参芪复方调控糖尿病血管PI3-K/Akt通路的实验研究
|
摘要
目的：通过观察具有养阴益气活血功效的参芪复方对糖尿病大血管病变的防治作用,从整体水平、细胞水平、分子水平评价参芪复方对糖尿病大血管GK大鼠的作用效果,由细胞信号转导的角度阐释参芪复方防治糖尿病并发大血管病变对于主动脉PI3-K／Akt通路的影响,为中医药防治糖尿病大血管病变的治疗机制、机体的反应机制做出相应研究。
方法：73只GK大鼠随机分为4组：GK组18只、模型组19只、西药阿托伐他汀组18只、中药参芪复方组18只,Wistar大鼠18只作为正常Wistar对照组。模型、西药、中药组给予eNOS抑制剂L-NAME 0.1mg·ml-1·d-1,加入饮用水中进行糖尿病大血管病变造模,造模时间为35天。造模同时开始给药,Wistar组喂饲普通饲料,其余各组喂饲高脂饲料。正常Wistar对照组按5ml·kg-1·d-1灌服生理盐水,GK组按5ml·kg-1·d-1灌服生理盐水,模型组按5ml·kg-1·d-1灌服生理盐水,西药阿托伐他汀组按1.6mg·kg-1·d-1灌服阿托伐他汀钙悬液,中药参芪复方组按1.44g·kg-1·d-1灌服参芪复方混悬液。35天后处死大鼠,检测各组血糖、血脂、血清CRP、INS水平,并利用实时荧光定量PCR技术检测各组大鼠腹主动脉PI3-KP85a、Akt、eNOS等mRNA表达量变化情况。
结果：通过光镜观察主动脉形态,模型组大鼠呈现典型动脉粥样硬化病理改变,血胆固醇、甘油三酯、CRP水平明显增高(P<0.05或P<0.01),HOMA-IRI明显高于其它各组(P<0.01)；参芪复方中药治疗可以促进糖尿病大血管病变GK大鼠体重增长,降低血糖水平,降低血清胆固醇及甘油三酯水平,降低血清胰岛素水平,改善胰岛素抵抗状态,降低血清CRP,减轻炎症反应,抑制主动脉PI3-KP85a、Akt、eNOS等mRNA表达；参芪复方治疗的中药组降低HOMA-IRI水平与阿托伐他汀治疗的西药组有明显差异性(P<0.05)。
结论：参芪复方可以恢复并改善其生长发育,改善糖、脂代谢,减轻模型大鼠炎症状态,并可减轻胰岛素抵抗,全面调节达到延缓糖尿病动脉粥样硬化的发生与发展的目的。抑制血管壁PI3-K-Akt-eNOS表达,从而阻止病理性新生血管形成延缓动脉粥样斑块形成和发展,可能是参芪复方保护糖尿病动脉粥样硬化发生发展的分子生物学机制之一。
Objective:To observe the influence of PI3-K/Akt signal transduction with ShenQi compound recipe(SQCR) in the diabetes mellitus macroangiopathy GK rat abdominal aorta vessel wall. And to evalute the contribution of SQCR with the function of tonifying Qi and Yin and promoting blood circulation to dissipate stasis to the signal transduction passway. Research the therapeutic mechanism of prevention and cure to the diabetes mellitus macroangiopathy and the reaction mechanism of the organism with Traditional Chinese Medicine (TCM).
Methods:Divided 73 GK male rats into four groups randomly: respectively 18 in GK group, drenched normal saline 5ml·kg-1·d-1,19 in model group, drenched normal saline 5ml·kg-1·d-1,18 in atorvastatin groups, drenched atorvastatin calcium suspension 1.6mg·kg-1·d-1,18 in SQCR group, drenched SQCR suspl 1.44g·kg-1·d-1.18 SPF Wistar rat act as the control group, drenched normal saline 5ml·kg-1·d-1. In order to build the diabetes mellitus macroangiopathy model, admin the Nω-nitro-L-arginine methyl ester(L-NAME) 0.1mg·ml-1·d-1 in the drinking water for the model, atorvatatin, SQCR groups with the administration simultaneously. Treated for 35 days, detect the blood glucose, blood fat, blood secum C reactive protein (CRP) and insulin, and the PI3-KP85a、Akt、eNOS mRNA expression in the abdominal aorta vessel wall by real-time PCR.
Result:The typical atheromatosis pathoalteration is observed in model group by light microscope in arteriae aorta appearance. Compared with other groups, the blood glucose, fat, CRP and INS raise up in model groups (P<0.05 or P<0.01), and the HOMA-IRI highten too (P<0.01). Increased body weight, degraded the blood glucose, fat, CRP and INS, the GK rats gained improved glycometabolism and fat metabolism, and relieved Inflammatory reaction with insulin resistance. At the same time, the SQCR can also restrain the PI3-KP85a, Akt and eNOS mRNA expression in abdominal aorta vessel wall.
Conclusion:SQCR could delay the development of the diabetes mellitus AS by improving the growth and development, gaining weight, depressing blood glucose and blood fat, degrading blood CRP, relieving IRI. One of the possible curing mechanisms in molecular biology is inhibiting the neovascularization for atheromatous plaque by restrain the expressing of PI3-K-Akt-eNOS mRNA in vessel wall.
方法：73只GK大鼠随机分为4组：GK组18只、模型组19只、西药阿托伐他汀组18只、中药参芪复方组18只,Wistar大鼠18只作为正常Wistar对照组。模型、西药、中药组给予eNOS抑制剂L-NAME 0.1mg·ml-1·d-1,加入饮用水中进行糖尿病大血管病变造模,造模时间为35天。造模同时开始给药,Wistar组喂饲普通饲料,其余各组喂饲高脂饲料。正常Wistar对照组按5ml·kg-1·d-1灌服生理盐水,GK组按5ml·kg-1·d-1灌服生理盐水,模型组按5ml·kg-1·d-1灌服生理盐水,西药阿托伐他汀组按1.6mg·kg-1·d-1灌服阿托伐他汀钙悬液,中药参芪复方组按1.44g·kg-1·d-1灌服参芪复方混悬液。35天后处死大鼠,检测各组血糖、血脂、血清CRP、INS水平,并利用实时荧光定量PCR技术检测各组大鼠腹主动脉PI3-KP85a、Akt、eNOS等mRNA表达量变化情况。
结果：通过光镜观察主动脉形态,模型组大鼠呈现典型动脉粥样硬化病理改变,血胆固醇、甘油三酯、CRP水平明显增高(P<0.05或P<0.01),HOMA-IRI明显高于其它各组(P<0.01)；参芪复方中药治疗可以促进糖尿病大血管病变GK大鼠体重增长,降低血糖水平,降低血清胆固醇及甘油三酯水平,降低血清胰岛素水平,改善胰岛素抵抗状态,降低血清CRP,减轻炎症反应,抑制主动脉PI3-KP85a、Akt、eNOS等mRNA表达；参芪复方治疗的中药组降低HOMA-IRI水平与阿托伐他汀治疗的西药组有明显差异性(P<0.05)。
结论：参芪复方可以恢复并改善其生长发育,改善糖、脂代谢,减轻模型大鼠炎症状态,并可减轻胰岛素抵抗,全面调节达到延缓糖尿病动脉粥样硬化的发生与发展的目的。抑制血管壁PI3-K-Akt-eNOS表达,从而阻止病理性新生血管形成延缓动脉粥样斑块形成和发展,可能是参芪复方保护糖尿病动脉粥样硬化发生发展的分子生物学机制之一。
Objective:To observe the influence of PI3-K/Akt signal transduction with ShenQi compound recipe(SQCR) in the diabetes mellitus macroangiopathy GK rat abdominal aorta vessel wall. And to evalute the contribution of SQCR with the function of tonifying Qi and Yin and promoting blood circulation to dissipate stasis to the signal transduction passway. Research the therapeutic mechanism of prevention and cure to the diabetes mellitus macroangiopathy and the reaction mechanism of the organism with Traditional Chinese Medicine (TCM).
