponins was purified with macroeticular resins.Different kinds of resins were applied to inspect the static and dynamic adsorption ability,to optimize the concentration,volume and flow rate of ehant.It was confirmed that the best purification process was AB-8 macroeticular resins,medical material dried resins being 3:1,sample fluid concentration being 0.075g dried medicinal herb per milliliter,eluted in order by 10BV distilled water,10BV 0.5%NaOH,10BV 10%ethanol,10BV 70% ethanol with flow rate of 1～3ml/min.70%ethanol part was collected,dried under vacuum and freeze drying resulting in the total saponins purity above 68.0%.Total saponins extract were prepared by 10 lots radix astragali.The studies established TLC method,confirmed the limits of loss on drying, established quantitative analysis method of total saponins by ultra-voilet spectrophotometry and astragalosideⅣby RP-HPLC-ELSD for establishing the criteria of quality control of radix astragali total saponins extract.
黄芪散古方源自《圣济总录》,组方为:葛根、黄芪、桑白皮。三药相伍,益气健脾,益气清热,生津止渴,三消并治,共奏标本兼顾之效。大量研究表明三药对T2DM或IR具有良好的疗效,其药效物质基础及作用机制各有所不同,因此认为该方可能通过多途径、多靶点的综合效应来改善T2DM-IR。目前基于黄芪散整方的研究未见有报道,这使得该方的临床应用及开发具有一定的局限性。本研究首先立足于整方,试图阐明黄芪散干预T2DM-IR的作用及作用机制,并采用一系列现代中药制剂技术,富集各药有效部位,为黄芪散的进一步制剂开发奠定基础。
第一部分文献研究
文献研究方面全面查阅了近年来国内外T2DM-IR的现代医学研究进展,包括IR的流行病学研究、病因研究以及发病机制等相关文献资料,同时对DM的中医认识、黄芪散各药的化学成分和药理学研究进展进行文献研究。对目前现代医学和中医学对于T2DM-IR的发病机理、治疗用药,T2DM-IR分子机制的近期研究成果,以及动物模型的建立及研究方法等概况进行了较为系统的总结和综述,掌握了相关项目科研的前沿动态。
第二部分实验研究
1.黄芪散干预实验性2型糖尿病胰岛素抵抗的作用及机制研究
通过建立STZ所致DM小鼠模型、氢化可的松琥珀酸钠(HCSS)诱导的IR小鼠模型初步评价黄芪散对DM及IR的干预作用。结果表明黄芪散降低DM小鼠的空腹血糖(FBG),增加糖耐量,同时提高糖耐量异常而尚未形成DM的小鼠对胰岛素的敏感性,改善胰岛素抵抗。
采用STZ及高脂饮食建立T2DM-IR大鼠模型。通过对模型大鼠FBG、空腹胰岛素水平(FINS)、糖耐量、胰岛素耐量、胰岛素敏感指数(ISI)和抵抗指数(HOMA-IR)、血清和肝脏的脂质代谢及游离脂肪酸(FFA)水平测定、胰腺HE染色病理形态学检查,探讨黄芪散对T2DM-IR的糖脂代谢和IR的影响。结果表明黄芪散显著降低T2DM-IR大鼠的FBG,改善糖耐量,降低IR所形成的高FINS水平,提高胰岛素耐量,增加ISI指数和降低HOMA-IR指数,对胰腺组织结构的病变具有保护作用;同时黄芪散可调节血脂、肝脂、下调血清及肝脏中FFA的水平。提示黄芪散可改善糖脂代谢、提高胰岛素的敏感性发挥其治疗IR的作用。
在建立T2DM-IR模型大鼠的基础上,通过采用放免法测定血清中肿瘤坏死因子(TNF-α)、瘦素(leptin)水平,RT-PCR和免疫组化法测定肝脏、骨骼肌和脂肪组织中GLUT-4、IRS-1的mRNA和蛋白的表达,RT-PCR法测定脂肪组织中PPAR-γmRNA,探讨黄芪散改善IR的机制。结果表明黄芪散改善IR的机制表现在:①上调T2DM-IR大鼠骨骼肌和脂肪组织中GLUT-4的mRNA和蛋白的表达,提高肝脏、骨骼肌和脂肪组织中IRS-1的mRNA和蛋白的表达,从而调节胰岛素信号转导通路,促进葡萄糖的转运,增加外周组织对胰岛素的敏感性;②显著下调TNF-α,leptin的水平,改善胰岛素信号通路转导,减少脂肪分解,纠正脂肪-胰岛内分泌轴的反馈机制,改善机体对瘦素的敏感性,从而改善机体对胰岛素的敏感性;③促进脂肪组织中调控胰岛素敏感性的重要受体PPAR-γmRNA的表达,间接发挥其改善IR的作用。
2.黄芪散的制剂基础研究
对不同产地葛根、黄芪药材进行质量考察,筛选质量中等的药材进行工艺考察。对葛根总黄酮的提取纯化工艺进行了研究,考察不同乙醇浓度,溶媒倍量,提取时间、提取次数和提取温度对总黄酮转移率和纯度的影响,建立了四因素三水平的正交试验,最终确立了最佳的提取工艺为:10倍量70%乙醇加热回流提取2次,每次2小时。采用大孔吸附树脂对总黄酮粗提物进行了纯化处理,筛选了不同型号的树脂,考察树脂的静态、动态吸附性能,并对上样液浓度和流速,洗脱溶剂浓度和体积等相关因素进行优化,确立了最佳的纯化工艺为:AB-8型大孔吸附树脂,药材与干树脂重量比2:1,上样液浓度为0.10g生药/ml,依次用10BV蒸馏水、10BV50%乙醇以1～3ml/min的洗脱速度洗脱,收集50%乙醇部分,减压回收乙醇,冷冻干燥,得到的总黄酮纯度在62.0%以上。对10个批次的葛根药材进行总黄酮提取物的制备,建立薄层鉴别方法;确定提取物干燥失重限度;建立紫外—可见分光光度法以及高效液相色谱法对提取物中总黄酮和葛根素的含量测定方法,初步建立葛根总黄酮提取物的质量标准。
对黄芪总皂苷的提取纯化工艺进行了研究,考察不同乙醇浓度,溶媒倍量,提取时间、提取次数和提取温度对总皂苷转移率和纯度的影响,建立了四因素三水平的正交试验,最终确立最佳提取工艺为:8倍量70%乙醇加热回流提取3次,每次1.5小时。采用大孔吸附树脂对总皂苷粗提物进行了纯化处理,筛选了不同型号的树脂,考察了树脂的静态、动态吸附性能,并对上样液浓度和流速,洗脱溶剂浓度和体积等相关因素进行了优化,确立了最佳的纯化工艺为:药材与干树脂重量比3:1,上样液浓度为0.075g生药/ml,依次用10BV蒸馏水、10BV0.5%NaOH、10BV10%乙醇、10BV70%乙醇以1～3ml/min的洗脱速度洗脱,收集70%乙醇部分,减压回收乙醇,冷冻干燥,得到的总皂苷纯度在68.0%以上。对10个批次的黄芪药材进行总皂苷提取物的制备,建立薄层鉴别方法;确定提取物干燥失重限度;建立紫外—可见分光光度法以及高效液相色谱法对提取物中总皂苷和黄芪甲苷的含量测定方法,初步建立黄芪总皂苷提取物的质量标准。
Insulin resistance(IR) is important factor and dominant feature in type 2 diabetes mellitus pathogenesis.Therefore IR treatment is the most important in prevention and treating diabetes mellitus and metabolic syndrome.Chinese medicine mainly apply compound recipe to treat disease,displaying features of integral regulation and combined therapy.Chinese herbal compound effective material basis are its chemical compositions or active sites,however just a few monomer compounds cannot be representing the whole recipe,should attach more important to the role of of chemical constituents group or active sites.Active sites effective application compatibility,there maybe present synergy,while reducing theextent of adverse reactions.Therefore,under the guidance of TCM theory,compatibility apply Chinese medicine active sites to develop innovative drugs,set up innovative Chinese medicine studying mode with demonstration effects,to improve the overall quality and competitiveness of Chinese medicine industry.
Huang QI San ancient recipe origin from《Shengji Zonglu》,composed by radix Pueraria,Radix Astragali,Cortex Mori.rhe three medicines compatible application,could be nourishing qi to invigorate spleen,benefiting vital energy and clean fever,nourishing qi to invigorate spleen,treating triple diabetes together,to play the role of treating appearance and substance together.Much research indicate that the three medicines have the good curative effect to T2DM or IR,which active material and mechanism of effect are all different,therefore the recipe is presumed be through multi-ways, and multi-target targets comprehensive effect improve T2DM-IR.At present, the study based on Huang Qi San has not been reported,so its clinical application and development has certain limitation.The research firstly based on the whole recipe,attempted to interpret the effect and mechanism of Huang Qi San intervention in T2DM-IR,then apply a series of modern Chinese medicine purification and pharmaceutical production technology,to gather each medicine active sites,to make foundation for further preparations development.
PartⅠ:Literature review
All recent relevant literature concerning T2DM-IR modern medicine research progression,concerning epidemiology,etiopathogenisis,and pathogenesis studies are documented.We also review the literature concerning TCM recognition in DM,chemical composition and Huang Qi San each medicine pharmacology research progression.So this study made a systematic review of mechanism,pathogenesis and allopathic medicine studies of IR in T2DM into consideration both TCM and modern medicine,latest molecule pathogenesis study achievement,and animal model establish and experiments study,to prehensile related advancing front research developments.
PartⅡ:Laboratory studies
1.The studies on effects and mechanisms of Huang Qi San interfere in laboratory IR in type 2 diabetes.
To assess the effects of Huang Qi San on streptozocin(STZ) inducing DM mouse model,Hydrocortisone Sodium Succinate(HSCC) inducing IR mouse model. The results showed that Hang Qi San can lower fasting blood sugar(FBG) and increase sugar tolerance,and increase insulin sensibility of mice with abnormal sugar tolerance but not DM,to improve insulin resistance.
Use STZ with high fat diet to set up T2DM-IR rat model.We determine model rat FBG,fasting insulin(FINS),sugar tolerance,insulin tolerance,insulin sensitivity index(ISI),and insulin resistance index(HOMA-IR),lipid metabolism and free fatty acids content of serum and hepatic,HE staining of pancreas,to observe the effects of Huang Qi San on glycolipid metabolism and insulin resistance in T2DM-IR.The results showed Huang Qi San can significant lower FBG,improve sugar tolerance,lower serum hyperinsulinism induced by IR,increase insulin tolerance,ISI,lower HOMA-IR index,and protect pancreatic tissue structure.Meanwhile,Huang Qi San can regulate blood fat, hepatic lipid,down regulate serum and hepatic FFA level.That indicate Huang Qi San can improve glycolipid metabolism,increase insulin sensitivity to cure IR.
On the basis of T2DM-IR model rats,apply radioimmunity(RI) method to determine TNF-α,leptin content in serum,apply RT-PCR method and immunohistochemical method to observe mRNA and protein expression of GLUT-4, IRS-lin liver,skeletal muscle and adipose tissue,apply RT-PCR method determine adipose tissue PPAR-γmRNA expression,to illuminate the mechanisms of Huang Qi San improve IR.The results showed the mechanisms of Huang Qi San improving IR followed as:①Up-regulate T2DM-IR rats skeletal muscle and adipose tissue GLUT-4 mRNA and protein expression,increase liver, skeletal muscle and adipose tissue IRS-1mRNA and protein expression,to regulate insulin signal transduction,promot glucose transportation,increase periphery tissue insulin sensitivity.②Down-regulate significantly TNF-α, leptin content in serum,improve organism leptin sensitivity,to improve organism insulin sensitivity.③Promote adipose tissue PPAR-γmRNA expressions,which are important receptor for controlling insulin sensitivity, improve indirectly IR.
2.The Preparation of Basic Research on Huang Qi San
Examine quality of radix puerariae and radix astragali from different habitats,to sieve mediocre quality medical material for technology study. Studies were carried on the extraction and purification process of total flavonoids by comparing total flavonoids extract yield and purity of the impact of ethanol concentration,ratio of herb to solvent,extraction time,extraction times and extraction temperature.Set up the L_9(3~4) orthogonal test and confirmed the best extraction process as 10BV 70%ethanol distilling two times, 2h per time.Extract of total flavonoids was purified with macroeticular resins. Different kinds of resins were applied to inspect the static and dynamic adsorption ability,to optimize the concentration,volume and flow rate of eluant.It was confirmed that the best purification process was AB-8 macroeticular resins,medical material dried resins being 2:1,sample fluid concentration being 0.10g dried medicinal herb per milliliter,eluted in order by 10BV distilled water,10BV 50%ethanol with flow rate of 1～3ml/min.50% ethanol part was collected,dried under vacuum and freeze drying resulting in the total flavonoids purity above 62.0%.Total flavonoids extract were prepared by 10 lots radix puerariae.The studies established TLC method. confirmed the limits of loss on drying,established quantitative analysis method of total flavonoids by ultra-voilet spectrophotometry and puerarin by RP-HPLC,for establishing the criteria of quality control of radix puerariae total flavonoids extract.
Studies were carried on the extraction and purification process of radix astragali total saponins by comparing total saponins extract yield and purity of the impact of ethanol concentration,ratio of herb to solvent,extraction time,extraction times and extraction temperature.Set up the L_9(3~4) orthogonal test and confirmed the best extraction process as 8BV 70%ethanol distilling three times,1.5h per time.Extract of total saponins was purified with macroeticular resins.Different kinds of resins were applied to inspect the static and dynamic adsorption ability,to optimize the concentration,volume and flow rate of ehant.It was confirmed that the best purification process was AB-8 macroeticular resins,medical material dried resins being 3:1,sample fluid concentration being 0.075g dried medicinal herb per milliliter,eluted in order by 10BV distilled water,10BV 0.5%NaOH,10BV 10%ethanol,10BV 70% ethanol with flow rate of 1～3ml/min.70%ethanol part was collected,dried under vacuum and freeze drying resulting in the total saponins purity above 68.0%.Total saponins extract were prepared by 10 lots radix astragali.The studies established TLC method,confirmed the limits of loss on drying, established quantitative analysis method of total saponins by ultra-voilet spectrophotometry and astragalosideⅣby RP-HPLC-ELSD for establishing the criteria of quality control of radix astragali total saponins extract.
引文
[1]World Health Organization.Obesity:Preventing and Manging the Global Epidemic Report of a WHO Consultation Technical Report Series.World Health Organization,Geneva,2000:236-240.
[2]Gisela Wilcox.Insulin and insulin resistance[J].Clin Biochem Rev,2005;26(5):19-39.
[3]潘长玉,尹士男.胰岛素抵抗发病机制的重要因素[J].中华内分泌代谢杂志,2000:16(1):56-57.
[4]Kruszynska YT,Yu JG,Olefsky JM,et al.Effects of troglitazone on blood concentrations of plasminogen activator inhibitor in patients with type 2 diabetes and in lean and obese normal subjects[J].Diabetes,2000;49:633-639.
[5]International Diabetes Federation.Diabetes Atlas(third edition)[R]J.2007.
[6]Beck-Nielsen H.General characteristics of the insulin resistance syndrome:prevalence and heritability.European Group for the Study of Insulin Resistance[J].Drugs,1999;58(Suppl1):7-10.
[7]Zachary T Bloomgarden,MD.Developments in Diabetes and Insulin Resistance —This is the second in a series of articles on presentations at the American Diabetes Association Annual Meeting,San Diego,California,2005,10.
[8]Bloomgarden Z T.Insulin resistance,exercise,and obesity[J].Diabetes Care,1999;22(3):517-522.
[9]全国糖尿病研究协作组调查研究组.全国14省市30万人口中糖尿病调查报告[J].中华内科杂志,1981:20:678.
[10]向红丁,吴纬,孙琦等.1989年全国糖尿病流行病学特点基线调查报告[J].中国糖尿病杂志,1998:6(3):131-133.
[11]Jie Wp,Xiang K S,Chen L,et al.Epidenmiologic study on metabolic syndrome in normal and overweight Chinese in Shanghai.Diabetes,2000;49(Suppl1):A148.
[12]吴家睿.2型糖尿病发生发展的分子机制研究[J].生命科学.2006:18(5):411-413.
[13]Ohlson LO,Larsson B,Bjorntorp P,et al.Risk of factors for type 2(non-insulin-dependent) diabetes mellitus.Thirteen and one-half years of follow-up of the participants in a study of Swedish men born in 1913[J].Diabetologia,1998,31(11):798-805.
[14]Knowler WC,Pettitt DJ,Saad MF,et al.Diabetes mellitus in the Pima Indians:incidence,risk factors and pathogenesis.Diabetes Metab Rev,1990,6(1):1-27.
[15]Brancati FL,Whelton PK,Kuller LH,et al.Diabetes mellitus,race,and socioeconomic status.A population-based study[J].Ann Epidemiol,1996;6(1):67-73.
[16]Haffner SM,Miettinen H,Stern MP.Nondiabetic Mexican-Americans donot have reduced insulin responses relative to nondiabetic non-Hispanic whites[J].Diabetes Care,1996;19(1):67-69.
[17]Willett WC.The Mediterranean diet:science and practice[J].Public Health Nutr,2006;9(1A):105-10.
[18]Le DS,Kusama K,Yamamoto S.A community-based picture of type 2 diabetes mellitus in Vietnam[J].J Atheroscler Thromb,2006;13(1):16-20.
[19]刘慧霞.高胰岛素血症加重高糖对PKB丝氨酸磷酸化的抑制作用[J].中国现代医学杂志,2002;12(9):38-40.
[20]池海谊,冯凭.抵抗素在肥胖与2型糖尿病间作用的研究现状[J].内蒙古医学杂志,2006;(3):43.
[21]张晓明,裴秀珍,戚海等[J].河北省糖尿病流行病学研究.实用预防医学,1998,5:68-71.
[22]Diamond J.The double puzzle of diabetes[J].Nature,2003;423:599-602.
[23]Sharma AM.The obese patient with diabetes mellitus:from research targets to treatment options[J].Am J Med,2006;119(5 Suppl1):S17-23.
[24]田坚,彭扬.腹型肥胖与胰岛素抵抗的关系[J].中华实用医学,2002;4(6)3-4.
[25]彭定琼,高妍.2型糖尿病病人脂肪组织胰岛素受体底物1和含2个SH2结构的蛋白酪氨酸磷酸酶的蛋白表达[J].民航医学,2002;12(1):1-4.
[26]江孙芳,高鑫,陆志强等.肥胖患者血清胰岛素原水平与胰岛素抵抗的关系[J].复旦学报(医学版),2002;29(3):200-204.
[27]王巍,赵列宾,梁伟等.老年男2型糖尿病合并高血压患者血清同型半胱氨酸水平变化与肥胖、胰岛素抵抗的关联性研究[J].中国临床康复,2002;6(9):1300-1301.
[28]睡眠不足:胰岛素抵抗及肥胖的危险因素(ADA2001年会,183-OR)[J].国外医学内分泌学分册,2002;22(1):59.
[29]Yaggi HK,Araujo AB,McKinlay JB.Sleep duration as a risk factor for the development of type 2 diabetes[J].Diabetes Care,2006;29(3):657-661.
[30]Helmrich SP,Ragland DR,Leung RW,et al.Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus[J].N Engl J Med, 1991;325(3):147-152.
[31]Kriska AM,LaPorte RE,Pettitt DJ,et al.The association of physical activity with obesity,fat distribution and glucose intolerance in Pima Indians[J].Diabetologia,1993,36(9):863-869.
[32]付利华.绝经后妇女糖代谢变化的相关因素研究[J].中华综合医学,2002:3(4):307-310.
[33]Uchimoto S,Tsumura K,Hayashi T,et al.Impact of cigarette smoking on the incidence of type 2 diabetes mellitus in middle-aged Japanese men:the Osaka Health Survey[J].Diabet Med.1999.16:951-955.
[34]Qiao Q,Valle T,Nissinen A,et al.Smoking and the risk of diabetes in elderly Finnish men.Retrospective an alysis of data from a 30-years follow-up study[J].Diabetes Care,1999,22:1821-1826.
[35]Wei M,Gibbsons LW,Mitchel WL,et al.Alcohol intake and incidence of type 2 diabetes in men[J].Diab etes Care,2000,23:18-22.
[36]Lee AV,Jachson JG,Gooch JL,et al.enhancement of insulin-like grouth factor signaling in human breast cancer,estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo[J].Mol Endocrinol,1999;13(5):787-796.
[37]Mallone R,Perin PC.Anti-CD38 autoantibodies in type 2 diabetes[J].Diabetes Metab Res Rev.2006;17.
[38]McKillop AM,Lindsay JR,Au S,et al.Meal-dependent regulation of circulating glycated insulin in type 2 diabetic subjects[J].Horm Metab Res,2006;38(2):94-97.
[39]谢乃强.胰高血糖素与2型糖尿病病人胰岛素抵抗关系研究[J].中国基层医药,2002:9(9):798-799.
[40]张芳林,刘小莺,林益川等.地塞米松诱发的大鼠胰岛素抵抗模型[J].中国应用生理学杂志,2002:18(1):99-101.
[41]Fasshauer M,Klein J,Lossner U,et al.Interleukin(IL)-6 mRNA Expression is Stimulated by Insulin,Isoproterenol,Tumour Necrosis Factor Alpha,Growth Hormone,and IL-6 in 3T3-L1 Adipocytes[J].Horm Metab Res,2003;35(3):147-52.
[42]李秀钧主编.胰岛素抵抗综合征[M].北京:人民卫生出版社,2001,第一版:25-41.
[43]White MF,Kahn CR.The insulin resistance and type 2 diabetes from knockout mouse models[J].J Clin Invest,2000;106(4):459-465.
[44]ValverdeAM,Burks DJ,Fabregat I,etal.Molecular mechanisms of insulin resistance in IRS-2 deficient hepatoeytes[J].Diabetes,2003;52(9):2239-2248.
[45]Kahn CR.Knockout mice challenge our concepts of glucose homeostasis and the pathogenesis of diabetes[J].Exp Diabesity Res,2003;4(3):169-182.
[46]Czech MP,Corvera S.Signaling mechanisms that regulate glucose transport[J].J Biol Chem,1999;274(4):1865-1868.
[47]Sun XJ,Rothenberg P,Kahn CR,et al.Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein[J].Nature,1991:352(6330):73-77.
[48]Yamauchi T,Tobe K,Tamemoto H,et al.Insulin signaling and insulin actions in the muscles and livers of insulin-resistant,insulin receptor substrate 1-deficient mice[J].Mol Cell Biol,1996;16(6):3074-3084.
[49]Goodyear LU,Giorgino F,Sherman LA,et al.Insulin receptor phosphorylation,insulin receptor subtrate-1 phosphorylation,and phosphatidyl inositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects[J].J Clin Invest,1995;95(5):2195-2204.
[50]Gual P,Gonzalez T,Gremeaux T,et al.Hyperosmotic stress inhibits IRS-1 function by distinct mechanisms in 3T3-L1 adipocytes[J].J Biol Chem,2003;278(29):26550-26557.
[51]Petersen KF,Shulman GI.Etiology of insulin resistance[J].Am J Med,2006;119(5 Suppl 1):S10-16.
[52]Nelson B A,Robinson K A,Buse M G.High glucose and glucosamine induce insulin resistance via different mechanisms in 3T3-L1 adipocytes[J].Diabetes,2000;49:981-991.
[53]Zierath J R,Krook A,Wallberg-Henriksson H.Insulin action in skeletal muscle from patients with NIDDM[J].Mol Cell Biochem,1998;182:153-160.
[54]Maier V H,Gould G W.Long-term insulin treatment of 3T3-L1 adipocytes results in mis-targeting of GLUT4:implications for insulin-stimulated glucose transport[J].Diabetologia,2000;43:1273-1281.
[55]Yonemitsu S,Nishimura H,Shintani M,et al.Troglitazone induces GLUT4 translocation in L6 myotubes[J].Diabetes,2001;50:1093-1101.
[56]Takahashi Y,Ide T.Dietary n-3 fatty acid affect mRNA level of brown adipose tissue uncoupling protein l,and white adipose tissue leptin and glucose transporter 4 in the rat[J].Br J Nutr,2000;84:175-184.
[57]Sevilla L,Guma A,Enrique-Tarnacon G,et al.Chronic high-fat feeding and middle-aging reduce in an additive fashion Glut4 expression in skeletal muscle and adipose tissue[J].Biochem Biophys Res Commun,1997;235:59-93.
[58]Kurokawa K,Oka Y.Insulin resistance and glucose transporter[J].Nippon Rinshl,2000;58(2):310-314.
[59]Almind K,Bjorbaek C,Vestergaard H,et al.Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus.Lancet,1993;342(8875):828-832.
[60]Kido Y,Burks DJ,Withers D,et al.Tissue-specific insulin resistance in mice with mutations in the insulin receptor,IRS-1,and IRS-2.J Clin Invest,2000;105(2):199-205.
[61]Meyre D,Froguel P.ENPP1,the first example of common genetic link between childhood and adult obesity and type 2 diabetes.Med Sci(Paris)[J].2006,22(3):308-312.
[62]Liu W,Liu M,Fan W,et al.The Gly146Ala variation in human SF-1 gene:Its association with insulin resistance and type 2 diabetes in Chinese[J].Diabetes Res Clin Pract,2OO6;[Epub ahead of print]
[63]Horikoshi M,nara K,Ohashi J,et al.A Polymorphism in the AMPK{alpha}2Subunit Gene Is Associated With Insulin Resistance and Type 2 Diabetes in the Japanese Population[J].Diabetes,2006;55(4):919-23.
[64]Saller B,Nemesszeghy P,Mann K,et al.Glucose and Lipid Metabolism in Young Lean Normotensive Males with the G Protein beta3 825T-Allele[J].Eur J Med Res,2003;8(3):91-97.
[65]Ilany J,Bilan PJ,Kapur S,et al.Overexpression of Rad in muscle worsens diet-induced insulin resistance and glucose intolerance and lowers plasma triglyceride level[J].Proc Natl Acad Sci USA,2006;103(12):4481-4486.
[66]李秀钧.脂肪组织是又一个新的内分泌器官[J].国外医学内分泌学分册,2002:22(3):129-131.
[67]Kershaw EE,Fliter JS.Adipose tissue as an endocrine organ[J].J Clin Endocrinol Metab,2004;89(6):2548-2556.
[68]Miles P D G,Barak Y,He W,et al.Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency[J].J Clin Invest,2000;105(3):287.
[69]Schinner S,Dellas C,Schroder M,et al.Repression of Glucagon Gene Transcription by Peroxisome Proliferator-activated Receptor gamma through Inhibition of Pax6 Transcriptional Activity[J].J Biol Chem,2002;277: 1941.
[70]Hsueh W A,Law R.The central role of fat and effect of peroxisome proliferator-activated receptor-gamma on progression of insulin resistance and cardiovascular disease[J].Am J Cardiol,2002;92(4A):3J.
[71]Steppan CM,Bailey ST,Bhat S,et al.The hormone resistin links obesity to diabetes[J].Nature,2001,409(6818):307-312.
[72]Leroy P,Dessolin S,Villageois P,et al.Expression of ob gene in adipose cell.Regulation by insulin[J].Biol Chem,1996;271:2365-2368.
[73]Kolaczyski JW,Nyce MR,Considine RV,et al.Acute and insulin on leptin production in humans:Studies in vivo and chronic effects of in vitro[J].Diabetes,1996,45:699-701.
[74]Kiefer TJ,Heller RS,Leeeh CA,et al.Leptin suppression insulin secretion by the activation of ATP-sensitive K~+ channels in pancreatic cells[J].Diabetes,1997;46:1087-1093.
[75]Stejskal D,Jedelsky L,Bartek J,et al.Leptin,insulin and proinsulin-their relationship[J].Vnitr Lek,1998;44:361-365.
[76]Banks WA,Kastin AJ,Huang W,et al.Leptin enters the brain by a saturable system independent of insulin[J].Peptides,.1996;17:305-311.
[77]陈刚,罗敏,丁伟等.瘦素受体基因变异与中国人肥胖的关系[J].中华内分泌代谢杂志,2001:17(5):298-300.
[78]Scarpace PJ,Matheny M,Tumer N.Hypothalamic leptin resistance is associated with impaired leptin signal transduction in aged obese rats[J].Neuroscience,2001;104(4):1111-1117.
[79]Shimizu H,Shimomura K,Negishi M,et al.Circulating concentrations of soluble leptin receptor:influence of menstrual cycle and diet therapy[J].Nutrition,2002;18(4):309-312.
[80]Bi S,Ladenheim EE,Schwartz GJ,et al.A role of NPY overexpression in the dorsomedial hypothalamus in hyperphagia and obesity of OLETF rats[J].Am J Physiol Regul Integur Comp Physiol,2001;281(1):8254-8260.
[81]Egawa M,Yoshimatsu H,Bray GA.Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue inrats[J].Am J physiol,1991;260(2Pt2):R328-334.
[82]Alice S,Ryan,Dariush Elahi,et al.The effects of acute hyperglycemia and hyperinsulinemia on plasma leptin levels:Its relationships with body fat,viscral adiposity,and age in women[J].J Clin Endocrinol Metab,1996;81:4433-438.
[83]Hotta K,Funahshi T,Bodkin N L,et al.Circulating concentrations of the adipocyte protein adiponectin are decreased inparallel with reduced insulin sensitivity during theprogression to type 2 diabetes in rhesus monkeys[J].Diabetes,2001;50(5):1126.
[84]Yamauchi T,Kamon J,Waki H,et al.The fat-derived hormone adiponectin reverse insulin resistance associated with both lipoatrophy and obesity[J].Nut Med,2001;7(8):941.
[85]Stefan N,Stumvoll M.Adiponectin-its role in metabolism and beyond[J].Horm Metab Res,2002;34(9):469.
[86]Barzilay JI,Abraham L,Heckhem SR,et al.The relation of markers of inflammation to the development of glucose disorders in the elderly:the cardiovascular health study[J].Diabetes,2001;50:2384-2389.
[87]Moiler DE.Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes[J].Trends Endocrinol Metab,2000;11(6):212-217.
[88]Tremblay F,Lavigne C,Jacques H,et al.Defective insulininduced GLUT4 translocation in skeletal muscle of high fat-fed rats is associated with alterations in both AKT/protein kinase B and atypical protein kinase C activitiesl[J].Diabetes,2001;50(8):1901-1910.
[89]Hauner H.The mode of action of thiazolidinediones[J].Diabetes Metab Res Rev,2002;18(suppl2):10-15.
[90]Senn JJ,Klover PJ,Nowak IA,et al.Suppressor of cytokine signaling-3(S0CS-3),a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes[J].J Biol Chem,2003,278(16):13740-13746.
[91]Guerre-Millo M.Adipose tissue and adipokines:for better or worse[J].Diabetes Metab,2004:30(1):13-9.
[92]Kershaw EE,Flier JS.Adipose tissue as an endocrine organ[J].J Clin Endocrinol Metab,2004;89(6):2548-2556.
[93]Frayn KN.Adipose tissue as a buffer for daily lipid flux[J].Diabetologia,2002:45(9):1201-1210.
[94]Yu YH,Ginsberg HN.Adipoeyte Signaling and Lipid Homeostasis Sequelae of Insulin-Resistant Adipose Tissue[J].Circ Res,2005:96(10):1042-1052.
[95]McGarry JD.Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes[J].Diabetes,2001;50(suppl2):6.