Methods:Divided 73 GK male rats into four groups randomly: respectively 18 in GK group, drenched normal saline 5ml·kg-1·d-1,19 in model group, drenched normal saline 5ml·kg-1·d-1,18 in atorvastatin groups, drenched atorvastatin calcium suspension 1.6mg·kg-1·d-1,18 in SQCR group, drenched SQCR suspl 1.44g·kg-1·d-1.18 SPF Wistar rat act as the control group, drenched normal saline 5ml·kg-1·d-1. In order to build the diabetes mellitus macroangiopathy model, admin the Nω-nitro-L-arginine methyl ester(L-NAME) 0.1mg·ml-1·d-1 in the drinking water for the model, atorvatatin, SQCR groups with the administration simultaneously. Treated for 35 days, detect the blood glucose, blood fat, blood secum C reactive protein (CRP) and insulin, and the PI3-KP85a、Akt、eNOS mRNA expression in the abdominal aorta vessel wall by real-time PCR.
Result:The typical atheromatosis pathoalteration is observed in model group by light microscope in arteriae aorta appearance. Compared with other groups, the blood glucose, fat, CRP and INS raise up in model groups (P<0.05 or P<0.01), and the HOMA-IRI highten too (P<0.01). Increased body weight, degraded the blood glucose, fat, CRP and INS, the GK rats gained improved glycometabolism and fat metabolism, and relieved Inflammatory reaction with insulin resistance. At the same time, the SQCR can also restrain the PI3-KP85a, Akt and eNOS mRNA expression in abdominal aorta vessel wall.
Conclusion:SQCR could delay the development of the diabetes mellitus AS by improving the growth and development, gaining weight, depressing blood glucose and blood fat, degrading blood CRP, relieving IRI. One of the possible curing mechanisms in molecular biology is inhibiting the neovascularization for atheromatous plaque by restrain the expressing of PI3-K-Akt-eNOS mRNA in vessel wall.
引文
[1]卫生部疾病控制司,中华医学会糖尿病学分会.《中国糖尿病防治指南》试行本节选[J].中国慢性病预防与控制,2004,12(6)：283—285.
[2.]赵家伟,李秀钧.炎症、糖尿病、大血管病变之间的临床联系与新认识[J].辽宁实用糖尿病杂志,2003,11(3)：49-51
[3]刘云海,刘月平,赵国良等.sVCAM-1与2型糖尿病血管并发症关系的临床探讨[J],实用老年医学.2004,18(3)：142-144.
[4]陶冶,刘小菁,强鸥.高糖环境对体外培养糖尿病大鼠大血管内皮细胞产生转化生长因子-的影响[J].华西医大学报,2001,32(1)：63～65.
[5]DeMartin R, Hoeth M, Hofer-WarbinekR, et al. The transcription factor NF-kappaBand the regulation of vascular cell function [J]. Arterioscler Thromb Vasc Bio,2000,20(11):E8
[6]王小瑞,张苏河.2型糖尿病并大血管并发症患者白细胞中核因子-κB检测[J],郑州大学学报(医学版),2007,42(1)：113-116
[7]Kobayashi T, Mats mol/Loto T, Kamata K. The P I3-K/Akt pathway:roles related to alterations in vasomotor responses in diabetic models. J Smooth Muscle Res, 2005,41:283-302.
[8]Freedman SB, Isner JM, Therapeutic angiogenesis for coronary artery disease. Ann Intern Med,2002,136:54-71.
[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.中华内科杂志,1981,20：678.
[10]王克安,李天霖,李新华,等.中国儿童1型糖尿病发病率的研究.中华内分泌代谢杂志,1999,15：327.
[11]Maahs, D.M., et al., Hypertension prevalence, awareness, treatment, and control in an adult type 1 diabetes population and a comparable general population. Diabetes Care,2005.28(2):301-306.
[12]向红丁,吴纬,刘灿群,等.1996年全国糖尿病流行病学特点基线调查报告.中国糖尿病杂志,1998,3：131.
[13]卫生部疾病控制司,中华医学会糖尿病分会.中国糖尿病防治指南.北京：北京 大学出版社,2004：3-4.
[14]中华医学会糖尿病分会糖尿病慢性并发症调查组.全国住院糖尿病患者慢性并发症及其相关危险因素10年回顾性调查分析[J].中国糖尿病杂志,2003,11(4)：232-238.
[15]唐光敏,余叶蓉,王艳丽.华西医院1996-2004年住院成人糖尿病患者病死率及死因分析[J],中国糖尿病杂志,2008,16(10)：897-898.
[16]徐静,易兰兰,徐琳,等.住院糖尿病患者死因分析[J].陕西医学杂志,2005,34：807-809.
[17]蒲琳,王汝莲,吴桐,等.5年住院糖尿病病人死亡原因分析[J].四川医学,2002,23：898-899.
[18]杨华章,赵媛媛,邝建,等.老年糖尿病住院患者病死率及死因分析[J].中华老年医学杂志,2001,20：194-196
[19]Sinisalo J, Paronen J, Mattila J, et al. Relation of inflammation to vascular function in patients with coronary heart disease [J]. Atherosclerosis,2000, 149:403-411.
[20]CDC's Diabetes Program-Data& Trends-Causes of Hospitalizations-Distribution of First-Listed Diagnoses Among Hospital Discharges with Diabetes as Any Listed Diagnosis, Adults Age 18 and Older[DB/OL]. Unite,2003.
[21]陈雪峰,余叶荣.华西医院1996-2005年糖尿病住院患者入院原因分析[J],中国循证医学杂志,2008,8(7)：525-528
[22]卫生部疾病控制司,中华医学会糖尿病学分会.《中国糖尿病防治指南》试行本节选[J].中国慢性病预防与控制,2004,12(6)：283-285.
[23]田代华整理.黄帝内经素问[M].人民卫生出版社,北京：2005,15.
[24]明·张介宾著,李继明,王大淳,等整理.景岳全书[M].人民卫生出版社,北京,2007,423.
[25]吕仁和,糖尿病及其并发症中西医诊治学[M].人民卫生出版社,北京：1997,2-5.
[26]田代华整理.黄帝内经素问[M].人民卫生出版社,北京：2005,92.
[27]田代华,刘更生整理.灵枢经[M].人民卫生出版社,北京：2005,97.
[28]田代华,刘更生整理.灵枢经[M].人民卫生出版社,北京：2005,59.
[29]清·魏之琇编著.续名医类案[M],人民卫生出版社影印,北京：1982,206.
[30]宋·赵佶编.圣济总录[M].人民卫生出版社,北京：1982,1064-1099.
[31]田代华,刘更生整理.灵枢经[M].人民卫生出版社,北京：2005,94
[32]清·喻昌著,徐复霖点校.医门法律[M].上海科学技术出版社,上海：1983,213.
[33]宋·赵佶编.圣济总录[M].人民卫生出版社,北京：1982,1064-1099.
[34]高泓,谢春光,赵旭.糖尿病大血管病变的中医病机分析[J],时珍国医国药,2009,9待发
[35]中国中西医结合学会糖尿病专业委员会.中西医结合糖尿病诊疗标准(草案)[J].中国中西医结合杂志,2005,25(1)：94-95.
[36]李振中,尹翠梅,丁学屏,等.再论痰浊与糖尿病血管病变[J].光明中医,2004,2：10.
[37]董振华,季元.祝堪予治疗糖尿病慢性并发症的经验[J].中医杂志1997,(1)：12.