[96]Charles MA,Eschwege E,Thibult N,et al.The role of non-esterified fatty acids in the deterioration of glucuse tolerence in Caucasian subjects:results of the paris prospective study[J].Diabetologia,1997;40:1101-1106.
[97]Paolisso G,Tataranni PA,Folry JE.A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM[J].Diabetologia,1995;38:1213-1217.
[98]McGarry JD,Dobbins RL.Fatty acids,lipotoxicity and insulin secretion[J].Diabetologia,1999;42:128-138.
[99]Boden G,Chen X,Iqbal N.Acute lowing of plasma fatty acids lower basal insulin secretion in diabetic and nondiabetic subjects[J].Diabetes,1998;47:1609-1612.
[100]Dobbins RL,Chester MW,Daniels MB.Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans[J].Diabetes,1998;47:1613-1618.
[101]Stein DT,Stevenson BE,Chester Mw,et al.The insulinotropic potency of fatty acids is influenced profoundly by their chain lengh and degree of saturation[J].J Clin invest,1997;100:398-403.
[102]Abadie JM,Malcom GT,Porter JR,et al.Canassociations between free fatty acid levels and metabolic parameters determine insulin resistance development in obese Zucker rats[J].Life Sci,2001;69:2675-2683.
[103]Ana TMGS,Guenther B,Maria ERS,et al.Overnigt lowering of free fatty acid with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects[J].Diabetes,1999;48:1836-1841.
[104]Prelevic GM.Insulin resistance in polycystic ovary syndrome[J].Curr Opin Obstet Gynecol,1997;9:193-201.
[105]Guenther B.Role of fatty acids in the pathogenesis of insulin resistance and NIDDM[J].Diabetes,1997;46:3-10.
[106]Boden G.Fatty acids and insulin resistance[J].Diabetes Care,1996;19(4):394-39.
[107]Steinberg GR,Dyck DJ,Calles-Escandon J,et al.Chronic leptin administration decreases fatty acid uptake and fatty acid transporters in rat skeletal Muscle[J].J Biol Chem,2002;277:8854-8860.
[108]Francesco,Roberto,Mafalde.Obesity and body fat distribution induce endothelial dysfunction by oxidative stress[J].Diabetes,2001;50: 159-165.
[109]Wiederkehr A,Wollheim CB.Implication of mitochondria in insulin secretion and action[J].Endocrinology,2006 Mar 23.[Epub ahead of print].
[110]Petersen KF,Shulman GI.Etiology of insulin resistance[J].Am J Med.2006;119(5 Suppl 1):S10-16.
[111]Sriwijitkamol A,Christ-Roberts C,Berria R,et al.Reduced skeletal muscle inhibitor of kappaB beta content is associated with insulin resistance in subjects with type 2 diabetes:reversal by exercise training[J].Diabetes,2006;55(3):760-767.
[112]Ahren B,Landin-Olsson M,Jansson PA,et al.Inhibition of dipeptidyl pepti-dase-4 reduces glycemia,sustains insulin levels,and reduces glucagon levels in type 2 diabetes[J].Clin Endocrinol Metab,2004;89(5):2078-2084.
[113]Gura T.Diabetes research:new lead found to a possible "insulin pill"[J].Science,1999,284(5416):886.
[114]黄帝内经素问[M].北京:人民卫生出版社,1963:212,261-262.
[115]陈言.三因极一病证方论[M].北京:人民卫生出版社,1957:137.
[116]张从正.儒门事亲[M].沈阳:辽宁科学技术出版社,1997:103-105.
[117]朱震亨.丹溪心法[M].沈阳:辽宁科学技术出版社,1997:55.
[118]徐文萍.“五脏脏真”与“消褐病”的关系[J].中国中医基础医学杂,2001:7(6):406
[119]白红艳,邹文俊,高小平.葛根对地塞米松诱导的胰岛素抵抗的影响[J].中国中药杂志,2004:29(4):356-358.
[120]周俐,张曙辉,于珍等.黄芪对糖尿病胰岛素抵抗及血清脂联素影响的临床研究[J].新中医,2007:39(5):82-83.
[121]范冠杰,唐咸玉,李双蕾等.降糖补肾方对2型糖尿病患者血清CRP、IL-6及TNF-α的影响[J].中国中西医结合杂志,2006:26(4):329-331.
[122]许武红,符燕.黄芪、葛根合剂配合科索亚联合治疗糖尿病肾病的疗效观察[J].吉林医学,2006:27(1):83-84.
[123]张丽君,吴平.益气滋阴活血法治疗2型糖尿病135例临床观察[J].中医药信息,2006;23(3):24.
[124]杨晓春,宛晓春等.葛根的研究及其开发前景[J].林业科技通讯,1996:(1):16.
[125]白红艳,邹文俊等.葛根对地塞米松诱导的胰岛素抵抗的影响[J].中国中药杂志,2004:(4):356.
[126]董英,徐斌,林琳等.葛根的化学成分研究[J].食品与机械,2005:21(6):85-88.
[127]石昌顺.中药葛根的研究[J].中草药,1994:25(9):496.
[128]杨林静,何可月等.葛根的药理学研究及临床应用进展[J].武警医学院学报.2002:11(2):138-140.
[129]于健,苏珂.葛根素对2型糖尿病病人胰岛素抵抗的影响[J].中国新药与临床杂志,2002:21(10):585-587.
[130]曾莉,顾振纶,茅彩萍.葛根素对糖尿病小鼠胰岛素抵抗的影响[J].中草药,2006:37(6):901-904.
[131]洪畋,毕会民,毕欣.葛根素对胰岛素抵抗大鼠肝脏中GSK-3表达的影响[J].中国临床药理学与治疗学,2006:11(2):207-210.
[132]刘蕴玲等.葛根素对2型糖尿病人胰岛素敏感性的影响[J].辽宁实用糖尿病杂志,2000;8(1):26.
[133]吕俊华,张世平,潘竞锵.葛根素对D-半乳糖诱导糖基化模型大鼠血糖和肝肾功能的影响[J].中国新药杂志,2006:15(18):1548-1551.
[134]郭妍等.老年糖尿病肾病血清Ⅳ型胶原变化及葛根素对其影响[J].实用老年医学,1999;13(6):296.
[135]刘亚明,牛欣,冯前进.葛根素治疗糖尿病评述[J].中国医药学报,2003;18(1):49-51.
[136]Shen P,Liu MH,Ng TY,et al.Differential Effects of Isoflavones,from Astragalus Membranaceus and Pueraria Thomsonii,on the Activation of PPAR{alpha},PPAR{gamma},and Adipocyte Differentiation In Vitro[J].J Nutr,2006:1364:899-905.
[137]赵荣华.518个糖尿病处方统计分析[J].云南中医学院学报,1997:20(2):20-23.
[138]吴炎.黄芪注射液对肝硬化患者肝功能的影响[J].中国中西医结合杂志,1999:19(6):364.
[139]李勤,刘宏.黄芪的药理作用及临床应用[J].医学综述,2004:10(10):634.
[140]卢彦琦,贺学礼.黄芪的化学成分及药理作用综述[J].保定师范专科学校学报,2004:17(4):40-42.
[141]陈蔚,夏燕萍,俞茂.黄芪多糖预防自身免疫性胰岛炎的病理变化[J].中国现代医学杂志,2000:7(2):146-148.
[142]吴朝妍,张莹雯.黄芪多糖对肾阳虚型糖尿病大鼠肾组织NF-κB、TGF-β1的影响[J].武汉大学学报(医学版),2006:27(3):381-384,388.
[143]叶红英,俞茂华,游利等.黄芪多糖对STZ糖尿病大鼠物质代谢和心功能的影响[J].上海医科大学学报,2000:27(5):357-358.
[144]杨红霞,朱敏怡.黄芪对糖尿病大鼠肾组织的保护作用[J].实用医学杂 志,2005;21(17):1964-1965.
[145]马洪喜,李冬梅.黄芪皂苷对糖尿病大鼠血清清激素水平的影响[J].微量元素与健康研究,2003:20(4):5-6.
[146]马宏秀,张治祥等.黄芪药理研究进展[J].陕西中医学院学报,2004:27(5):147-149.
[147]吴志平,谈建中,顾振纶.中药桑白皮化学成分及药理活性研究进展[J].中国野生植物资源,2004;23(5):10-13.
[148]吴志平,周巧霞,顾振纶等.桑树不同药用部位的降糖效果比较[J].蚕业科学,2005;31(2):215-217.
[149]汪宁,朱荃,周义维等.桑白皮等中药提取物对胰岛素促进离体肝脏葡萄糖消耗的影响[J].时珍国医国药,2006:17(4):513-514.
[150]杨海霞,朱祥瑞.1-脱氧野尻霉素(DNJ)的研究进展[J].蚕桑通报,2003;34(1):6-10.
[151]#12
[152]Hikino H,Mizuno T,Oshima Y,et al.Validity of the oriental medicines.80Antidiabetes drugs.4 Isolation and hypoglycemic activity of moran A.a glycoprotein of Morus alba root barks[J].Planta Med,1985;(2):159.
[153]膝德义,经广纬,吴松云.复方桑白皮浓缩液的降血糖试验[J].西北药学杂志,1998:13(6):255.
[154]钟国连.桑白皮水提取液对糖尿病模型大鼠血糖血脂的影响[J].赣南医学院学报,2003:23(1):23-24.
[1]Kruszynska YT,Yu JG,Olefsky JM,et al.Effects of troglitazone on blood concentrations of plasminogen activator inhibitor in patients with type 2 diabetes and in lean and obese normal subjects[J].Diabetes,2000:49:633-639.
[2]Reaven GM.Insulin resistance and com pensatoryhyper- insulinemia:role in hypertension,dyslipidemia,and coronary heart disease[J].Am Heart J,1991;121(4Pt2):1283-1288.
[3]Haffner SM.Epidemiology of insulin resistance and its relation to coronary artery disease[J].American Journal of Cardiology,1999;84(IA):11-14.
[4]Tripathy D,Carlsson M,Almgren P,et al.Insulin secretion and insulin sensitivity inrelation to glueose tolerance:lessons from the Botnia Study[J].Diabetes,2000;49(6):975-980.
[5]GrooP L,Orho-Melander M.The dysmetabolic syndrome[J].Journal of Internal Medicine,2001;250(2):105-120.
[6]Jia Weiping,Xiang Kunsan,Chen Lei,et al.A comparison of the application of two working definitions of metabolic syndrome in Chinese population[J].Natl Med J China,2004;84(7):534-538.
[7]Liu Xing,Wang Yalou,et al.Present states and developmental trends of therapeutic drugs for typeⅡdiabetes[J].Journal of Pharmaceutieal Practice,2004;21(1):1-4.
[8]Cai Zhong de,Wu Jie,Zhu Hui rong.The General situation of the study of Chinese Traditional Medicine Curing Diabetes Mellitus[J].Chinese Journal of Experimental Traditional Medical Formulae,2002;8(6):56-59.
[9]白红艳,邹文俊,高小平.葛根对地塞米松诱导的胰岛素抵抗的影响[J].中国中药杂志,2004:29(4):356-358.
[10]周俐,张曙辉,于珍等.黄芪对糖尿病胰岛素抵抗及血清脂联素影响的临床研究[J].新中医,2007:39(5):82-83.
[11]杨凌辉,邹大进,冯正康等.黄芪改善高脂饲养大鼠胰岛素敏感性的机制研究[J].第二军医大学学报,2004,25(4):407-409.
[12]范冠杰,唐咸玉,李双蕾等.降糖补肾方对2型糖尿病患者血清CRP、IL-6及TNF-α的影响[J].中国中西医结合杂志,2006;26(4):329-331.
[13]许武红,符燕.黄芪、葛根合剂配合科索亚联合治疗糖尿病肾病的疗效观察[J].吉林医学,2006:27(1):83-84.
[14]张丽君,吴平.益气滋阴活血法治疗2型糖尿病135例临床观察[J].中医药信息,2006;23(3):24.
[15]Greene DA.Acute and chronic complications of diabetes mellitus in older patients[J].American Journal of medicine.1986,80(5A):39-53.
[16]李仪奎.中药药理实验方法学[M].上海:上海科技出版社,2006,第二版:602-603,608-609.
[17]Wu Jian,Lei Moxian.New consideration on the relation of insulin resistance and type 2 diabetic[J].Medicine and Philosophy,2004;25(2):4-5.
[18]Moller DE,Flier JS.Insulin resistance mechanism,syndromes,and implications[J].N Eng J med,1991;325(13):928-948.
[19]Gisela Wilcox.Insulin and insulin resistance[J].Clin Biochem Rev,2005;26(5):19-39.
[20]潘长玉,尹士男.胰岛素抵抗发病机制的重要因素[J].中华内分泌代谢杂志,2000;16(1):56-57.
[21]Storlien LH,JamesDE,BurleighKM,etal.Fat feeding causes widespread in vivo insulin resistance,decreased energy expenditure,and obesity in rats[J].AmJ Physiol,1986;251:E576-583.
[22]Ding Shiying,Shen Zhufang,Chen Yueteng,et al.Using euglycemic clamp technique estimate two type of insulin-resistance animal model[J].Chinese Diabetes magazine,2001;9(5):286-289.
[23]Li Chenzhong,Zhang Suhua,Shu Changda,et al.High fat meal induce insulin-resistance rats.Basic Medical Sciences and Clinics,2000;20(3):93-95.
[24]郝玉美,刘洪琪.苦瓜 黄芪 黄芩苷对2型糖尿病大鼠模型胰岛素抵抗的影响[J].辽宁中医药大学学报.2007;9(5):6-7.
[25]李勇,刘孟宇,王颜刚.生芪降糖颗粒对胰岛素抵抗鼠的作用及机制研究[J].中国中西医结合杂志,2007;27(5):449-451.
[26]陈奇.中药药效研究思路与方法[M].北京:人民卫生出版社,2005,第一版:611-623.
[27]李秀钧主编.胰岛素抵抗综合征[M].北京:人民卫生出版社,2001,第一版:44-57.
[28]Hanley AJ,Williams K,Gonzalez C,et al.Prediction of type 2 diabetes using simple measures of insulin resistance:combined results from the San Antonio Heart Study,the Mexico City Diabetes Study,and the Insulin Resistance Atherosclerosis Study[J].Diabetes,2003;52:463-469.
[29]鲁瑾,邹大进,张家庆.高脂饮食诱发大鼠胰岛素抵抗后肿瘤坏死因子-α的改变[J].中国糖尿病杂志,1999:7(5):284-286.
[30]葛学美,郭俊生,赵法极等.高脂诱发2型糖尿病模型建立及谷氨酸胺的保护作用研究[J].解放军预防医学杂志,2000:18(1):21-23.
[31]姚峰,王宗保,谭翔文等.贵州小型猪2型糖尿病动物模型的建立[J].南华大学学报医学版.2004,32(3):294.
[32]乔凤霞,申竹芳,叶菲等.链脲佐菌素糖尿病金黄地鼠模型建立的研究[J].中国糖尿病杂志.2000:8(4):215-218.
[33]王志刚,岳辉.丹参对实验性2型糖尿病大鼠肾损害的保护作用[J].牡丹江医学院学报.2005:26(1):20-21.
[34]张亚非.Ⅱ型糖尿病实验模型[J].国外医学卫生学分册,2000;27(6):328-330.31
[35]Arison RN,Ciaccio EI,Glitzer MS,et al.Light and electron microscopy of lesions in rats rendered diabetic with streptozotocin[J].Diabetes,1967;16:51-56.
[36]赵凌云.链脲佐菌素实验性糖尿病研究—Ⅰ、Ⅱ、Ⅲ、Ⅳ[J].四川医学院学报,1985,16(4):289.
[37]Junod A,Lamber AE Orci L,et al.Studies of the diabetogenic action of streptozotocin[J].PTOC Soc Exp Biol Med,1967;125:201.