[38]季长春,程汉桥,董志,等.浅析糖尿病血管病变[J].中医药信息,2007,24(6)：40-42
[39]林兰主编.现代中医糖尿病学[M].北京：人民卫生出版社,2008.737-739
[40]张延群,韩清,和贵章,等.2080例糖尿病患者证候与血栓关系分析[J].中医杂志,1996,37(10)：617—619
[41]朗江明,魏爱生,方湃,等.广东省佛山城区成年人糖尿病流行病学调查[J].中国糖尿病杂志,1999,7(3)：175
[42]王(?)生,赵文累,夏军,等.益气养阴活血方对气阴两虚血瘀型搪尿病患者血浆内皮素与一氧化氮水平的影响[J].中国中西医结合杂志,2000,20(8)：571
[43]王姮,杨永年.糖尿病现代治疗学[M],北京科学出版社,2006：345-353.
[44]Maahs, D.M., et al., Hypertension prevalence, awareness, treatment, and control in an adult type 1 diabetes population and a comparable general population. Diabetes Care,2005.28(2):301-306.
[45]Colivicchi, F., et al., Differences between diabetic and non-diabetic hypertensive patients with first acute non-ST elevation myocardial infarction and predictors of in-hospital complications. J Cardiovasc Med(Hagerstown),2008.9(3):267-272.
[46]Longo-Mbenza, B, et al., [Risk factors of stroke among Congolese black hypertensive diabetics]. Ann Cardiol Angeiol (Paris),2008.57(1):37-43.
[47]Lonati, C., et al., Prevalence of type 2 diabetes among patients with hypertension under the care of 30 Italian clinics of hypertension:results of the (Iper) tensione and (dia)bete study. J Hypertens,2008,26(9):1801-1808.
[48]Cook CB, Erdman DM, Ryan GJ, et al. The pattern of dyslipidemia urban African-Americans with type2 diabetes [J]. Diabetes Care,2000,23:319-324
[49]Tai ES, Lin SC, Chew SK, et al. Homeostasis model assessment in a population with mixed ethnicity:the 1992 Singapore National Health Survey [J]. Diabetes Res Clin Prac,2000,49:159-168
[50]Reaven, G.M., Insulin resistance, the insulin resistance syndrome, and cardiovascular disease. Panminerva Med,2005.47(4):201-210
[51]平田恭信.NO与动脉粥样硬化[J].日本医学介绍,2005,26(7)324-325.
[52]王秀红,路方红.内皮素、一氧化氮与心血管疾病[J]中国慢性病预防与控制,2005,13(3)：139-141
[53]刘景生主编.细胞信息与调控[M].北京:中国协和医科大学出版社,2003,355-370.
[54]谢毅强,指导：谢春光.参芪复方对GK大鼠2型糖尿病大血管病变血管内皮细胞保护的实验研究.中国博士学位论文全文数据库,http://e34.cnki.net/kns50
[55]周智广,陈小燕.对血糖控制防治糖尿病大血管病变作用的评价[J].中国循证医学杂志,2004,4(7)：439-443
[56]周智广,庞翠军.糖尿病大血管病变的发病基础与防治策略[J].中国医师杂志,2006,8(1)：1-2.
[57]Dandona P, Aljada A, Chaudhuri A, Bandyopadhyay A.The potential influence of inflammation and insulin resistance on the pathogenesis and treatment of atherosclerosis related complications in type 2 diabetes [J]. J Clin Endocrinol Metab,2003; 88 (6):2422-2429
[58]GOde P, Vedel P, Larsen N, Jensen GV H, Parving HH,Pederson 01 Multif actorial intervention and cardiovascular disease in patients with type 2 diabetes [J]1 N Engl J Med,2003; 348 (5):383-393
[59]李振中,尹翠梅,丁学屏等.再论痰浊与糖尿病血管病变[J].光明中医,2004,2：10.
[60]席守民,廉馨,王宗保,等.高脂高蔗糖饲料诱导贵州小香猪发生糖尿病和动脉粥样硬化病变[J].中国动脉硬化杂志,2004,12(1)：5-10.
[61]Edwards IJ, Wagner JD, Vogl-Willis CA, et. Arterial heparan sulfate is negatively associated wi th h-qDerglycemia an d atheresclemsis in diabetic monkeysl J1. Cardiovasc Diabetol,2004,29(4):3-6.
[62]Brown, D.J., et al., Endothelial cell activation of the smooth muscle cell phosphoinositide 3-kinase/Akt pathway promotes differentiation. J Vasc Surg, 2005.41(3):509-516.
[63]席守民,廉馨,王宗保,等.高脂高蔗糖饲料诱导贵州小香猪发生糖尿病和动脉粥样硬化病变[J].中国动脉硬化杂志,2004,12(1)：5-10.
[64]He Xue-ling, Yin Hai-lin. Investigative current situation and existing problem of Artherosclerosis animal model. [J] Lalwratory Animal Science and Management, 2006,23(4):41-44(In Chinese)
[65]Vikramadithyan RK, Hu Y, Noh IlL, et. Human aldose reductase expression accelerates diabetic atherosclerosis in transgenic mice[J]. J Clin Invest,2005, 115(9):2434-2443.
[66]王宁,谢自敬,阿布力克木·吐尔地,等.糖尿病大鼠动脉粥样硬化与游离脂肪酸表达的关系[J].中国动脉硬化杂志,2005,13(5)：563—566.
[67]Renard CB, Kralner F, Johansson F,et al. Diabetes and diabetes associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions[J].J Clin invest,2004,114(5):659-668.
[68]张王月,王雁南,刘明.糖尿病动脉硬化动物模型的建立及评价[J].医学综述,2007,13(10)：758-760
[69]徐梓辉,周世文,钱桂生,等.2型糖尿病合并动脉粥样硬化大鼠模型的建立[J].中国病理生理杂志,2006,22(1)：205—208
[70]Cheng ZJ, Vaskonen T, Tikkanenl,et al. Endothelial dysfunction and salt-sensitive hypertension in spontaneously diabetic Goto-Kakizaki rats[J]. Hypertension, 2001,37(2 Part 2):433-439.
[71]Ling ZC,Hong LC,Ostenson CG.et al.Hyperglycemia contributes to impaired insulin response in GK rat islets[J].Diabetes,2001,5 Suppl 1:S108-S112.
[72]Hughes SJ, Suzuki K, Goto Y. The role of islet secretory function in the development of diabetes in the GK Wistar rat[J]. Diabetologia,1994,37 (9):863-870.
[73]王宝金,代解杰.糖尿病动物模型的研究进展[[J].上海实验动物科学,2003,23(2)：116.
[74]Hidehiko Ono, Yuko Ono, Atsuko Takanohashi, et al. Vascular Endothelial Growth Factor Is Necessary in the Development of Arteriosclerosis by Recruiting/Activating Monocytes in a Rat Model of Long-Term Inhibition of Nitric Oxide Synthesis[J].Circulation,2002,105:1110-1115
[75]Makoto Katoh, Kensuke Egashira, Chu Kataoka, et al. Regression by ACE inhibition of arteriosclerotic changes induced by chronic blockade of NO synthesis in rats[J]. Am J Physiol Heart Circ Physiol,2004; 286 (2):H768-H774.
[76]张树生,马长武主编.神农本草经贯通[M].北京：中国医药科技出版社,1996
[77]王芬,何华亮,张红敏,等.参芪复方对GK大鼠脂代谢异常的实验研究[J].天津中医药,2007,24(6)：507-508
[78]谢毅强,李军茹,张红敏等.参芪复方治疗2型糖尿病胰岛素抵抗的临床研究[J].中华实用中西医杂志,2005,18(17)：844-846
[79]张红敏,陈世伟,谢春光等.参芪复方对GK大鼠白色脂肪组织脂联素基因表达的影响[J].中成药,2006,28(7)：996-1001
[80]张红敏,陈世伟,谢春光等.参芪复方抗自发性糖尿病GK大鼠早期动脉粥样硬化的作用机制[J].中国中药杂志,2006,31(15)：1272-1276
[81]沈应君主编.中药药理学[M].人民卫生出版社,2000：96-97.