[38]景远,关晓萍,蔺威等.实验性糖尿病大鼠的血液流变性变化[J].中国微循环,2002:6(1):34-35.
[39]刘霆,张桂珍,牟明威等.STZ小剂量多次注射诱导大鼠胰岛素依赖性糖尿病动物模型探讨[J].白求恩医科大学学报,2001,27(6):578-580.
[40]王军,李利,董砚虎.胰岛β细胞的病理与胰岛素抵抗研究进展—第37届欧洲糖尿病研究协会年会侧记[J].国外医学内分泌分册,2002:22(2):119-122.
[41]付荣霞,杨红艳,孙长颢等.不同饲料构成诱导大鼠肥胖模型的研究[J].中华临床新医学,2002;2(7):579-580.
[42]郭啸华,刘志红,李恒等.实验性2型糖尿病大鼠模型的建立[J].肾脏病与透析肾移植杂志,2000;9(4):351-355.
[43]丁世英,申竹芳,谢明智.PAPR与胰岛素抵抗[J].中国药理学通报,2002;18(3):241-245.
[44]徐成,王莉莉,曹颖林等.PPARs:脂代谢调节与胰岛素增敏治疗药物的作用靶标[J].中国药理学通报,2004;20(3):241-244.
[45]Stumvoll M.Haring H U.Glitazones:clinical effects and molecular mechansisms[J].Ann Med,2002;34:224-217.
[46]Dubos M,Vantyghem M C.Schoonjans K,elal.Thiazolidiones in type 2diabete.Role of peroxisome proliferator-activated receptor gamma(PPAR-γ)[J].Ann Endocrinol(Paris).2002;63:523-511.
[47]Pasteri V,Wu HD,Eillerson JT,el al.Modulation of vascular inflammation it:vitro and in vivo by peroxisome proliferators activated receptor-gamma activators[J].Circulation,2000;1(11):238-235.
[48]Guo Q,Sahoo SP,Wang PR,etal.A novel peroxisome porliferator-activated receptor alpha/gamma dual agonist demonstrates favorable effects on lipid homeostasis[J].Endocrinology,2004;145(4):1640-1648.
[49]Yki-Jarvinen H.Thiazolidinediones[J].N Engl J Med,2004;351(11):1106-1118.
[50]Zambre Y,Ling Z,Hou X,et al.Impaired beta-cell functions induced by chronic exposure of cultured human pancreatic islets to high glucose[J].Diabetes,1999;48(6):1230-1236.
[51]De Fronzo R A,Tobin J D,Andres R.Glucose clamp technique:a method for quantifying insulin secretion and resistance[J].Am J Physiol,1979;237:E214-332.
[52]Bergman R N,Finegood D T,Ader M.Assessment of insulin sensitivity in vivo[J].Endocri Rew,1985;6(1):45-52.
[53]Coates P A,Luzio S D,Bmnel P,et al.Comparison of estimates of insulin sensitivity from minimal model analysis of the insulin-modified frequently sampled intravenous glucose tolerance test and isoglycentic hyperinsulinemic clamp in subjects with NIDDM[J].Diabetes,1995;44(6):631-635.
[54]Haffner SM,Gonzalez C,Mietinen H,et al.A prospective analysis of the Homa model.The Mexico City Diabetes Study[J].Diabetes Care,1996;19:1138-1141.
[55]李光伟,潘孝仁,Lillioia S等.检测人群胰岛素敏感性的一项新指数[J].中华内科杂志,1993;32(10):656-660.
[56]Li Guangwei and Pan Xiaoren.A New insulin-sensitivity index for epidemiological study[J].Chinese Medical Journal,1995;108:552-561.
[57]任艳,刘秉文,田浩明等.2型糖尿病患者血清载脂蛋白AⅠ、AⅡ、B100、CⅡ、CⅢ、E含量分析[J]。华西医大学学报,2001;32:48-51.
[58]Bergstrom RW,Leonetti DL,Newell-Morris LL,et al.Association of plasma triglyceride and C-peptide with coronary heart disease in Japanese-American men with a high prevalence of glucose intolerance[J].Diabetologia,1990;33(8):489-496.
[59]徐燕华,任艳.2型糖尿病患者血清HDL亚类组成的研究[J].中国糖尿病杂志,2001:9:160-162.
[60]Griffin BA,Freeman DJ,Tait GW,et al.Role of plasma triglyceride in the regulation of plasma low density lipoprotein(LDL) subfractions:relative contribution of small,dense LDL to coronary heart disease risk.Atherosclerosis,1994;106(2):241-253.
[61]McGarry JD.Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes[J].Diabetes,2001;50(suppl2):6.
[62]李秀钧,董砚虎,程丽霞等.糖尿病研究进展—第16届国际糖尿病联盟大会纪要[J].中华内分泌代谢杂志,1998:14(2):72-77.
[63]Charles MA,Eschwege E,Thibult N,et al.The role of non-esterified fatty acids in the deterioration of glucuse tolerence in Caucasian subjects:results of the paris prospective study[J].Diabetologia,1997;40:1101-1106.
[64]Paolisso G,Tataranni PA,Folry JE.A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM[J].Diabetologia,1995,38:1213-1217.
[65]McGarry JD,Dobbins RL.Fatty acids,lipotoxicity and insulin secretion[J].Diabetologia,1999;42:128-138.
[66]Boden G,Chen X,Iqbal N.Acute lowing of plasma fatty acids lower basal insulin secretion in diabetic and nondiabetic subjects[J].Diabetes,1998;47:1609-1612.
[67]Dobbins RL,Chester MW,Daniels MB.Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans[J].Diabetes,1998;47:1613-1618.
[68]Stein DT,Stevenson BE,Chester Mw,et al.The insulinotropic potency of fatty acids is influenced profoundly by their chain lengh and degree of saturation[J].J Clin invest,1997;100:398-403.
[69]Ana TMGS,Guenther B,Maria ERS,et al.Overnigt lowering of free fatty acid with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects[J].Diabetes,1999;48:1836-1841.
[70]Prelevic GM.Insulin resistance in polycystic ovary syndrome[J].Curr Opin Obstet Gynecol,1997;9:193-201.
[71]Guenther B.Role of fatty acids in the pathogenesis of insulin resistance and NIDDM[J].Diabetes,1997;46:3-10.
[72]Boden G.Fatty acids and insulin resistance[J].Diabetes Care,1996;19(4):394-39.
[73]Steinberg GR,Dyck DJ,Calles-Escandon J,et al.Chronic leptin administration decreases fatty acid uptake and fatty acid transporters in rat skeletal Muscle[J].J Biol Chem,2002;277:8854-8860.
[74]Francesco,Roberto,Mafalde.Obesity and body fat distribution induce endothelial dysfunction by oxidative stress[J].Diabetes,2001;50:159-165.
[75]Chang AY.Comparison of highly inbred diabetic and nondiabetic lines in the Upjohn colong of Chinese hamsters[J].Diabetes Res,1997;26(1):63.
[76]姬秋和,苏慧慈.中国地鼠糖尿病模型胰岛A、B细胞数量及分数改变[J].中华内分泌代谢杂志,1996:12(1):31-33.
[77]Rakieten N,Rakieten ML,Nadkarni MV.Studies on the diabetogenic action of streptozotocin(NSC-37917)[J].Cancer Chemother Rep,1963;29:92-98.
[78]徐叔云.药理实验方法学[M].北京:人民卫生出版社.2001,第三版:1258-1259.
[79]王开成,方朝晖,王佑民等.罗格列酮提高胰岛素抵抗大鼠大网膜脂肪细胞PPAR-γmRNA的表达水平[J].江西医药.2006:41(11):847-850.
[80]李秀钧.脂肪组织是又一个新的内分泌器官[J].国外医学内分泌学分册,2002:22(3):129-131.
[81]Kershaw EE,Fliter JS.Adipose tissue as an endocrine organ[J].J Clin Endocrinol Metab,2004;89(6):2548-2556.
[82]Barzilay JI,Abraham L,Heckhem SR,et al.The relation of markers of inflammation to the development of glucose disorders in the elderly:the cardiovascular health study[J].Diabetes,2001;50:2384-2389.
[83]Moiler DE.Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes[J].rrends Endocrinol Metab,2000;11(6):212-217.
[84]Tremblay F,Lavigne C,Jacques H,et al.Defective insulininduced GLUT4translocation in skeletal muscle of high fat-fed rats is associated with alterations in both AKT/protein kinase B and atypical protein kinase C activitiesI[J].Diabetes,2001;50(8):1901-1910.
[85]Hauner H.The mode of action of thiazolidinediones[J].Diabetes Metab Res Rev,2002;18(suppl 2):10-15.
[86]Leroy P,Dessolin S,Villageois P,et al.Expression of obgene in adipose cell.Regulation by insulin[J].Biol them,1996;271:2365-2368.
[87]Kolaczyski JW,Nyce MR,Considine RV,et al.Acute and insulin on leptin production in humans:Studies in vivo and chronic effects of in vitro[J].Diabetes,1996;45:699-701.
[88]Kiefer TJ,Heller RS,Leeeh CA,et al.Leptin suppression insulin secretion by the activation of ATP-sensitive K~+ channels in pancreatic cells.Diabetes,1997;46:1087-1093.
[89]Stejskal D,Jedelsky L,Bartek J,et al.Leptin,insulin and proinsulin-their relationship[J].Vnitr Lek,1998;44:361-365.
[90]Banks WA,Kastin AJ,Huang W,et al.Leptin enters the brain by a saturable system independent of insulin[J].Peptidesm,1996;17:305-311.
[91]陈刚,罗敏,丁伟等.瘦素受体基因变异与中国人肥胖的关系[J].中华内分泌代谢杂志,2001:17(5):298-300.
[92]Scarpace PJ,Matheny M,Tumer N.Hypothalamic leptin resistance is associated with impaired leptin signal transduction in aged obese rats[J].Neuroscience,2001;104(4):1111-1117.
[93]Shimizu H,Shimomura K,Negishi M,et al.Circulating concentrations of soluble leptin receptor:influence of menstrual cycle and diet therapy[J].Nutrition,2002;18(4):309-312.
[94]Bi S,Ladenheim EE,Schwartz GJ,et al.A role of NPY overexpression in the dorsomedial hypothalamus in hyperphagia and obesity of OLETF rats[J].Am J Physiol Regul Integur Comp Physiol,2001,281(1):8254-8260.
[95]Egawa M,Yoshimatsu H,Bray GA.Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue inrats[J].Am J physiol,1991;260(2Pt2):R328-334.
[96]Alice S,Ryan,Dariush Elahi,et al.The effects of acute hyperglycemia and hyperinsulinemia on plasma leptin levels:Its relationships with body fat,viscral adiposity,and age in women[J].J Clin Endocrinol Metab,1996;81:4433-438.
[97]Goodyear LU,Giorgino F,Sherman LA,et al.lnsulin receptor phosphorylation,insulin receptor subtrate-1 phosphorylation,and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects[J].J Clin Invest,1995,95(5):2195-2204.
[98]彭定琼,高妍.2型糖尿病病人脂肪组织胰岛素受体底物1和含2个SH2结构的蛋白酪氨酸磷酸酶的蛋白表达[J].民航医学,2002;12(1):1-4.
[99]Gual P,Gonzalez T,Gremeaux T,et al.Hyperosmotic stress inhibits IRS-1function by distinct mechanisms in 3T3-L1 adipocytes[J].J Biol Chem,2003;278(29):26550-26557.
[100]Aguirre V,Wemer ED,Giraud J,et al.Phosphorylation of Ser 307in insulin receptor substrate-1 blocks interactions with insulin receptor and inhibits insulin action[J].J Biol Chem,2002;277:1531-1537.
[101]Le Roith D,Zick Y.Recent advances in our understanding of insulin action and insulin resistance[J].Diabetes Care,2001;24:588-597.
[102]Egawa K,Nakashima N,Sharma PM,et al.Persistent activation of phosphatidylinositol3-kinase cause insulin resistance due to accelerated insulin induced insulin receptor substrate degradation in 3T3-L1adipocytes[J].Endocrinology,2000;141:1930-1935.
[103]Zhande R,Mitchell JJ,Wu J,et al.Molecular mechanism of insulin induced degradation of insulin receptor substrate-1[J].Mol Cell Biol,2002;4:1016-1026.
[104]张中成,刘志诚.2型糖尿病胰岛素受体后水平研究现状[J].医学综述,2002;8(3):166-167.
[105]Petersen KF,Shulman GI.Etiology of insulin resistance[J].Am J Med,2006;119(5 Suppl 1):S10-16.
[106]Karlsson M,Thorn H,Parpal S,et al.Insulin induces translocation of glucose transporter GLUT4 to plasma membrane caveolae in adipocytes [J.FASEB J,2002;16:249.
[107]Shewan AM,Marsh BJ,Melvin DR,et al.The cytosolic C-terminus of the glucose transporter GLUT4 contains an acidic cluster endosomal targeting motif distal to the dileucine signal[J].Biochem J.2000;350 Pt 1:99-107.
[108]Nelson B A,Robinson K A,Buse M G.High glucose and glucosamine induce insulin resistance via different mechanisms in 3T3-L1 adipocytes [J].Diabetes,2000;49:981-991.
[109]Zierath J R,Krook A,Wallberg-Henriksson H.Insulin action in skeletal muscle from patients with NIDDM[J].Mol Cell Biochem,1998;182:153-160.
[110]Maier V H,Gould G W.Long-term insulin treatment of 3T3-L1 adipocytes results in mis-targeting of GLUT4:implications for insulin-stimulated glucose transport[J].Diabetologia,2000;43:1273-1281.
[111]Yonemitsu S,Nishimura H,Shintani M,et al.Troglitazone induces GLUT4translocation in L6 myotubes[J].Diabetes,2001,50:1093-1101.
[112]Takahashi Y,Ide T.Dietary n-3 fatty acid affect mRNA level of brown adipose tissue uncoupling protein 1,and white adipose tissue leptin and glucose transporter 4 in the rat[J].Br J Nutrm,2000;84:175-184.
[113]Sevilla L,Guma A,Enrique-Tarnacon G,et al.Chronic high-fat feeding and middle-aging reduce in an additive fashion Glut4 expression in skeletal muscle and adipose tissue[J].Biochem Biophys Res Commun,1997;235:59-93.
[114]Quinn L.Mechanisms in the development of type 2 diabetes mellitus[J].J Cardiovasc Nurs,2002;16:1.
[115]Miles P D G,Barak Y,He W,et al.Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency[J].J Clin Invest,2000;105(3):287-92.
[116]Schinner S,Dellas C,Schroder M,et al.Repression of Glucagon Gene Transcription by Peroxisome Proliferator- activated Receptor gamma through Inhibition of Pax6 Transcriptional Activity[J].J Biol Chem,2002;277:1941.
[117]Hsueh W A,Law R.The central role of fat and effect of peroxisome proliferator-activated receptor-gamma on progression of insulin resistance and cardiovascular disease[J].Am J Cardiol,2002;92(4A):3J.
[118]徐世义,张国刚,张洪霞.桑白皮药材质量控制研究[J].中药材,2006:29(2):184-186.
[119]李宇亮,李剑敏,吴雅睿.1-脱氧野尻霉素提取分离方法研究[J].应用化工,2006:35(9):659-665.
[120]马静,刘树兴.桑枝中卜脱氧野尻霉素(DNJ)的研究进展[J].食品科技,2006:9:112-115.
[121]梁建宁,陈正收,吴璐等.高效液相色谱—蒸发光散射法测定桑白皮1-脱氧野尻霉素的含量[J].药物分析杂志,2006:26(7):905-907.
[122]中华人民共和国药典委员会.中华人民共和国药典[s]:一部[M].北京:人民卫生出版社,2005:203.
[123]田宏哲,王华,关亚风.液质联用分析葛根提取物及中药片剂中异黄酮类化合物[J].色谱,2005;23(5):477-481.