[82]Van-de-Ree, Huisman MV. Strong decrease of high sensitively O-reactive pritein with high-dose atorvastatin in patients with type 2 diabetes mellitus[J]. Atherosculerosis,2003,166(1):129-135
[83]Topol EJ. Intensive Statin Therapy-A sea change in cardiovascular prevention. N Engl J Med,2004,350:1562-1564
[84]Auer J, Berent R, Weber T, et al. Clinical significance of pleiotropic effects of statins:lipid reduction and beyond[J].Curt Med Chem,2002,9(20):1831-1850
[85]Lars.Circulating markers of inflammation and atherosclerosis [J].Atherosculerosis, 2003169(4):203-214.
[86]Vozarova B,Weyer C,Lindsay RS,et al.High white blood cell count is associated with a worsening of insulin sensitivity and predicts the development of type 2 diabete [J]. Circulation,2002,51(2):455-461.
[87]Greenberg AS. The expanding scope of the metabolic syndrome and implications for the management of cardiovascular risk in type 2 diaberes with particular focus on the emerging rote of the thiazolidinediones [J].J Diabetes Complications,2003, 17(4):218-228.
[88]Dandona P, Aljada A,Mohanty Pet al.Insulin inhibits intranuclear nuclear factor kappaB and stimulates Ⅰ kappaB in mononuclear cells in obese subjects:evidence for an anti-inflammatory effect[J]J Clin Endocrinol Metab,2001,86(7):3257-3265.
[89]赵水平主编.他汀类药物治疗学[M],长沙：中南大学出版社,2005.451
[90]Johnston TP, Baker JC, Hall D, et al. Regression of poloxamer 407-induced atherosclerotic lesions in C57BL/6 mice using atorvastain. Atherosclerosis,2000, 149(2):303-313
[91]Nissen SE, Tuzcu EM, Schoenhagen P, et al, Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis:a randomized controlled trial. JAMA,2004,291 (9):1071-1080
[92]Maron DJ, Fazion S, Linton MF.Current perspectives on statins. Circulation,2000, 101:207-213
[93]赵水平主编.他汀类药物治疗学[M],长沙：中南大学出版社,2005.451
[94]王宏宇主编.血管病学[M],北京：人民军医出版社,2006,191.
[95]Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med,2004, 350:1495-1504
[96]黄继汉,黄晓晖,陈志扬,等.药理试验中动物间和动物与人体间的等效剂量换算[J].中国临床药理学与治疗学,2004,9(9)：1069-1072
[97]张红敏,指导：谢春光.参芪复方对GK大鼠低度炎症和大血管病变的影响及机理研究.中国博士学位论文全文数据库,http://e34.cnki.net/kns50
[98]李稻主编.医学功能学科—实验原理与方法[M].人民卫生出版社,北京：2008,33-35.
[99]邓欣,郭玲玲.糖尿病大血管病变与胰岛素抵抗[J].中西医结合心脑血管病杂志,2005,3(8)：725-727.
[100]HaidariM, Javadi E, Sadegh iB, et al. Evaluation of C-reactive protein, a sensitive marker of inflammation, as a risk facto r for stable coronary artery disease. Clin Biochem,2001,33:309-315.
[101]Freeman DJ, Nomie J, Caslake MJ, etal. C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes,2002,51(5):1596-1600
[102]Pradhan AD,Manson JE,Rifai N,etal.C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus.JAMA,2001,286:327-334
[103]Barzilay JI, Abraham L, Heckbert SR, etal.The relation of markers of inflammation to the development of glucose disorders in the elderly:the Cardiovascular Health Study.Diabetes,2001,50:2384-2389
[104]吴伟华,张中超,刘国良.C-反应蛋白与2型糖尿病大血管病变的相关性研究[J].中国糖尿病杂志,2003,11(4)：247-249.
[105]张晓梅,黄咏齐,陈风玲等.糖尿病血清C反应蛋白与大血管并发症关系的探讨[M].中国现代应用药学,2003,20(5)：424-426.
[106]Mako to F, Hideki K, Kouichi I, etal.Structure and function of phosphatidylinositol-3,4kinase.Cell Signal,2000,12(3):135-142
[107]董砚虎,南海荣,王军,等.磷脂酰肌醇32激酶P85 α亚单位基因Met326Ile变异与2型糖尿病的相关关系[J].中国糖尿病杂志,2006,(14)6：417-419.
[108]Jones P F, Jakubowicz T, Pitossi F J, et al. Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily. Proc Natl Acad Sci USA,1991,88:4171～4175
[109]Coffer P J, Woodgett J R.Molecular cloning and characterization of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families.Eur J Biochem,1991,201:475～481
[110]Matsuura, E., et al., Oxidized LDL/beta2-glycoprotein I complexes:new aspects in atherosclerosis. Lupus,2005.14(9):736-741.
[111]Maier, U., Babich, A. and Nurnberg, B.(1999).Roles of non-catalytic subunits in Gbetagamma-induced activation of class I phosphoinositide 3-kinase isoforms beta and gamma. J. Biol. Chem.274:29311-29317.
[112]Anai, M., Funaki, M., Ogihara, T, Terasaki, J., Inukai, K., Katagiri, H., Fukushima, Y, Yazaki, Y., Kikuchi, M., Oka, Y. and Asano, T.(1998).Altered expression levels and impaired steps in the pathway to phosphatidylinositol 3-kinase activation via insulin receptor substrates 1 and 2 in Zucker fatty rats. Diabetes 47:13-23.
[113]Mauvais-Jarvis, F., Ueki, K., Fruman, D.A., Hirshman, M.F., Sakamoto, K., Goodyear, L.J, Iannacone, M., Accili, D, Cantley, L.C. and Kahn, C.R. (2002).Reduced expression of the murine p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. J. Clin. Invest. 109:141-149.
[114]Yki-Jarvinen,et al.Best Pract Res ClinEndocrinol Metab,2003,17:411-430
[115]Fulton D,Gratton JP.,McCabe TJ,et al.Regulation of en-dotuelium-derived nitric oxide production by the protein kinase AKT[J].Nature,1999,399:597-601
[116]Celermajer,ET AL.A Am Coll Cardiol,1997,30:325-333
[117]Khan BV,Harrison DG,Olbrych MT,er al.Nitric oxide regulates vascular cell adhension molecrlar 1 gne expression and redox-sensi-tive transcriptional events in human vascular endothelial cells[J].Proc Natl Acad Sci USA,1996,93:9 114-119
[118]Ritchie,er al.Clin Sience,2004,107:519-532
[119]王军,姜宏卫,磷脂酰肌醇3激酶与2型糖尿病.国外医学.内分泌学分册,2001(06).
[120]Sun Y, Tian H, Xiao FM, PI3K p85alpha expression and its role in the progression of colorectal cancer [J], Nan Fang Yi Ke Da Xue Xue Bao,2009, 29(3):416-417.
[121]迟素敏.内分泌生理学[M].西安：第四军医大学出版社,2006.11-13.
[122]金丹,陆付耳.P13K在2型糖尿病发病机制中的作用[J].医学综述,2007(13)1：21-23
[123]Bjnholm M, Kawano Y, Lehtihet M, etal.Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activety in skeletal muscle from NIDDM subject s after in vivo insulin stimulation1 Diabetes,1997, 46:524-527.
[124]Ishizuka T, Miura A, Kajita K, et al. Alterations in insulin induced post receptor signaling in adipocytes of t he Ot suka Long-Evans Tokushima fatty rat strain1 J Endocrinol,1998,156:1-13.
[125]Miura A,Ishizuka T,Kanoh Y. Effect of tumor necrosis factor-alpha on insulin signal transduction in rat adipocytes:relation to PKC beta and zeta translocation [J].Biochem Biophys Acta,1999,1449:227-238.
[126]杨永宗.动脉粥样硬化性心血管病基础与临床[M].北京：科学出版社,2004,619-620
[127]Fulvio Morello, Alessia Perino, Emilio Hirsch. Phosphoinositide 3-kinase signaling in the vascular system [J].Cardiovascular Research,2008,18,1-11
[128]Young LH, Ikeda Y, Scalia R, Lefer AM. Wortmannin, a potent antineutrophil agent, exerts cardioprotective effects in myocardial ischemia/reperfusion. J Pharmacol Exp Ther 2000;295:37-43
[129]Mourani PM, Garl PJ, Wenzlau JM, Carpenter TC, Stenmark KR, Weiser-Evans MCM. Unique, highly proliferative growth phenotype expressed by embryonic and neointimal smooth muscle cells is driven by constitutive Akt, mTOR, and p70S6K signaling and is actively repressed by PTEN. Circulation 2004;109:1299-1306.
[130]Sousa JE, Costa MA, Abizaid A, Abizaid AS, Feres F, Pinto IMF et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries:A Quantitative Coronary Angiography and Three-Dimensional Intravascular Ultrasound Study. Circulation 2001; 103:192-195.
[131]Poon M, Badimon JJ, Fuster V. Overcoming restenosis with sirolimus:from alphabet soup to clinical reality. Lancet 2002;359:619-622.
[132]王新,闻勤生,黄裕新.L-NAME对肝硬化大鼠胃肠道中一氧化氮合酶亚型表达的影响[J].第四军医大学学报,2001,22(9)：
[133]Li J P, De Fea K, Roth R A. Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an Akt/phosphatidy linositol 3-kinase pathway. J Biol Chem, 1999,274:9351～9356.
[1]王芬,何华亮,张红敏,等.参芪复方对GK大鼠脂代谢异常的实验研究[J].天津中医药,2007,24(6)：507-508
[2]谢毅强,李军茹,张红敏等.参芪复方治疗2型糖尿病胰岛素抵抗的临床研究[J].中华实用中西医杂志,2005,18(17)：844-846
[3]张红敏,陈世伟,谢春光等.参芪复方对GK大鼠白色脂肪组织脂联素基因表达的影响[J].中成药,2006,28(7)：996-1001
[4]张红敏,陈世伟,谢春光等.参芪复方抗自发性糖尿病GK大鼠早期动脉粥样硬化的作用机制[J].中国中药杂志,2006,31(15)：1272-1276
[5]许曼音,陆广华,陈名道.糖尿病学[M].上海科学技术出版社,上海：2003,365-366
[6]Vuksan V, Sievenpiper J L, Koo VYY, etc.American Crinseng (Panax quinquefolius L) reduces postprandial glycemia in nondiabetic subjects and subjects with type 2diabetes mellitus. Arch Intern Med.2000,160:1009-1013.
[7]Anoja S.Attele, Yun-Ping Zhou, Jing-Tian Xie, etc.Antidiabetic Effects of Panax ginseng Berry Extract and the Identification of an Effective Component.DIABETES.51 (7):1851-1858
[8]张树生,马长武主编.神农本草经贯通[M].中国医药科技出版社,北京：1996
[9]朴春梅.黄芪对糖尿病的药理机理研究近况[J].云南中医中药杂志,2005,26(2)：54-56
[10]李先荣,康永,程霞,等.注射用黄芪多糖药理作用的研究,对血糖及其肝糖原含量的影响[J].中成药,1989,11(9)：32-34.
[11]毛先晴,欧阳静萍,吴勇.中药黄芪多糖对糖尿病大鼠心肌GLUT4表达的影响[J].武汉大学学报(医学版),2005,26(4)：457-459.
[12]高美风,黄容,陈云芳.黄芪多糖的提取及其治疗糖尿病药理作用进展[J].辽宁中医药大学学报,2008,10(6)：38-40.
[13]吴勇,欧阳静萍,涂淑珍.黄芪多糖对糖尿病大鼠血管内皮细胞的影响[J].辽宁中医杂志,2002,29(1)：22-23.
[14]Haneda Ⅲ,Araki S,Togawa Ⅲ,et al.Mitogen-activated protein kinase cascade is activated in glomeruli of diabetic rats and glomerular mesangial cells cultured under high glucose conditions [J]. Diabetes,1997, (46):847～853.
[15]李英,张益民,吴文倩,等,野黄芪甙原对糖尿病肾脏蛋白激酶C活性作用的研究[J].中华肾脏病杂志,2000,16(2)：89-92.
[16]张汝学,周金黄,贾正平.地黄寡糖抗糖尿病药理作用及机制研究回顾[J].中药药理与临床,2003,19(2)：48-50
[17]于震,王军,李更生,等.地黄甙D滋阴补血和降血糖作用的实验研究[J].辽宁中医杂志,2001,28(4)：240-242.
[18]张汝学,正萍,景文,等.老年大鼠糖代谢变化及地黄寡糖对其的改善作用[J].中国老年学杂志,2002,22(5)：408～409.
[19]Zhang R, Zhou J, J IA Z, Zhang Y, GU G..Hypoglycemic effect of Rehmannia glutino sa oligo saccharide in hyperglycemic and alloxan2induced diabetic rats and its mechanism [J].J Ethnopharmaco 1,2004,90 (1):39～43.
[20]王晓莉,张汝学,贾正平.地黄寡糖灌胃对糖尿病大鼠的降糖作用及对肠道菌群的影响[J].西北国防医学杂志,2003,24(2)：121-123.
[21]张汝学,贾正平,周金黄.地黄寡糖抗糖尿病药理作用及机制研究[J].中医药学刊,2003,21(12)：3012-3014.
[22]李振红,陆阳,刘晶星.天花粉化学成分与药理活性[J].国外医药植物药分册,2003,18(1)：1-4.
[23]李振红,陆阳,刘晶星.天花粉化学成分与药理活性[J].国外医药植物药分册,2003,18(1)：1-4.
[24]姚宏兵,吴伸,董贻诚.天花粉蛋白Y14F／R22L定点突变及其活性研究[J].中国生物化学与分子生物学报,1998,14(3)：264-268
[25]张聪,金德章.山茱萸的研究进展[J].上海医药,2008,29(10)：464-468
[26]刘宝林,朱丹妮,禹志颖,等.山茱萸醇提物对实验动物血糖、血脂和血小板聚集的影响[J].中国药科大学学报,1992,23(1)：19—21.
[27]刘洪,许惠琴,时艳.山茱萸环烯醚萜总苷对2型糖尿病心脏病变大鼠胰岛素抵抗及血脂含量的影响[J].中药药理与临床,2007,23(3)：36-40.
[28]许惠琴,刘洪,郝海平.山茱萸环烯醚萜总苷对糖尿病大鼠胸主动脉血管内皮的保护作用[J].中国药理学通报,2003,19(6)：713-715.
[29]郝海平,许惠琴,朱荃.山茱萸环烯醚萜总苷对由链脲佐菌素诱导的糖尿病血管并发症大鼠血清Sicam-1、TNF-a的影响[J].中药药理与临床,2002,18(4)：13-14.
[30]皮文霞,蔡宝昌,许惠琴.山茱萸环烯醚萜总苷对糖尿病血管并发症模型大鼠血清SOD的影响[J].中药新药与临床药理,2003,14(1)：23-24.