[124]Junei K Junko C Junko C.Isoflavonoids and related compounds in the roots and the voluble stems[J].Chem Pharm Bull,1987;35(12):4846-4850.
[125]许海琴,许列琴,许江苇.常用天然提取物质量标准参考手册[M].北京:化学工业出版社,2004,第一版:120-121.
[126]Rong H,Stevens JF,Deinzer,et al.Identification of isoflavones in the roots of Pueraria lobata[J].Plalnta Medica,1998,64(7):620-627.126
[127]冯瑞芝,陈碧珠,林文琰等.葛根的资源调查[J].中国药学杂志,1993:28(5):273-275.
[128]郑水庆,曾明.云南葛属药用植物资源调查[J].中草药,2002:33(8):755-756.
[129]李青坡,王永圣,游剑等.葛根总异黄酮提取工艺的研究[J].制剂技术,2004;13(5):46-47.
[130]周文斌.葛根总黄酮提取工艺条件的研究[J].渝州大学学报(自然科学版),2002;19(4):9-11.
[131]安伟建,郭瑞.不同产地葛根总黄酮含量的比较[J].中国中药杂志,1999;24(6):339-339.
[132]黄兆龙,郭俊明,张东璧.葛根有效成分的提取和测定[J].医药导报,2003;22(5):333-334.
[133]梁桂贤,李勤.葛根黄酮提取分离方法及制剂研究进展[J].山西中医学院学报,2001;2(4):47-49.
[134]向纪明,李金灿,柳林等.吸附法提取分离葛根素的研究[J].天然产物研究与开发,2003;15(3):242-244.
[135]米靖宇,宋纯清.大孔吸附树脂在中草药研究中的应用进展[J].中成药,2001;23(12):914-916.
[136]范碧亭.中药药剂学[M].上海:上海科学技术出版社,1998;第一版:138.
[137]余淑娴,郝晓霞,罗明.真空冷冻干燥技术及其应用[J].食品科技,2007;10:23-25.
[138]李艳萍.冻干技术研究进展[J].微生物学免疫学进展,1994;22(4):48-51.
[139]贺素艳,李云飞.冻干工艺中升华结束点和残余水分测量方法简述[J].真空与低温,2002;8(3):135-139.
[140]赵荣华.518个糖尿病处方统计分析[J].云南中医学院学报,1997;20(2):20-23.
[141]段亚丽,谢梅冬.黄芪化学成分及其有效成分黄芪甲苷含量测定的研究现状[J].中国兽药杂志,2005,39(3):35-38.
[142]卢彦琦,贺学礼.黄芪化学成分及药理作用综述[J].保定师范专科学校学报,2004:17(4):40-42.
[143]陈蔚,夏燕萍,俞茂.黄芪多糖预防自身免疫性胰岛炎的病理变化[J].中国现代医学杂志,2000:7(2):146-148.
[144]吴朝妍,张莹雯.黄芪多糖对肾阳虚型糖尿病大鼠肾组织NF-κB、TGF-β1的影响[J].武汉大学学报(医学版),2006;27(3):381-384,388.
[145]叶红英,俞茂华,游利等.黄芪多糖对STZ糖尿病大鼠物质代谢和心功能的影响[J].上海医科大学学报,2000;27(5):357-358.
[146]杨红霞,朱敏怡.黄芪对糖尿病大鼠肾组织的保护作用[J].实用医学杂志,2005:21(17):1964-1965.
[147]马洪喜,李冬梅.黄芪皂苷对糖尿病大鼠血清清激素水平的影响[J].微量元素与健康研究,2003:20(4):5-6.
[148]马宏秀,张治祥等.黄芪药理研究进展[J].陕西中医学院学报,2004:27(5):147-149.
[149]谭周静,谢达平.多糖的研究进展[J].食品科技,2002:3:10-12.
[150]吴丽,刘婷婷,梁剑锋.黄芪多糖的分离和纯化[J].食品与药品,2007:9(04):62-64.
[151]闫巧娟,韩鲁佳,江正强.酶法脱除黄芪多糖中的蛋白质[J].食品科技,2004:(6):23-26.
[152]苗明三,李振国.现代实用中药质量控制技术[M].北京:人民卫生出版社,2003,第一版:890-899.
[153]赵复中,庄碧年,钱雯.生药膜荚黄芪中黄芪总皂苷含量测定[J].南京医科大学学报,1994:14(2):215-217.
[154]Kitagawa I,Wang H K,Takagi A,et al.Saponin and sapogenol ⅩⅩⅩ Ⅳ.Chemical constituents of Astragalus radix,the 9,19-cyclolanostane-type aglycone of astragalosides,and the artifact aglycone astragenol[J].Chem Pharm Buil,1983;31(2):689.
[155]曹正中,俞家华.膜荚黄芪化学成分研究[J].中草药,1985:16:278.
[156]HirotaniM.Zhou Y,Lui H K.Astragalosides from hairy root culture of Astragalus membraneceus[J].Phytochem,1994;36(3):665-670.
[157]HirotaniM,Zhou Y,Lui H K.Cycloanane triterpeneglycosides from the hairy root cultures of Astragalusm embranaceus[J].Phytochem,1994;37(5):1403-1407.
[158]He Z Q,Findlay J A.Constituents of Astragalus m em branaceus[J].J N atur Prod,1991;54(3):810-815.
[159]王惠康,何侃,叶嘉麟.内蒙黄芪化学成分的研究[J].中草药,1987:18(1):5-7.
[160]Zhu Y Z,Lu S H,Okada Y T,et al.Two new cycloartanetype glycosides,mongholicoside Ⅰ and Ⅱ from the aerial part of Astragalus mongholicus Bunge[J].Chem Pharm Bull,1992;40(8):2230-2232.
[161]胡海云,王伟华,段启.HPLC-ELSD法测定不同产地黄芪中黄芪甲苷[J].中草药,2006:37(12):1886-1888.
[162]国家药典委员会编.中华人民共和国药典[s]:一部[M].北京:化学工业出版社,2005:212.
[163]王举涛,徐文方,刘金旗等.HPLC-ELSD法测定黄芪中黄芪甲苷的含量[J].安徽医药,2006:10(1):28-29.
[164]原田正敏.日本常用生药的定量方法—黄芪[J].国外医药:植物药分册,1990:5(5):201-202.
[165]李伟东,贾晓斌,蔡宝昌.黄芪总皂苷提取工艺研究[J].成都中医药大学学报,2004:27(2):43-45.
[166]贾晓斌,陈彦,蔡宝昌等.黄芪皂苷纯化工艺研究[J].中成药,2003:25(11):866-868.
[167]蔡雄,刘中秋,王培训等.大孔吸附树脂富集纯化人参总皂苷工艺[J].中成药,2001:23(9):631-634.
[168]唐第光.大孔吸附树脂法提取三七总皂苷工艺探讨[J].中成药,1990:12(8):5-6.
[169]芦金清,刘尚桃,刘再刚等.大孔吸附树脂法提取绞股蓝总皂苷[J].中成药,1992:14(4):2-3.
[170]鱼红闪.树脂法提取甘草中甘草苷的研究[J].食品与发酵工业,1999:25(1):40-43.
[171]胡军,周跃华.大孔吸附树脂在中药成分精制纯化中的应用[J].中成药,2002:24(2):127-130.
[2]Gisela Wilcox.Insulin and insulin resistance[J].Clin Biochem Rev,2005;26(5):19-39.
[3]潘长玉,尹士男.胰岛素抵抗发病机制的重要因素[J].中华内分泌代谢杂志,2000:16(1):56-57.
[4]Kruszynska YT,Yu JG,Olefsky JM,et al.Effects of troglitazone on blood concentrations of plasminogen activator inhibitor in patients with type 2 diabetes and in lean and obese normal subjects[J].Diabetes,2000;49:633-639.
[5]International Diabetes Federation.Diabetes Atlas(third edition)[R]J.2007.
[6]Beck-Nielsen H.General characteristics of the insulin resistance syndrome:prevalence and heritability.European Group for the Study of Insulin Resistance[J].Drugs,1999;58(Suppl1):7-10.
[7]Zachary T Bloomgarden,MD.Developments in Diabetes and Insulin Resistance —This is the second in a series of articles on presentations at the American Diabetes Association Annual Meeting,San Diego,California,2005,10.
[8]Bloomgarden Z T.Insulin resistance,exercise,and obesity[J].Diabetes Care,1999;22(3):517-522.
[9]全国糖尿病研究协作组调查研究组.全国14省市30万人口中糖尿病调查报告[J].中华内科杂志,1981:20:678.
[10]向红丁,吴纬,孙琦等.1989年全国糖尿病流行病学特点基线调查报告[J].中国糖尿病杂志,1998:6(3):131-133.
[11]Jie Wp,Xiang K S,Chen L,et al.Epidenmiologic study on metabolic syndrome in normal and overweight Chinese in Shanghai.Diabetes,2000;49(Suppl1):A148.
[12]吴家睿.2型糖尿病发生发展的分子机制研究[J].生命科学.2006:18(5):411-413.
[13]Ohlson LO,Larsson B,Bjorntorp P,et al.Risk of factors for type 2(non-insulin-dependent) diabetes mellitus.Thirteen and one-half years of follow-up of the participants in a study of Swedish men born in 1913[J].Diabetologia,1998,31(11):798-805.
[14]Knowler WC,Pettitt DJ,Saad MF,et al.Diabetes mellitus in the Pima Indians:incidence,risk factors and pathogenesis.Diabetes Metab Rev,1990,6(1):1-27.
[15]Brancati FL,Whelton PK,Kuller LH,et al.Diabetes mellitus,race,and socioeconomic status.A population-based study[J].Ann Epidemiol,1996;6(1):67-73.
[16]Haffner SM,Miettinen H,Stern MP.Nondiabetic Mexican-Americans donot have reduced insulin responses relative to nondiabetic non-Hispanic whites[J].Diabetes Care,1996;19(1):67-69.
[17]Willett WC.The Mediterranean diet:science and practice[J].Public Health Nutr,2006;9(1A):105-10.
[18]Le DS,Kusama K,Yamamoto S.A community-based picture of type 2 diabetes mellitus in Vietnam[J].J Atheroscler Thromb,2006;13(1):16-20.
[19]刘慧霞.高胰岛素血症加重高糖对PKB丝氨酸磷酸化的抑制作用[J].中国现代医学杂志,2002;12(9):38-40.
[20]池海谊,冯凭.抵抗素在肥胖与2型糖尿病间作用的研究现状[J].内蒙古医学杂志,2006;(3):43.
[21]张晓明,裴秀珍,戚海等[J].河北省糖尿病流行病学研究.实用预防医学,1998,5:68-71.
[22]Diamond J.The double puzzle of diabetes[J].Nature,2003;423:599-602.
[23]Sharma AM.The obese patient with diabetes mellitus:from research targets to treatment options[J].Am J Med,2006;119(5 Suppl1):S17-23.
[24]田坚,彭扬.腹型肥胖与胰岛素抵抗的关系[J].中华实用医学,2002;4(6)3-4.
[25]彭定琼,高妍.2型糖尿病病人脂肪组织胰岛素受体底物1和含2个SH2结构的蛋白酪氨酸磷酸酶的蛋白表达[J].民航医学,2002;12(1):1-4.
[26]江孙芳,高鑫,陆志强等.肥胖患者血清胰岛素原水平与胰岛素抵抗的关系[J].复旦学报(医学版),2002;29(3):200-204.
[27]王巍,赵列宾,梁伟等.老年男2型糖尿病合并高血压患者血清同型半胱氨酸水平变化与肥胖、胰岛素抵抗的关联性研究[J].中国临床康复,2002;6(9):1300-1301.
[28]睡眠不足:胰岛素抵抗及肥胖的危险因素(ADA2001年会,183-OR)[J].国外医学内分泌学分册,2002;22(1):59.
[29]Yaggi HK,Araujo AB,McKinlay JB.Sleep duration as a risk factor for the development of type 2 diabetes[J].Diabetes Care,2006;29(3):657-661.
[30]Helmrich SP,Ragland DR,Leung RW,et al.Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus[J].N Engl J Med, 1991;325(3):147-152.
[31]Kriska AM,LaPorte RE,Pettitt DJ,et al.The association of physical activity with obesity,fat distribution and glucose intolerance in Pima Indians[J].Diabetologia,1993,36(9):863-869.
[32]付利华.绝经后妇女糖代谢变化的相关因素研究[J].中华综合医学,2002:3(4):307-310.
[33]Uchimoto S,Tsumura K,Hayashi T,et al.Impact of cigarette smoking on the incidence of type 2 diabetes mellitus in middle-aged Japanese men:the Osaka Health Survey[J].Diabet Med.1999.16:951-955.
[34]Qiao Q,Valle T,Nissinen A,et al.Smoking and the risk of diabetes in elderly Finnish men.Retrospective an alysis of data from a 30-years follow-up study[J].Diabetes Care,1999,22:1821-1826.
[35]Wei M,Gibbsons LW,Mitchel WL,et al.Alcohol intake and incidence of type 2 diabetes in men[J].Diab etes Care,2000,23:18-22.
[36]Lee AV,Jachson JG,Gooch JL,et al.enhancement of insulin-like grouth factor signaling in human breast cancer,estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo[J].Mol Endocrinol,1999;13(5):787-796.
[37]Mallone R,Perin PC.Anti-CD38 autoantibodies in type 2 diabetes[J].Diabetes Metab Res Rev.2006;17.
[38]McKillop AM,Lindsay JR,Au S,et al.Meal-dependent regulation of circulating glycated insulin in type 2 diabetic subjects[J].Horm Metab Res,2006;38(2):94-97.
[39]谢乃强.胰高血糖素与2型糖尿病病人胰岛素抵抗关系研究[J].中国基层医药,2002:9(9):798-799.
[40]张芳林,刘小莺,林益川等.地塞米松诱发的大鼠胰岛素抵抗模型[J].中国应用生理学杂志,2002:18(1):99-101.
[41]Fasshauer M,Klein J,Lossner U,et al.Interleukin(IL)-6 mRNA Expression is Stimulated by Insulin,Isoproterenol,Tumour Necrosis Factor Alpha,Growth Hormone,and IL-6 in 3T3-L1 Adipocytes[J].Horm Metab Res,2003;35(3):147-52.
[42]李秀钧主编.胰岛素抵抗综合征[M].北京:人民卫生出版社,2001,第一版:25-41.
[43]White MF,Kahn CR.The insulin resistance and type 2 diabetes from knockout mouse models[J].J Clin Invest,2000;106(4):459-465.
[44]ValverdeAM,Burks DJ,Fabregat I,etal.Molecular mechanisms of insulin resistance in IRS-2 deficient hepatoeytes[J].Diabetes,2003;52(9):2239-2248.
[45]Kahn CR.Knockout mice challenge our concepts of glucose homeostasis and the pathogenesis of diabetes[J].Exp Diabesity Res,2003;4(3):169-182.
[46]Czech MP,Corvera S.Signaling mechanisms that regulate glucose transport[J].J Biol Chem,1999;274(4):1865-1868.
[47]Sun XJ,Rothenberg P,Kahn CR,et al.Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein[J].Nature,1991:352(6330):73-77.
[48]Yamauchi T,Tobe K,Tamemoto H,et al.Insulin signaling and insulin actions in the muscles and livers of insulin-resistant,insulin receptor substrate 1-deficient mice[J].Mol Cell Biol,1996;16(6):3074-3084.
[49]Goodyear LU,Giorgino F,Sherman LA,et al.Insulin receptor phosphorylation,insulin receptor subtrate-1 phosphorylation,and phosphatidyl inositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects[J].J Clin Invest,1995;95(5):2195-2204.
[50]Gual P,Gonzalez T,Gremeaux T,et al.Hyperosmotic stress inhibits IRS-1 function by distinct mechanisms in 3T3-L1 adipocytes[J].J Biol Chem,2003;278(29):26550-26557.