[31]黄桂东,钟先锋,易军鹏.山药的研究概况[J].农产品加工·学刊,2006,7：55-57
[32]李锋涛,陈毓.山药的研究进展[J].海峡药学,2008,20(10)：19-21.
[33]郜红利,肖本见,梁文梅.山药多糖对糖尿病小鼠降血糖作用[J].中国公共卫生,2006,22(7)：804-805
[34]胡国强,杨保华,张忠泉.山药多糖对大鼠血糖及胰岛释放的影响[J-].山东中医杂志,2004,23(4)：230-231.
[35]唐涛,郭伟强,王珏,等.丹参酮Ⅱ 2A在RAW264.7细胞系中的抗炎症作用机制[J].生物技术通讯,2007,18(1)：51-53.
[36]卢志坤,陈一平.酚妥拉明联合丹参酮治疗糖尿病周围神经病变临床观察[J].浙江临床医学,2007,9(4)：30.
[37]林英辉,黄小琪.阿伐他汀联合丹参酮II A磺酸钠对糖尿病肾病患者TGF-β1、CTGF表达水平的影响[J].医学临床研究,2007,24(12)：2049-2051.
[38]杨泽平,蔡景英.丹参酮ⅡA磺酸钠治疗对2型糖尿病患者血管性假血友病因子和超敏C反应蛋白的影响[J].中国医师杂志,2007,9(11)：1559-1560.
[39]李志刚,王章阳,刘松青.大黄素对家兔离体主动脉平滑肌细胞增殖影响的可能途径[J].中国临床康复,2005,9(27)：135
[40]王苑铭,田林红,张娟.大黄多糖对糖尿病动脉粥样硬化大鼠血糖、血脂、肝脂酶活性的影响[J].中国现代医药杂志,2008,10(4)：6-10.
[41]刘志红,郑敬民,吴义超,等.db／db糖尿病肾病小鼠肾脏基因表达谱及大黄酸对其的影响(J).肾脏病与透析肾移植杂志,2002,11(3)：201-205
[42]刘志红,朱加明,黄海东,等.大黄酸对转化生长因子诱导内皮细胞纤溶酶原激活物抑制物1表达的影响[J].中华肾脏病杂志,2002,18(5)：337～341.
[43]郭啸华,刘志红,戴春笋,等.大黄酸抑制TGF-β1诱导的肾小管上皮细胞肥大及细胞外基质产生[J].肾脏病与透析肾移植杂志,2001,10(2)：101～105
[44]刘凯,郑海生.大黄酸的药理作用研究述略[J].中医药学刊,2004,22(9)：1732-1736.
[45]田风胜,李振彬,王元松,等.大黄对糖尿病大鼠血管病变保护机制的研究[J].中国中药杂志.2008,33(6)：673-677.
[2.]赵家伟,李秀钧.炎症、糖尿病、大血管病变之间的临床联系与新认识[J].辽宁实用糖尿病杂志,2003,11(3)：49-51
[3]刘云海,刘月平,赵国良等.sVCAM-1与2型糖尿病血管并发症关系的临床探讨[J],实用老年医学.2004,18(3)：142-144.
[4]陶冶,刘小菁,强鸥.高糖环境对体外培养糖尿病大鼠大血管内皮细胞产生转化生长因子-的影响[J].华西医大学报,2001,32(1)：63～65.
[5]DeMartin R, Hoeth M, Hofer-WarbinekR, et al. The transcription factor NF-kappaBand the regulation of vascular cell function [J]. Arterioscler Thromb Vasc Bio,2000,20(11):E8
[6]王小瑞,张苏河.2型糖尿病并大血管并发症患者白细胞中核因子-κB检测[J],郑州大学学报(医学版),2007,42(1)：113-116
[7]Kobayashi T, Mats mol/Loto T, Kamata K. The P I3-K/Akt pathway:roles related to alterations in vasomotor responses in diabetic models. J Smooth Muscle Res, 2005,41:283-302.
[8]Freedman SB, Isner JM, Therapeutic angiogenesis for coronary artery disease. Ann Intern Med,2002,136:54-71.
[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.中华内科杂志,1981,20：678.
[10]王克安,李天霖,李新华,等.中国儿童1型糖尿病发病率的研究.中华内分泌代谢杂志,1999,15：327.
[11]Maahs, D.M., et al., Hypertension prevalence, awareness, treatment, and control in an adult type 1 diabetes population and a comparable general population. Diabetes Care,2005.28(2):301-306.
[12]向红丁,吴纬,刘灿群,等.1996年全国糖尿病流行病学特点基线调查报告.中国糖尿病杂志,1998,3：131.
[13]卫生部疾病控制司,中华医学会糖尿病分会.中国糖尿病防治指南.北京：北京 大学出版社,2004：3-4.
[14]中华医学会糖尿病分会糖尿病慢性并发症调查组.全国住院糖尿病患者慢性并发症及其相关危险因素10年回顾性调查分析[J].中国糖尿病杂志,2003,11(4)：232-238.
[15]唐光敏,余叶蓉,王艳丽.华西医院1996-2004年住院成人糖尿病患者病死率及死因分析[J],中国糖尿病杂志,2008,16(10)：897-898.
[16]徐静,易兰兰,徐琳,等.住院糖尿病患者死因分析[J].陕西医学杂志,2005,34：807-809.
[17]蒲琳,王汝莲,吴桐,等.5年住院糖尿病病人死亡原因分析[J].四川医学,2002,23：898-899.
[18]杨华章,赵媛媛,邝建,等.老年糖尿病住院患者病死率及死因分析[J].中华老年医学杂志,2001,20：194-196
[19]Sinisalo J, Paronen J, Mattila J, et al. Relation of inflammation to vascular function in patients with coronary heart disease [J]. Atherosclerosis,2000, 149:403-411.
[20]CDC's Diabetes Program-Data& Trends-Causes of Hospitalizations-Distribution of First-Listed Diagnoses Among Hospital Discharges with Diabetes as Any Listed Diagnosis, Adults Age 18 and Older[DB/OL]. Unite,2003.
[21]陈雪峰,余叶荣.华西医院1996-2005年糖尿病住院患者入院原因分析[J],中国循证医学杂志,2008,8(7)：525-528
[22]卫生部疾病控制司,中华医学会糖尿病学分会.《中国糖尿病防治指南》试行本节选[J].中国慢性病预防与控制,2004,12(6)：283-285.
[23]田代华整理.黄帝内经素问[M].人民卫生出版社,北京：2005,15.
[24]明·张介宾著,李继明,王大淳,等整理.景岳全书[M].人民卫生出版社,北京,2007,423.
[25]吕仁和,糖尿病及其并发症中西医诊治学[M].人民卫生出版社,北京：1997,2-5.
[26]田代华整理.黄帝内经素问[M].人民卫生出版社,北京：2005,92.
[27]田代华,刘更生整理.灵枢经[M].人民卫生出版社,北京：2005,97.
[28]田代华,刘更生整理.灵枢经[M].人民卫生出版社,北京：2005,59.
[29]清·魏之琇编著.续名医类案[M],人民卫生出版社影印,北京：1982,206.
[30]宋·赵佶编.圣济总录[M].人民卫生出版社,北京：1982,1064-1099.
[31]田代华,刘更生整理.灵枢经[M].人民卫生出版社,北京：2005,94
[32]清·喻昌著,徐复霖点校.医门法律[M].上海科学技术出版社,上海：1983,213.
[33]宋·赵佶编.圣济总录[M].人民卫生出版社,北京：1982,1064-1099.
[34]高泓,谢春光,赵旭.糖尿病大血管病变的中医病机分析[J],时珍国医国药,2009,9待发
[35]中国中西医结合学会糖尿病专业委员会.中西医结合糖尿病诊疗标准(草案)[J].中国中西医结合杂志,2005,25(1)：94-95.