[51]Petersen KF,Shulman GI.Etiology of insulin resistance[J].Am J Med,2006;119(5 Suppl 1):S10-16.
[52]Nelson B A,Robinson K A,Buse M G.High glucose and glucosamine induce insulin resistance via different mechanisms in 3T3-L1 adipocytes[J].Diabetes,2000;49:981-991.
[53]Zierath J R,Krook A,Wallberg-Henriksson H.Insulin action in skeletal muscle from patients with NIDDM[J].Mol Cell Biochem,1998;182:153-160.
[54]Maier V H,Gould G W.Long-term insulin treatment of 3T3-L1 adipocytes results in mis-targeting of GLUT4:implications for insulin-stimulated glucose transport[J].Diabetologia,2000;43:1273-1281.
[55]Yonemitsu S,Nishimura H,Shintani M,et al.Troglitazone induces GLUT4 translocation in L6 myotubes[J].Diabetes,2001;50:1093-1101.
[56]Takahashi Y,Ide T.Dietary n-3 fatty acid affect mRNA level of brown adipose tissue uncoupling protein l,and white adipose tissue leptin and glucose transporter 4 in the rat[J].Br J Nutr,2000;84:175-184.
[57]Sevilla L,Guma A,Enrique-Tarnacon G,et al.Chronic high-fat feeding and middle-aging reduce in an additive fashion Glut4 expression in skeletal muscle and adipose tissue[J].Biochem Biophys Res Commun,1997;235:59-93.
[58]Kurokawa K,Oka Y.Insulin resistance and glucose transporter[J].Nippon Rinshl,2000;58(2):310-314.
[59]Almind K,Bjorbaek C,Vestergaard H,et al.Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus.Lancet,1993;342(8875):828-832.
[60]Kido Y,Burks DJ,Withers D,et al.Tissue-specific insulin resistance in mice with mutations in the insulin receptor,IRS-1,and IRS-2.J Clin Invest,2000;105(2):199-205.
[61]Meyre D,Froguel P.ENPP1,the first example of common genetic link between childhood and adult obesity and type 2 diabetes.Med Sci(Paris)[J].2006,22(3):308-312.
[62]Liu W,Liu M,Fan W,et al.The Gly146Ala variation in human SF-1 gene:Its association with insulin resistance and type 2 diabetes in Chinese[J].Diabetes Res Clin Pract,2OO6;[Epub ahead of print]
[63]Horikoshi M,nara K,Ohashi J,et al.A Polymorphism in the AMPK{alpha}2Subunit Gene Is Associated With Insulin Resistance and Type 2 Diabetes in the Japanese Population[J].Diabetes,2006;55(4):919-23.
[64]Saller B,Nemesszeghy P,Mann K,et al.Glucose and Lipid Metabolism in Young Lean Normotensive Males with the G Protein beta3 825T-Allele[J].Eur J Med Res,2003;8(3):91-97.
[65]Ilany J,Bilan PJ,Kapur S,et al.Overexpression of Rad in muscle worsens diet-induced insulin resistance and glucose intolerance and lowers plasma triglyceride level[J].Proc Natl Acad Sci USA,2006;103(12):4481-4486.
[66]李秀钧.脂肪组织是又一个新的内分泌器官[J].国外医学内分泌学分册,2002:22(3):129-131.
[67]Kershaw EE,Fliter JS.Adipose tissue as an endocrine organ[J].J Clin Endocrinol Metab,2004;89(6):2548-2556.
[68]Miles P D G,Barak Y,He W,et al.Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency[J].J Clin Invest,2000;105(3):287.
[69]Schinner S,Dellas C,Schroder M,et al.Repression of Glucagon Gene Transcription by Peroxisome Proliferator-activated Receptor gamma through Inhibition of Pax6 Transcriptional Activity[J].J Biol Chem,2002;277: 1941.
[70]Hsueh W A,Law R.The central role of fat and effect of peroxisome proliferator-activated receptor-gamma on progression of insulin resistance and cardiovascular disease[J].Am J Cardiol,2002;92(4A):3J.
[71]Steppan CM,Bailey ST,Bhat S,et al.The hormone resistin links obesity to diabetes[J].Nature,2001,409(6818):307-312.
[72]Leroy P,Dessolin S,Villageois P,et al.Expression of ob gene in adipose cell.Regulation by insulin[J].Biol Chem,1996;271:2365-2368.
[73]Kolaczyski JW,Nyce MR,Considine RV,et al.Acute and insulin on leptin production in humans:Studies in vivo and chronic effects of in vitro[J].Diabetes,1996,45:699-701.
[74]Kiefer TJ,Heller RS,Leeeh CA,et al.Leptin suppression insulin secretion by the activation of ATP-sensitive K~+ channels in pancreatic cells[J].Diabetes,1997;46:1087-1093.
[75]Stejskal D,Jedelsky L,Bartek J,et al.Leptin,insulin and proinsulin-their relationship[J].Vnitr Lek,1998;44:361-365.
[76]Banks WA,Kastin AJ,Huang W,et al.Leptin enters the brain by a saturable system independent of insulin[J].Peptides,.1996;17:305-311.
[77]陈刚,罗敏,丁伟等.瘦素受体基因变异与中国人肥胖的关系[J].中华内分泌代谢杂志,2001:17(5):298-300.
[78]Scarpace PJ,Matheny M,Tumer N.Hypothalamic leptin resistance is associated with impaired leptin signal transduction in aged obese rats[J].Neuroscience,2001;104(4):1111-1117.
[79]Shimizu H,Shimomura K,Negishi M,et al.Circulating concentrations of soluble leptin receptor:influence of menstrual cycle and diet therapy[J].Nutrition,2002;18(4):309-312.
[80]Bi S,Ladenheim EE,Schwartz GJ,et al.A role of NPY overexpression in the dorsomedial hypothalamus in hyperphagia and obesity of OLETF rats[J].Am J Physiol Regul Integur Comp Physiol,2001;281(1):8254-8260.
[81]Egawa M,Yoshimatsu H,Bray GA.Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue inrats[J].Am J physiol,1991;260(2Pt2):R328-334.
[82]Alice S,Ryan,Dariush Elahi,et al.The effects of acute hyperglycemia and hyperinsulinemia on plasma leptin levels:Its relationships with body fat,viscral adiposity,and age in women[J].J Clin Endocrinol Metab,1996;81:4433-438.
[83]Hotta K,Funahshi T,Bodkin N L,et al.Circulating concentrations of the adipocyte protein adiponectin are decreased inparallel with reduced insulin sensitivity during theprogression to type 2 diabetes in rhesus monkeys[J].Diabetes,2001;50(5):1126.
[84]Yamauchi T,Kamon J,Waki H,et al.The fat-derived hormone adiponectin reverse insulin resistance associated with both lipoatrophy and obesity[J].Nut Med,2001;7(8):941.
[85]Stefan N,Stumvoll M.Adiponectin-its role in metabolism and beyond[J].Horm Metab Res,2002;34(9):469.
[86]Barzilay JI,Abraham L,Heckhem SR,et al.The relation of markers of inflammation to the development of glucose disorders in the elderly:the cardiovascular health study[J].Diabetes,2001;50:2384-2389.
[87]Moiler DE.Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes[J].Trends Endocrinol Metab,2000;11(6):212-217.
[88]Tremblay F,Lavigne C,Jacques H,et al.Defective insulininduced GLUT4 translocation in skeletal muscle of high fat-fed rats is associated with alterations in both AKT/protein kinase B and atypical protein kinase C activitiesl[J].Diabetes,2001;50(8):1901-1910.
[89]Hauner H.The mode of action of thiazolidinediones[J].Diabetes Metab Res Rev,2002;18(suppl2):10-15.
[90]Senn JJ,Klover PJ,Nowak IA,et al.Suppressor of cytokine signaling-3(S0CS-3),a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes[J].J Biol Chem,2003,278(16):13740-13746.
[91]Guerre-Millo M.Adipose tissue and adipokines:for better or worse[J].Diabetes Metab,2004:30(1):13-9.
[92]Kershaw EE,Flier JS.Adipose tissue as an endocrine organ[J].J Clin Endocrinol Metab,2004;89(6):2548-2556.
[93]Frayn KN.Adipose tissue as a buffer for daily lipid flux[J].Diabetologia,2002:45(9):1201-1210.
[94]Yu YH,Ginsberg HN.Adipoeyte Signaling and Lipid Homeostasis Sequelae of Insulin-Resistant Adipose Tissue[J].Circ Res,2005:96(10):1042-1052.
[95]McGarry JD.Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes[J].Diabetes,2001;50(suppl2):6.
[96]Charles MA,Eschwege E,Thibult N,et al.The role of non-esterified fatty acids in the deterioration of glucuse tolerence in Caucasian subjects:results of the paris prospective study[J].Diabetologia,1997;40:1101-1106.
[97]Paolisso G,Tataranni PA,Folry JE.A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM[J].Diabetologia,1995;38:1213-1217.
[98]McGarry JD,Dobbins RL.Fatty acids,lipotoxicity and insulin secretion[J].Diabetologia,1999;42:128-138.
[99]Boden G,Chen X,Iqbal N.Acute lowing of plasma fatty acids lower basal insulin secretion in diabetic and nondiabetic subjects[J].Diabetes,1998;47:1609-1612.
[100]Dobbins RL,Chester MW,Daniels MB.Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans[J].Diabetes,1998;47:1613-1618.
[101]Stein DT,Stevenson BE,Chester Mw,et al.The insulinotropic potency of fatty acids is influenced profoundly by their chain lengh and degree of saturation[J].J Clin invest,1997;100:398-403.
[102]Abadie JM,Malcom GT,Porter JR,et al.Canassociations between free fatty acid levels and metabolic parameters determine insulin resistance development in obese Zucker rats[J].Life Sci,2001;69:2675-2683.
[103]Ana TMGS,Guenther B,Maria ERS,et al.Overnigt lowering of free fatty acid with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects[J].Diabetes,1999;48:1836-1841.
[104]Prelevic GM.Insulin resistance in polycystic ovary syndrome[J].Curr Opin Obstet Gynecol,1997;9:193-201.
[105]Guenther B.Role of fatty acids in the pathogenesis of insulin resistance and NIDDM[J].Diabetes,1997;46:3-10.
[106]Boden G.Fatty acids and insulin resistance[J].Diabetes Care,1996;19(4):394-39.
[107]Steinberg GR,Dyck DJ,Calles-Escandon J,et al.Chronic leptin administration decreases fatty acid uptake and fatty acid transporters in rat skeletal Muscle[J].J Biol Chem,2002;277:8854-8860.
[108]Francesco,Roberto,Mafalde.Obesity and body fat distribution induce endothelial dysfunction by oxidative stress[J].Diabetes,2001;50: 159-165.
[109]Wiederkehr A,Wollheim CB.Implication of mitochondria in insulin secretion and action[J].Endocrinology,2006 Mar 23.[Epub ahead of print].
[110]Petersen KF,Shulman GI.Etiology of insulin resistance[J].Am J Med.2006;119(5 Suppl 1):S10-16.
[111]Sriwijitkamol A,Christ-Roberts C,Berria R,et al.Reduced skeletal muscle inhibitor of kappaB beta content is associated with insulin resistance in subjects with type 2 diabetes:reversal by exercise training[J].Diabetes,2006;55(3):760-767.
[112]Ahren B,Landin-Olsson M,Jansson PA,et al.Inhibition of dipeptidyl pepti-dase-4 reduces glycemia,sustains insulin levels,and reduces glucagon levels in type 2 diabetes[J].Clin Endocrinol Metab,2004;89(5):2078-2084.
[113]Gura T.Diabetes research:new lead found to a possible "insulin pill"[J].Science,1999,284(5416):886.
[114]黄帝内经素问[M].北京:人民卫生出版社,1963:212,261-262.
[115]陈言.三因极一病证方论[M].北京:人民卫生出版社,1957:137.
[116]张从正.儒门事亲[M].沈阳:辽宁科学技术出版社,1997:103-105.
[117]朱震亨.丹溪心法[M].沈阳:辽宁科学技术出版社,1997:55.
[118]徐文萍.“五脏脏真”与“消褐病”的关系[J].中国中医基础医学杂,2001:7(6):406
[119]白红艳,邹文俊,高小平.葛根对地塞米松诱导的胰岛素抵抗的影响[J].中国中药杂志,2004:29(4):356-358.
[120]周俐,张曙辉,于珍等.黄芪对糖尿病胰岛素抵抗及血清脂联素影响的临床研究[J].新中医,2007:39(5):82-83.
[121]范冠杰,唐咸玉,李双蕾等.降糖补肾方对2型糖尿病患者血清CRP、IL-6及TNF-α的影响[J].中国中西医结合杂志,2006:26(4):329-331.
[122]许武红,符燕.黄芪、葛根合剂配合科索亚联合治疗糖尿病肾病的疗效观察[J].吉林医学,2006:27(1):83-84.
[123]张丽君,吴平.益气滋阴活血法治疗2型糖尿病135例临床观察[J].中医药信息,2006;23(3):24.
[124]杨晓春,宛晓春等.葛根的研究及其开发前景[J].林业科技通讯,1996:(1):16.
[125]白红艳,邹文俊等.葛根对地塞米松诱导的胰岛素抵抗的影响[J].中国中药杂志,2004:(4):356.
[126]董英,徐斌,林琳等.葛根的化学成分研究[J].食品与机械,2005:21(6):85-88.
[127]石昌顺.中药葛根的研究[J].中草药,1994:25(9):496.
[128]杨林静,何可月等.葛根的药理学研究及临床应用进展[J].武警医学院学报.2002:11(2):138-140.
[129]于健,苏珂.葛根素对2型糖尿病病人胰岛素抵抗的影响[J].中国新药与临床杂志,2002:21(10):585-587.
[130]曾莉,顾振纶,茅彩萍.葛根素对糖尿病小鼠胰岛素抵抗的影响[J].中草药,2006:37(6):901-904.
[131]洪畋,毕会民,毕欣.葛根素对胰岛素抵抗大鼠肝脏中GSK-3表达的影响[J].中国临床药理学与治疗学,2006:11(2):207-210.
[132]刘蕴玲等.葛根素对2型糖尿病人胰岛素敏感性的影响[J].辽宁实用糖尿病杂志,2000;8(1):26.
[133]吕俊华,张世平,潘竞锵.葛根素对D-半乳糖诱导糖基化模型大鼠血糖和肝肾功能的影响[J].中国新药杂志,2006:15(18):1548-1551.
[134]郭妍等.老年糖尿病肾病血清Ⅳ型胶原变化及葛根素对其影响[J].实用老年医学,1999;13(6):296.
[135]刘亚明,牛欣,冯前进.葛根素治疗糖尿病评述[J].中国医药学报,2003;18(1):49-51.
[136]Shen P,Liu MH,Ng TY,et al.Differential Effects of Isoflavones,from Astragalus Membranaceus and Pueraria Thomsonii,on the Activation of PPAR{alpha},PPAR{gamma},and Adipocyte Differentiation In Vitro[J].J Nutr,2006:1364:899-905.
[137]赵荣华.518个糖尿病处方统计分析[J].云南中医学院学报,1997:20(2):20-23.
[138]吴炎.黄芪注射液对肝硬化患者肝功能的影响[J].中国中西医结合杂志,1999:19(6):364.
[139]李勤,刘宏.黄芪的药理作用及临床应用[J].医学综述,2004:10(10):634.
[140]卢彦琦,贺学礼.黄芪的化学成分及药理作用综述[J].保定师范专科学校学报,2004:17(4):40-42.
[141]陈蔚,夏燕萍,俞茂.黄芪多糖预防自身免疫性胰岛炎的病理变化[J].中国现代医学杂志,2000:7(2):146-148.