[36]李振中,尹翠梅,丁学屏,等.再论痰浊与糖尿病血管病变[J].光明中医,2004,2：10.
[37]董振华,季元.祝堪予治疗糖尿病慢性并发症的经验[J].中医杂志1997,(1)：12.
[38]季长春,程汉桥,董志,等.浅析糖尿病血管病变[J].中医药信息,2007,24(6)：40-42
[39]林兰主编.现代中医糖尿病学[M].北京：人民卫生出版社,2008.737-739
[40]张延群,韩清,和贵章,等.2080例糖尿病患者证候与血栓关系分析[J].中医杂志,1996,37(10)：617—619
[41]朗江明,魏爱生,方湃,等.广东省佛山城区成年人糖尿病流行病学调查[J].中国糖尿病杂志,1999,7(3)：175
[42]王(?)生,赵文累,夏军,等.益气养阴活血方对气阴两虚血瘀型搪尿病患者血浆内皮素与一氧化氮水平的影响[J].中国中西医结合杂志,2000,20(8)：571
[43]王姮,杨永年.糖尿病现代治疗学[M],北京科学出版社,2006：345-353.
[44]Maahs, D.M., et al., Hypertension prevalence, awareness, treatment, and control in an adult type 1 diabetes population and a comparable general population. Diabetes Care,2005.28(2):301-306.
[45]Colivicchi, F., et al., Differences between diabetic and non-diabetic hypertensive patients with first acute non-ST elevation myocardial infarction and predictors of in-hospital complications. J Cardiovasc Med(Hagerstown),2008.9(3):267-272.
[46]Longo-Mbenza, B, et al., [Risk factors of stroke among Congolese black hypertensive diabetics]. Ann Cardiol Angeiol (Paris),2008.57(1):37-43.
[47]Lonati, C., et al., Prevalence of type 2 diabetes among patients with hypertension under the care of 30 Italian clinics of hypertension:results of the (Iper) tensione and (dia)bete study. J Hypertens,2008,26(9):1801-1808.
[48]Cook CB, Erdman DM, Ryan GJ, et al. The pattern of dyslipidemia urban African-Americans with type2 diabetes [J]. Diabetes Care,2000,23:319-324
[49]Tai ES, Lin SC, Chew SK, et al. Homeostasis model assessment in a population with mixed ethnicity:the 1992 Singapore National Health Survey [J]. Diabetes Res Clin Prac,2000,49:159-168
[50]Reaven, G.M., Insulin resistance, the insulin resistance syndrome, and cardiovascular disease. Panminerva Med,2005.47(4):201-210
[51]平田恭信.NO与动脉粥样硬化[J].日本医学介绍,2005,26(7)324-325.
[52]王秀红,路方红.内皮素、一氧化氮与心血管疾病[J]中国慢性病预防与控制,2005,13(3)：139-141
[53]刘景生主编.细胞信息与调控[M].北京:中国协和医科大学出版社,2003,355-370.
[54]谢毅强,指导：谢春光.参芪复方对GK大鼠2型糖尿病大血管病变血管内皮细胞保护的实验研究.中国博士学位论文全文数据库,http://e34.cnki.net/kns50
[55]周智广,陈小燕.对血糖控制防治糖尿病大血管病变作用的评价[J].中国循证医学杂志,2004,4(7)：439-443
[56]周智广,庞翠军.糖尿病大血管病变的发病基础与防治策略[J].中国医师杂志,2006,8(1)：1-2.
[57]Dandona P, Aljada A, Chaudhuri A, Bandyopadhyay A.The potential influence of inflammation and insulin resistance on the pathogenesis and treatment of atherosclerosis related complications in type 2 diabetes [J]. J Clin Endocrinol Metab,2003; 88 (6):2422-2429
[58]GOde P, Vedel P, Larsen N, Jensen GV H, Parving HH,Pederson 01 Multif actorial intervention and cardiovascular disease in patients with type 2 diabetes [J]1 N Engl J Med,2003; 348 (5):383-393
[59]李振中,尹翠梅,丁学屏等.再论痰浊与糖尿病血管病变[J].光明中医,2004,2：10.
[60]席守民,廉馨,王宗保,等.高脂高蔗糖饲料诱导贵州小香猪发生糖尿病和动脉粥样硬化病变[J].中国动脉硬化杂志,2004,12(1)：5-10.
[61]Edwards IJ, Wagner JD, Vogl-Willis CA, et. Arterial heparan sulfate is negatively associated wi th h-qDerglycemia an d atheresclemsis in diabetic monkeysl J1. Cardiovasc Diabetol,2004,29(4):3-6.
[62]Brown, D.J., et al., Endothelial cell activation of the smooth muscle cell phosphoinositide 3-kinase/Akt pathway promotes differentiation. J Vasc Surg, 2005.41(3):509-516.
[63]席守民,廉馨,王宗保,等.高脂高蔗糖饲料诱导贵州小香猪发生糖尿病和动脉粥样硬化病变[J].中国动脉硬化杂志,2004,12(1)：5-10.
[64]He Xue-ling, Yin Hai-lin. Investigative current situation and existing problem of Artherosclerosis animal model. [J] Lalwratory Animal Science and Management, 2006,23(4):41-44(In Chinese)
[65]Vikramadithyan RK, Hu Y, Noh IlL, et. Human aldose reductase expression accelerates diabetic atherosclerosis in transgenic mice[J]. J Clin Invest,2005, 115(9):2434-2443.
[66]王宁,谢自敬,阿布力克木·吐尔地,等.糖尿病大鼠动脉粥样硬化与游离脂肪酸表达的关系[J].中国动脉硬化杂志,2005,13(5)：563—566.
[67]Renard CB, Kralner F, Johansson F,et al. Diabetes and diabetes associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions[J].J Clin invest,2004,114(5):659-668.
[68]张王月,王雁南,刘明.糖尿病动脉硬化动物模型的建立及评价[J].医学综述,2007,13(10)：758-760
[69]徐梓辉,周世文,钱桂生,等.2型糖尿病合并动脉粥样硬化大鼠模型的建立[J].中国病理生理杂志,2006,22(1)：205—208
[70]Cheng ZJ, Vaskonen T, Tikkanenl,et al. Endothelial dysfunction and salt-sensitive hypertension in spontaneously diabetic Goto-Kakizaki rats[J]. Hypertension, 2001,37(2 Part 2):433-439.
[71]Ling ZC,Hong LC,Ostenson CG.et al.Hyperglycemia contributes to impaired insulin response in GK rat islets[J].Diabetes,2001,5 Suppl 1:S108-S112.
[72]Hughes SJ, Suzuki K, Goto Y. The role of islet secretory function in the development of diabetes in the GK Wistar rat[J]. Diabetologia,1994,37 (9):863-870.
[73]王宝金,代解杰.糖尿病动物模型的研究进展[[J].上海实验动物科学,2003,23(2)：116.
[74]Hidehiko Ono, Yuko Ono, Atsuko Takanohashi, et al. Vascular Endothelial Growth Factor Is Necessary in the Development of Arteriosclerosis by Recruiting/Activating Monocytes in a Rat Model of Long-Term Inhibition of Nitric Oxide Synthesis[J].Circulation,2002,105:1110-1115
[75]Makoto Katoh, Kensuke Egashira, Chu Kataoka, et al. Regression by ACE inhibition of arteriosclerotic changes induced by chronic blockade of NO synthesis in rats[J]. Am J Physiol Heart Circ Physiol,2004; 286 (2):H768-H774.