[142]吴朝妍,张莹雯.黄芪多糖对肾阳虚型糖尿病大鼠肾组织NF-κB、TGF-β1的影响[J].武汉大学学报(医学版),2006:27(3):381-384,388.
[143]叶红英,俞茂华,游利等.黄芪多糖对STZ糖尿病大鼠物质代谢和心功能的影响[J].上海医科大学学报,2000:27(5):357-358.
[144]杨红霞,朱敏怡.黄芪对糖尿病大鼠肾组织的保护作用[J].实用医学杂 志,2005;21(17):1964-1965.
[145]马洪喜,李冬梅.黄芪皂苷对糖尿病大鼠血清清激素水平的影响[J].微量元素与健康研究,2003:20(4):5-6.
[146]马宏秀,张治祥等.黄芪药理研究进展[J].陕西中医学院学报,2004:27(5):147-149.
[147]吴志平,谈建中,顾振纶.中药桑白皮化学成分及药理活性研究进展[J].中国野生植物资源,2004;23(5):10-13.
[148]吴志平,周巧霞,顾振纶等.桑树不同药用部位的降糖效果比较[J].蚕业科学,2005;31(2):215-217.
[149]汪宁,朱荃,周义维等.桑白皮等中药提取物对胰岛素促进离体肝脏葡萄糖消耗的影响[J].时珍国医国药,2006:17(4):513-514.
[150]杨海霞,朱祥瑞.1-脱氧野尻霉素(DNJ)的研究进展[J].蚕桑通报,2003;34(1):6-10.
[151]#12
[152]Hikino H,Mizuno T,Oshima Y,et al.Validity of the oriental medicines.80Antidiabetes drugs.4 Isolation and hypoglycemic activity of moran A.a glycoprotein of Morus alba root barks[J].Planta Med,1985;(2):159.
[153]膝德义,经广纬,吴松云.复方桑白皮浓缩液的降血糖试验[J].西北药学杂志,1998:13(6):255.
[154]钟国连.桑白皮水提取液对糖尿病模型大鼠血糖血脂的影响[J].赣南医学院学报,2003:23(1):23-24.
[1]Kruszynska YT,Yu JG,Olefsky JM,et al.Effects of troglitazone on blood concentrations of plasminogen activator inhibitor in patients with type 2 diabetes and in lean and obese normal subjects[J].Diabetes,2000:49:633-639.
[2]Reaven GM.Insulin resistance and com pensatoryhyper- insulinemia:role in hypertension,dyslipidemia,and coronary heart disease[J].Am Heart J,1991;121(4Pt2):1283-1288.
[3]Haffner SM.Epidemiology of insulin resistance and its relation to coronary artery disease[J].American Journal of Cardiology,1999;84(IA):11-14.
[4]Tripathy D,Carlsson M,Almgren P,et al.Insulin secretion and insulin sensitivity inrelation to glueose tolerance:lessons from the Botnia Study[J].Diabetes,2000;49(6):975-980.
[5]GrooP L,Orho-Melander M.The dysmetabolic syndrome[J].Journal of Internal Medicine,2001;250(2):105-120.
[6]Jia Weiping,Xiang Kunsan,Chen Lei,et al.A comparison of the application of two working definitions of metabolic syndrome in Chinese population[J].Natl Med J China,2004;84(7):534-538.
[7]Liu Xing,Wang Yalou,et al.Present states and developmental trends of therapeutic drugs for typeⅡdiabetes[J].Journal of Pharmaceutieal Practice,2004;21(1):1-4.
[8]Cai Zhong de,Wu Jie,Zhu Hui rong.The General situation of the study of Chinese Traditional Medicine Curing Diabetes Mellitus[J].Chinese Journal of Experimental Traditional Medical Formulae,2002;8(6):56-59.
[9]白红艳,邹文俊,高小平.葛根对地塞米松诱导的胰岛素抵抗的影响[J].中国中药杂志,2004:29(4):356-358.
[10]周俐,张曙辉,于珍等.黄芪对糖尿病胰岛素抵抗及血清脂联素影响的临床研究[J].新中医,2007:39(5):82-83.
[11]杨凌辉,邹大进,冯正康等.黄芪改善高脂饲养大鼠胰岛素敏感性的机制研究[J].第二军医大学学报,2004,25(4):407-409.
[12]范冠杰,唐咸玉,李双蕾等.降糖补肾方对2型糖尿病患者血清CRP、IL-6及TNF-α的影响[J].中国中西医结合杂志,2006;26(4):329-331.
[13]许武红,符燕.黄芪、葛根合剂配合科索亚联合治疗糖尿病肾病的疗效观察[J].吉林医学,2006:27(1):83-84.
[14]张丽君,吴平.益气滋阴活血法治疗2型糖尿病135例临床观察[J].中医药信息,2006;23(3):24.
[15]Greene DA.Acute and chronic complications of diabetes mellitus in older patients[J].American Journal of medicine.1986,80(5A):39-53.
[16]李仪奎.中药药理实验方法学[M].上海:上海科技出版社,2006,第二版:602-603,608-609.
[17]Wu Jian,Lei Moxian.New consideration on the relation of insulin resistance and type 2 diabetic[J].Medicine and Philosophy,2004;25(2):4-5.
[18]Moller DE,Flier JS.Insulin resistance mechanism,syndromes,and implications[J].N Eng J med,1991;325(13):928-948.
[19]Gisela Wilcox.Insulin and insulin resistance[J].Clin Biochem Rev,2005;26(5):19-39.
[20]潘长玉,尹士男.胰岛素抵抗发病机制的重要因素[J].中华内分泌代谢杂志,2000;16(1):56-57.
[21]Storlien LH,JamesDE,BurleighKM,etal.Fat feeding causes widespread in vivo insulin resistance,decreased energy expenditure,and obesity in rats[J].AmJ Physiol,1986;251:E576-583.
[22]Ding Shiying,Shen Zhufang,Chen Yueteng,et al.Using euglycemic clamp technique estimate two type of insulin-resistance animal model[J].Chinese Diabetes magazine,2001;9(5):286-289.
[23]Li Chenzhong,Zhang Suhua,Shu Changda,et al.High fat meal induce insulin-resistance rats.Basic Medical Sciences and Clinics,2000;20(3):93-95.
[24]郝玉美,刘洪琪.苦瓜 黄芪 黄芩苷对2型糖尿病大鼠模型胰岛素抵抗的影响[J].辽宁中医药大学学报.2007;9(5):6-7.
[25]李勇,刘孟宇,王颜刚.生芪降糖颗粒对胰岛素抵抗鼠的作用及机制研究[J].中国中西医结合杂志,2007;27(5):449-451.
[26]陈奇.中药药效研究思路与方法[M].北京:人民卫生出版社,2005,第一版:611-623.
[27]李秀钧主编.胰岛素抵抗综合征[M].北京:人民卫生出版社,2001,第一版:44-57.
[28]Hanley AJ,Williams K,Gonzalez C,et al.Prediction of type 2 diabetes using simple measures of insulin resistance:combined results from the San Antonio Heart Study,the Mexico City Diabetes Study,and the Insulin Resistance Atherosclerosis Study[J].Diabetes,2003;52:463-469.
[29]鲁瑾,邹大进,张家庆.高脂饮食诱发大鼠胰岛素抵抗后肿瘤坏死因子-α的改变[J].中国糖尿病杂志,1999:7(5):284-286.
[30]葛学美,郭俊生,赵法极等.高脂诱发2型糖尿病模型建立及谷氨酸胺的保护作用研究[J].解放军预防医学杂志,2000:18(1):21-23.
[31]姚峰,王宗保,谭翔文等.贵州小型猪2型糖尿病动物模型的建立[J].南华大学学报医学版.2004,32(3):294.
[32]乔凤霞,申竹芳,叶菲等.链脲佐菌素糖尿病金黄地鼠模型建立的研究[J].中国糖尿病杂志.2000:8(4):215-218.
[33]王志刚,岳辉.丹参对实验性2型糖尿病大鼠肾损害的保护作用[J].牡丹江医学院学报.2005:26(1):20-21.
[34]张亚非.Ⅱ型糖尿病实验模型[J].国外医学卫生学分册,2000;27(6):328-330.31
[35]Arison RN,Ciaccio EI,Glitzer MS,et al.Light and electron microscopy of lesions in rats rendered diabetic with streptozotocin[J].Diabetes,1967;16:51-56.
[36]赵凌云.链脲佐菌素实验性糖尿病研究—Ⅰ、Ⅱ、Ⅲ、Ⅳ[J].四川医学院学报,1985,16(4):289.
[37]Junod A,Lamber AE Orci L,et al.Studies of the diabetogenic action of streptozotocin[J].PTOC Soc Exp Biol Med,1967;125:201.
[38]景远,关晓萍,蔺威等.实验性糖尿病大鼠的血液流变性变化[J].中国微循环,2002:6(1):34-35.
[39]刘霆,张桂珍,牟明威等.STZ小剂量多次注射诱导大鼠胰岛素依赖性糖尿病动物模型探讨[J].白求恩医科大学学报,2001,27(6):578-580.
[40]王军,李利,董砚虎.胰岛β细胞的病理与胰岛素抵抗研究进展—第37届欧洲糖尿病研究协会年会侧记[J].国外医学内分泌分册,2002:22(2):119-122.
[41]付荣霞,杨红艳,孙长颢等.不同饲料构成诱导大鼠肥胖模型的研究[J].中华临床新医学,2002;2(7):579-580.
[42]郭啸华,刘志红,李恒等.实验性2型糖尿病大鼠模型的建立[J].肾脏病与透析肾移植杂志,2000;9(4):351-355.
[43]丁世英,申竹芳,谢明智.PAPR与胰岛素抵抗[J].中国药理学通报,2002;18(3):241-245.
[44]徐成,王莉莉,曹颖林等.PPARs:脂代谢调节与胰岛素增敏治疗药物的作用靶标[J].中国药理学通报,2004;20(3):241-244.
[45]Stumvoll M.Haring H U.Glitazones:clinical effects and molecular mechansisms[J].Ann Med,2002;34:224-217.
[46]Dubos M,Vantyghem M C.Schoonjans K,elal.Thiazolidiones in type 2diabete.Role of peroxisome proliferator-activated receptor gamma(PPAR-γ)[J].Ann Endocrinol(Paris).2002;63:523-511.
[47]Pasteri V,Wu HD,Eillerson JT,el al.Modulation of vascular inflammation it:vitro and in vivo by peroxisome proliferators activated receptor-gamma activators[J].Circulation,2000;1(11):238-235.
[48]Guo Q,Sahoo SP,Wang PR,etal.A novel peroxisome porliferator-activated receptor alpha/gamma dual agonist demonstrates favorable effects on lipid homeostasis[J].Endocrinology,2004;145(4):1640-1648.
[49]Yki-Jarvinen H.Thiazolidinediones[J].N Engl J Med,2004;351(11):1106-1118.
[50]Zambre Y,Ling Z,Hou X,et al.Impaired beta-cell functions induced by chronic exposure of cultured human pancreatic islets to high glucose[J].Diabetes,1999;48(6):1230-1236.
[51]De Fronzo R A,Tobin J D,Andres R.Glucose clamp technique:a method for quantifying insulin secretion and resistance[J].Am J Physiol,1979;237:E214-332.
[52]Bergman R N,Finegood D T,Ader M.Assessment of insulin sensitivity in vivo[J].Endocri Rew,1985;6(1):45-52.
[53]Coates P A,Luzio S D,Bmnel P,et al.Comparison of estimates of insulin sensitivity from minimal model analysis of the insulin-modified frequently sampled intravenous glucose tolerance test and isoglycentic hyperinsulinemic clamp in subjects with NIDDM[J].Diabetes,1995;44(6):631-635.
[54]Haffner SM,Gonzalez C,Mietinen H,et al.A prospective analysis of the Homa model.The Mexico City Diabetes Study[J].Diabetes Care,1996;19:1138-1141.
[55]李光伟,潘孝仁,Lillioia S等.检测人群胰岛素敏感性的一项新指数[J].中华内科杂志,1993;32(10):656-660.
[56]Li Guangwei and Pan Xiaoren.A New insulin-sensitivity index for epidemiological study[J].Chinese Medical Journal,1995;108:552-561.
[57]任艳,刘秉文,田浩明等.2型糖尿病患者血清载脂蛋白AⅠ、AⅡ、B100、CⅡ、CⅢ、E含量分析[J]。华西医大学学报,2001;32:48-51.
[58]Bergstrom RW,Leonetti DL,Newell-Morris LL,et al.Association of plasma triglyceride and C-peptide with coronary heart disease in Japanese-American men with a high prevalence of glucose intolerance[J].Diabetologia,1990;33(8):489-496.
[59]徐燕华,任艳.2型糖尿病患者血清HDL亚类组成的研究[J].中国糖尿病杂志,2001:9:160-162.
[60]Griffin BA,Freeman DJ,Tait GW,et al.Role of plasma triglyceride in the regulation of plasma low density lipoprotein(LDL) subfractions:relative contribution of small,dense LDL to coronary heart disease risk.Atherosclerosis,1994;106(2):241-253.
[61]McGarry JD.Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes[J].Diabetes,2001;50(suppl2):6.
[62]李秀钧,董砚虎,程丽霞等.糖尿病研究进展—第16届国际糖尿病联盟大会纪要[J].中华内分泌代谢杂志,1998:14(2):72-77.
[63]Charles MA,Eschwege E,Thibult N,et al.The role of non-esterified fatty acids in the deterioration of glucuse tolerence in Caucasian subjects:results of the paris prospective study[J].Diabetologia,1997;40:1101-1106.
[64]Paolisso G,Tataranni PA,Folry JE.A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM[J].Diabetologia,1995,38:1213-1217.
[65]McGarry JD,Dobbins RL.Fatty acids,lipotoxicity and insulin secretion[J].Diabetologia,1999;42:128-138.
[66]Boden G,Chen X,Iqbal N.Acute lowing of plasma fatty acids lower basal insulin secretion in diabetic and nondiabetic subjects[J].Diabetes,1998;47:1609-1612.
[67]Dobbins RL,Chester MW,Daniels MB.Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans[J].Diabetes,1998;47:1613-1618.
[68]Stein DT,Stevenson BE,Chester Mw,et al.The insulinotropic potency of fatty acids is influenced profoundly by their chain lengh and degree of saturation[J].J Clin invest,1997;100:398-403.
[69]Ana TMGS,Guenther B,Maria ERS,et al.Overnigt lowering of free fatty acid with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects[J].Diabetes,1999;48:1836-1841.
[70]Prelevic GM.Insulin resistance in polycystic ovary syndrome[J].Curr Opin Obstet Gynecol,1997;9:193-201.
[71]Guenther B.Role of fatty acids in the pathogenesis of insulin resistance and NIDDM[J].Diabetes,1997;46:3-10.
[72]Boden G.Fatty acids and insulin resistance[J].Diabetes Care,1996;19(4):394-39.
[73]Steinberg GR,Dyck DJ,Calles-Escandon J,et al.Chronic leptin administration decreases fatty acid uptake and fatty acid transporters in rat skeletal Muscle[J].J Biol Chem,2002;277:8854-8860.
[74]Francesco,Roberto,Mafalde.Obesity and body fat distribution induce endothelial dysfunction by oxidative stress[J].Diabetes,2001;50:159-165.
[75]Chang AY.Comparison of highly inbred diabetic and nondiabetic lines in the Upjohn colong of Chinese hamsters[J].Diabetes Res,1997;26(1):63.
[76]姬秋和,苏慧慈.中国地鼠糖尿病模型胰岛A、B细胞数量及分数改变[J].中华内分泌代谢杂志,1996:12(1):31-33.
[77]Rakieten N,Rakieten ML,Nadkarni MV.Studies on the diabetogenic action of streptozotocin(NSC-37917)[J].Cancer Chemother Rep,1963;29:92-98.
[78]徐叔云.药理实验方法学[M].北京:人民卫生出版社.2001,第三版:1258-1259.
[79]王开成,方朝晖,王佑民等.罗格列酮提高胰岛素抵抗大鼠大网膜脂肪细胞PPAR-γmRNA的表达水平[J].江西医药.2006:41(11):847-850.
[80]李秀钧.脂肪组织是又一个新的内分泌器官[J].国外医学内分泌学分册,2002:22(3):129-131.
[81]Kershaw EE,Fliter JS.Adipose tissue as an endocrine organ[J].J Clin Endocrinol Metab,2004;89(6):2548-2556.
[82]Barzilay JI,Abraham L,Heckhem SR,et al.The relation of markers of inflammation to the development of glucose disorders in the elderly:the cardiovascular health study[J].Diabetes,2001;50:2384-2389.
[83]Moiler DE.Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes[J].rrends Endocrinol Metab,2000;11(6):212-217.
[84]Tremblay F,Lavigne C,Jacques H,et al.Defective insulininduced GLUT4translocation in skeletal muscle of high fat-fed rats is associated with alterations in both AKT/protein kinase B and atypical protein kinase C activitiesI[J].Diabetes,2001;50(8):1901-1910.
[85]Hauner H.The mode of action of thiazolidinediones[J].Diabetes Metab Res Rev,2002;18(suppl 2):10-15.
[86]Leroy P,Dessolin S,Villageois P,et al.Expression of obgene in adipose cell.Regulation by insulin[J].Biol them,1996;271:2365-2368.
[87]Kolaczyski JW,Nyce MR,Considine RV,et al.Acute and insulin on leptin production in humans:Studies in vivo and chronic effects of in vitro[J].Diabetes,1996;45:699-701.
[88]Kiefer TJ,Heller RS,Leeeh CA,et al.Leptin suppression insulin secretion by the activation of ATP-sensitive K~+ channels in pancreatic cells.Diabetes,1997;46:1087-1093.
[89]Stejskal D,Jedelsky L,Bartek J,et al.Leptin,insulin and proinsulin-their relationship[J].Vnitr Lek,1998;44:361-365.
[90]Banks WA,Kastin AJ,Huang W,et al.Leptin enters the brain by a saturable system independent of insulin[J].Peptidesm,1996;17:305-311.
[91]陈刚,罗敏,丁伟等.瘦素受体基因变异与中国人肥胖的关系[J].中华内分泌代谢杂志,2001:17(5):298-300.
[92]Scarpace PJ,Matheny M,Tumer N.Hypothalamic leptin resistance is associated with impaired leptin signal transduction in aged obese rats[J].Neuroscience,2001;104(4):1111-1117.
[93]Shimizu H,Shimomura K,Negishi M,et al.Circulating concentrations of soluble leptin receptor:influence of menstrual cycle and diet therapy[J].Nutrition,2002;18(4):309-312.
[94]Bi S,Ladenheim EE,Schwartz GJ,et al.A role of NPY overexpression in the dorsomedial hypothalamus in hyperphagia and obesity of OLETF rats[J].Am J Physiol Regul Integur Comp Physiol,2001,281(1):8254-8260.
[95]Egawa M,Yoshimatsu H,Bray GA.Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue inrats[J].Am J physiol,1991;260(2Pt2):R328-334.
[96]Alice S,Ryan,Dariush Elahi,et al.The effects of acute hyperglycemia and hyperinsulinemia on plasma leptin levels:Its relationships with body fat,viscral adiposity,and age in women[J].J Clin Endocrinol Metab,1996;81:4433-438.
[97]Goodyear LU,Giorgino F,Sherman LA,et al.lnsulin receptor phosphorylation,insulin receptor subtrate-1 phosphorylation,and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects[J].J Clin Invest,1995,95(5):2195-2204.
[98]彭定琼,高妍.2型糖尿病病人脂肪组织胰岛素受体底物1和含2个SH2结构的蛋白酪氨酸磷酸酶的蛋白表达[J].民航医学,2002;12(1):1-4.
[99]Gual P,Gonzalez T,Gremeaux T,et al.Hyperosmotic stress inhibits IRS-1function by distinct mechanisms in 3T3-L1 adipocytes[J].J Biol Chem,2003;278(29):26550-26557.
[100]Aguirre V,Wemer ED,Giraud J,et al.Phosphorylation of Ser 307in insulin receptor substrate-1 blocks interactions with insulin receptor and inhibits insulin action[J].J Biol Chem,2002;277:1531-1537.
[101]Le Roith D,Zick Y.Recent advances in our understanding of insulin action and insulin resistance[J].Diabetes Care,2001;24:588-597.
[102]Egawa K,Nakashima N,Sharma PM,et al.Persistent activation of phosphatidylinositol3-kinase cause insulin resistance due to accelerated insulin induced insulin receptor substrate degradation in 3T3-L1adipocytes[J].Endocrinology,2000;141:1930-1935.
[103]Zhande R,Mitchell JJ,Wu J,et al.Molecular mechanism of insulin induced degradation of insulin receptor substrate-1[J].Mol Cell Biol,2002;4:1016-1026.
[104]张中成,刘志诚.2型糖尿病胰岛素受体后水平研究现状[J].医学综述,2002;8(3):166-167.
[105]Petersen KF,Shulman GI.Etiology of insulin resistance[J].Am J Med,2006;119(5 Suppl 1):S10-16.
[106]Karlsson M,Thorn H,Parpal S,et al.Insulin induces translocation of glucose transporter GLUT4 to plasma membrane caveolae in adipocytes [J.FASEB J,2002;16:249.
[107]Shewan AM,Marsh BJ,Melvin DR,et al.The cytosolic C-terminus of the glucose transporter GLUT4 contains an acidic cluster endosomal targeting motif distal to the dileucine signal[J].Biochem J.2000;350 Pt 1:99-107.
[108]Nelson B A,Robinson K A,Buse M G.High glucose and glucosamine induce insulin resistance via different mechanisms in 3T3-L1 adipocytes [J].Diabetes,2000;49:981-991.
[109]Zierath J R,Krook A,Wallberg-Henriksson H.Insulin action in skeletal muscle from patients with NIDDM[J].Mol Cell Biochem,1998;182:153-160.
[110]Maier V H,Gould G W.Long-term insulin treatment of 3T3-L1 adipocytes results in mis-targeting of GLUT4:implications for insulin-stimulated glucose transport[J].Diabetologia,2000;43:1273-1281.
[111]Yonemitsu S,Nishimura H,Shintani M,et al.Troglitazone induces GLUT4translocation in L6 myotubes[J].Diabetes,2001,50:1093-1101.
[112]Takahashi Y,Ide T.Dietary n-3 fatty acid affect mRNA level of brown adipose tissue uncoupling protein 1,and white adipose tissue leptin and glucose transporter 4 in the rat[J].Br J Nutrm,2000;84:175-184.
[113]Sevilla L,Guma A,Enrique-Tarnacon G,et al.Chronic high-fat feeding and middle-aging reduce in an additive fashion Glut4 expression in skeletal muscle and adipose tissue[J].Biochem Biophys Res Commun,1997;235:59-93.
[114]Quinn L.Mechanisms in the development of type 2 diabetes mellitus[J].J Cardiovasc Nurs,2002;16:1.
[115]Miles P D G,Barak Y,He W,et al.Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency[J].J Clin Invest,2000;105(3):287-92.
[116]Schinner S,Dellas C,Schroder M,et al.Repression of Glucagon Gene Transcription by Peroxisome Proliferator- activated Receptor gamma through Inhibition of Pax6 Transcriptional Activity[J].J Biol Chem,2002;277:1941.
[117]Hsueh W A,Law R.The central role of fat and effect of peroxisome proliferator-activated receptor-gamma on progression of insulin resistance and cardiovascular disease[J].Am J Cardiol,2002;92(4A):3J.
[118]徐世义,张国刚,张洪霞.桑白皮药材质量控制研究[J].中药材,2006:29(2):184-186.
[119]李宇亮,李剑敏,吴雅睿.1-脱氧野尻霉素提取分离方法研究[J].应用化工,2006:35(9):659-665.
[120]马静,刘树兴.桑枝中卜脱氧野尻霉素(DNJ)的研究进展[J].食品科技,2006:9:112-115.
[121]梁建宁,陈正收,吴璐等.高效液相色谱—蒸发光散射法测定桑白皮1-脱氧野尻霉素的含量[J].药物分析杂志,2006:26(7):905-907.
[122]中华人民共和国药典委员会.中华人民共和国药典[s]:一部[M].北京:人民卫生出版社,2005:203.
[123]田宏哲,王华,关亚风.液质联用分析葛根提取物及中药片剂中异黄酮类化合物[J].色谱,2005;23(5):477-481.
[124]Junei K Junko C Junko C.Isoflavonoids and related compounds in the roots and the voluble stems[J].Chem Pharm Bull,1987;35(12):4846-4850.
[125]许海琴,许列琴,许江苇.常用天然提取物质量标准参考手册[M].北京:化学工业出版社,2004,第一版:120-121.
[126]Rong H,Stevens JF,Deinzer,et al.Identification of isoflavones in the roots of Pueraria lobata[J].Plalnta Medica,1998,64(7):620-627.126
[127]冯瑞芝,陈碧珠,林文琰等.葛根的资源调查[J].中国药学杂志,1993:28(5):273-275.
[128]郑水庆,曾明.云南葛属药用植物资源调查[J].中草药,2002:33(8):755-756.
[129]李青坡,王永圣,游剑等.葛根总异黄酮提取工艺的研究[J].制剂技术,2004;13(5):46-47.
[130]周文斌.葛根总黄酮提取工艺条件的研究[J].渝州大学学报(自然科学版),2002;19(4):9-11.
[131]安伟建,郭瑞.不同产地葛根总黄酮含量的比较[J].中国中药杂志,1999;24(6):339-339.
[132]黄兆龙,郭俊明,张东璧.葛根有效成分的提取和测定[J].医药导报,2003;22(5):333-334.
[133]梁桂贤,李勤.葛根黄酮提取分离方法及制剂研究进展[J].山西中医学院学报,2001;2(4):47-49.
[134]向纪明,李金灿,柳林等.吸附法提取分离葛根素的研究[J].天然产物研究与开发,2003;15(3):242-244.
[135]米靖宇,宋纯清.大孔吸附树脂在中草药研究中的应用进展[J].中成药,2001;23(12):914-916.
[136]范碧亭.中药药剂学[M].上海:上海科学技术出版社,1998;第一版:138.
[137]余淑娴,郝晓霞,罗明.真空冷冻干燥技术及其应用[J].食品科技,2007;10:23-25.
[138]李艳萍.冻干技术研究进展[J].微生物学免疫学进展,1994;22(4):48-51.
[139]贺素艳,李云飞.冻干工艺中升华结束点和残余水分测量方法简述[J].真空与低温,2002;8(3):135-139.
[140]赵荣华.518个糖尿病处方统计分析[J].云南中医学院学报,1997;20(2):20-23.
[141]段亚丽,谢梅冬.黄芪化学成分及其有效成分黄芪甲苷含量测定的研究现状[J].中国兽药杂志,2005,39(3):35-38.
[142]卢彦琦,贺学礼.黄芪化学成分及药理作用综述[J].保定师范专科学校学报,2004:17(4):40-42.
[143]陈蔚,夏燕萍,俞茂.黄芪多糖预防自身免疫性胰岛炎的病理变化[J].中国现代医学杂志,2000:7(2):146-148.
[144]吴朝妍,张莹雯.黄芪多糖对肾阳虚型糖尿病大鼠肾组织NF-κB、TGF-β1的影响[J].武汉大学学报(医学版),2006;27(3):381-384,388.
[145]叶红英,俞茂华,游利等.黄芪多糖对STZ糖尿病大鼠物质代谢和心功能的影响[J].上海医科大学学报,2000;27(5):357-358.
[146]杨红霞,朱敏怡.黄芪对糖尿病大鼠肾组织的保护作用[J].实用医学杂志,2005:21(17):1964-1965.
[147]马洪喜,李冬梅.黄芪皂苷对糖尿病大鼠血清清激素水平的影响[J].微量元素与健康研究,2003:20(4):5-6.
[148]马宏秀,张治祥等.黄芪药理研究进展[J].陕西中医学院学报,2004:27(5):147-149.
[149]谭周静,谢达平.多糖的研究进展[J].食品科技,2002:3:10-12.
[150]吴丽,刘婷婷,梁剑锋.黄芪多糖的分离和纯化[J].食品与药品,2007:9(04):62-64.
[151]闫巧娟,韩鲁佳,江正强.酶法脱除黄芪多糖中的蛋白质[J].食品科技,2004:(6):23-26.
[152]苗明三,李振国.现代实用中药质量控制技术[M].北京:人民卫生出版社,2003,第一版:890-899.
[153]赵复中,庄碧年,钱雯.生药膜荚黄芪中黄芪总皂苷含量测定[J].南京医科大学学报,1994:14(2):215-217.
[154]Kitagawa I,Wang H K,Takagi A,et al.Saponin and sapogenol ⅩⅩⅩ Ⅳ.Chemical constituents of Astragalus radix,the 9,19-cyclolanostane-type aglycone of astragalosides,and the artifact aglycone astragenol[J].Chem Pharm Buil,1983;31(2):689.
[155]曹正中,俞家华.膜荚黄芪化学成分研究[J].中草药,1985:16:278.
[156]HirotaniM.Zhou Y,Lui H K.Astragalosides from hairy root culture of Astragalus membraneceus[J].Phytochem,1994;36(3):665-670.
[157]HirotaniM,Zhou Y,Lui H K.Cycloanane triterpeneglycosides from the hairy root cultures of Astragalusm embranaceus[J].Phytochem,1994;37(5):1403-1407.
[158]He Z Q,Findlay J A.Constituents of Astragalus m em branaceus[J].J N atur Prod,1991;54(3):810-815.
[159]王惠康,何侃,叶嘉麟.内蒙黄芪化学成分的研究[J].中草药,1987:18(1):5-7.
[160]Zhu Y Z,Lu S H,Okada Y T,et al.Two new cycloartanetype glycosides,mongholicoside Ⅰ and Ⅱ from the aerial part of Astragalus mongholicus Bunge[J].Chem Pharm Bull,1992;40(8):2230-2232.
[161]胡海云,王伟华,段启.HPLC-ELSD法测定不同产地黄芪中黄芪甲苷[J].中草药,2006:37(12):1886-1888.
[162]国家药典委员会编.中华人民共和国药典[s]:一部[M].北京:化学工业出版社,2005:212.
[163]王举涛,徐文方,刘金旗等.HPLC-ELSD法测定黄芪中黄芪甲苷的含量[J].安徽医药,2006:10(1):28-29.
[164]原田正敏.日本常用生药的定量方法—黄芪[J].国外医药:植物药分册,1990:5(5):201-202.
[165]李伟东,贾晓斌,蔡宝昌.黄芪总皂苷提取工艺研究[J].成都中医药大学学报,2004:27(2):43-45.
[166]贾晓斌,陈彦,蔡宝昌等.黄芪皂苷纯化工艺研究[J].中成药,2003:25(11):866-868.
[167]蔡雄,刘中秋,王培训等.大孔吸附树脂富集纯化人参总皂苷工艺[J].中成药,2001:23(9):631-634.
[168]唐第光.大孔吸附树脂法提取三七总皂苷工艺探讨[J].中成药,1990:12(8):5-6.
[169]芦金清,刘尚桃,刘再刚等.大孔吸附树脂法提取绞股蓝总皂苷[J].中成药,1992:14(4):2-3.
[170]鱼红闪.树脂法提取甘草中甘草苷的研究[J].食品与发酵工业,1999:25(1):40-43.
[171]胡军,周跃华.大孔吸附树脂在中药成分精制纯化中的应用[J].中成药,2002:24(2):127-130.