[76]张树生,马长武主编.神农本草经贯通[M].北京：中国医药科技出版社,1996
[77]王芬,何华亮,张红敏,等.参芪复方对GK大鼠脂代谢异常的实验研究[J].天津中医药,2007,24(6)：507-508
[78]谢毅强,李军茹,张红敏等.参芪复方治疗2型糖尿病胰岛素抵抗的临床研究[J].中华实用中西医杂志,2005,18(17)：844-846
[79]张红敏,陈世伟,谢春光等.参芪复方对GK大鼠白色脂肪组织脂联素基因表达的影响[J].中成药,2006,28(7)：996-1001
[80]张红敏,陈世伟,谢春光等.参芪复方抗自发性糖尿病GK大鼠早期动脉粥样硬化的作用机制[J].中国中药杂志,2006,31(15)：1272-1276
[81]沈应君主编.中药药理学[M].人民卫生出版社,2000：96-97.
[82]Van-de-Ree, Huisman MV. Strong decrease of high sensitively O-reactive pritein with high-dose atorvastatin in patients with type 2 diabetes mellitus[J]. Atherosculerosis,2003,166(1):129-135
[83]Topol EJ. Intensive Statin Therapy-A sea change in cardiovascular prevention. N Engl J Med,2004,350:1562-1564
[84]Auer J, Berent R, Weber T, et al. Clinical significance of pleiotropic effects of statins:lipid reduction and beyond[J].Curt Med Chem,2002,9(20):1831-1850
[85]Lars.Circulating markers of inflammation and atherosclerosis [J].Atherosculerosis, 2003169(4):203-214.
[86]Vozarova B,Weyer C,Lindsay RS,et al.High white blood cell count is associated with a worsening of insulin sensitivity and predicts the development of type 2 diabete [J]. Circulation,2002,51(2):455-461.
[87]Greenberg AS. The expanding scope of the metabolic syndrome and implications for the management of cardiovascular risk in type 2 diaberes with particular focus on the emerging rote of the thiazolidinediones [J].J Diabetes Complications,2003, 17(4):218-228.
[88]Dandona P, Aljada A,Mohanty Pet al.Insulin inhibits intranuclear nuclear factor kappaB and stimulates Ⅰ kappaB in mononuclear cells in obese subjects:evidence for an anti-inflammatory effect[J]J Clin Endocrinol Metab,2001,86(7):3257-3265.
[89]赵水平主编.他汀类药物治疗学[M],长沙：中南大学出版社,2005.451
[90]Johnston TP, Baker JC, Hall D, et al. Regression of poloxamer 407-induced atherosclerotic lesions in C57BL/6 mice using atorvastain. Atherosclerosis,2000, 149(2):303-313
[91]Nissen SE, Tuzcu EM, Schoenhagen P, et al, Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis:a randomized controlled trial. JAMA,2004,291 (9):1071-1080
[92]Maron DJ, Fazion S, Linton MF.Current perspectives on statins. Circulation,2000, 101:207-213
[93]赵水平主编.他汀类药物治疗学[M],长沙：中南大学出版社,2005.451
[94]王宏宇主编.血管病学[M],北京：人民军医出版社,2006,191.
[95]Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med,2004, 350:1495-1504
[96]黄继汉,黄晓晖,陈志扬,等.药理试验中动物间和动物与人体间的等效剂量换算[J].中国临床药理学与治疗学,2004,9(9)：1069-1072
[97]张红敏,指导：谢春光.参芪复方对GK大鼠低度炎症和大血管病变的影响及机理研究.中国博士学位论文全文数据库,http://e34.cnki.net/kns50
[98]李稻主编.医学功能学科—实验原理与方法[M].人民卫生出版社,北京：2008,33-35.
[99]邓欣,郭玲玲.糖尿病大血管病变与胰岛素抵抗[J].中西医结合心脑血管病杂志,2005,3(8)：725-727.
[100]HaidariM, Javadi E, Sadegh iB, et al. Evaluation of C-reactive protein, a sensitive marker of inflammation, as a risk facto r for stable coronary artery disease. Clin Biochem,2001,33:309-315.
[101]Freeman DJ, Nomie J, Caslake MJ, etal. C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes,2002,51(5):1596-1600
[102]Pradhan AD,Manson JE,Rifai N,etal.C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus.JAMA,2001,286:327-334
[103]Barzilay JI, Abraham L, Heckbert SR, etal.The relation of markers of inflammation to the development of glucose disorders in the elderly:the Cardiovascular Health Study.Diabetes,2001,50:2384-2389
[104]吴伟华,张中超,刘国良.C-反应蛋白与2型糖尿病大血管病变的相关性研究[J].中国糖尿病杂志,2003,11(4)：247-249.
[105]张晓梅,黄咏齐,陈风玲等.糖尿病血清C反应蛋白与大血管并发症关系的探讨[M].中国现代应用药学,2003,20(5)：424-426.
[106]Mako to F, Hideki K, Kouichi I, etal.Structure and function of phosphatidylinositol-3,4kinase.Cell Signal,2000,12(3):135-142
[107]董砚虎,南海荣,王军,等.磷脂酰肌醇32激酶P85 α亚单位基因Met326Ile变异与2型糖尿病的相关关系[J].中国糖尿病杂志,2006,(14)6：417-419.
[108]Jones P F, Jakubowicz T, Pitossi F J, et al. Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily. Proc Natl Acad Sci USA,1991,88:4171～4175
[109]Coffer P J, Woodgett J R.Molecular cloning and characterization of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families.Eur J Biochem,1991,201:475～481
[110]Matsuura, E., et al., Oxidized LDL/beta2-glycoprotein I complexes:new aspects in atherosclerosis. Lupus,2005.14(9):736-741.
[111]Maier, U., Babich, A. and Nurnberg, B.(1999).Roles of non-catalytic subunits in Gbetagamma-induced activation of class I phosphoinositide 3-kinase isoforms beta and gamma. J. Biol. Chem.274:29311-29317.
[112]Anai, M., Funaki, M., Ogihara, T, Terasaki, J., Inukai, K., Katagiri, H., Fukushima, Y, Yazaki, Y., Kikuchi, M., Oka, Y. and Asano, T.(1998).Altered expression levels and impaired steps in the pathway to phosphatidylinositol 3-kinase activation via insulin receptor substrates 1 and 2 in Zucker fatty rats. Diabetes 47:13-23.
[113]Mauvais-Jarvis, F., Ueki, K., Fruman, D.A., Hirshman, M.F., Sakamoto, K., Goodyear, L.J, Iannacone, M., Accili, D, Cantley, L.C. and Kahn, C.R. (2002).Reduced expression of the murine p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. J. Clin. Invest. 109:141-149.
[114]Yki-Jarvinen,et al.Best Pract Res ClinEndocrinol Metab,2003,17:411-430
[115]Fulton D,Gratton JP.,McCabe TJ,et al.Regulation of en-dotuelium-derived nitric oxide production by the protein kinase AKT[J].Nature,1999,399:597-601
[116]Celermajer,ET AL.A Am Coll Cardiol,1997,30:325-333
[117]Khan BV,Harrison DG,Olbrych MT,er al.Nitric oxide regulates vascular cell adhension molecrlar 1 gne expression and redox-sensi-tive transcriptional events in human vascular endothelial cells[J].Proc Natl Acad Sci USA,1996,93:9 114-119
[118]Ritchie,er al.Clin Sience,2004,107:519-532
[119]王军,姜宏卫,磷脂酰肌醇3激酶与2型糖尿病.国外医学.内分泌学分册,2001(06).
[120]Sun Y, Tian H, Xiao FM, PI3K p85alpha expression and its role in the progression of colorectal cancer [J], Nan Fang Yi Ke Da Xue Xue Bao,2009, 29(3):416-417.
[121]迟素敏.内分泌生理学[M].西安：第四军医大学出版社,2006.11-13.
[122]金丹,陆付耳.P13K在2型糖尿病发病机制中的作用[J].医学综述,2007(13)1：21-23
[123]Bjnholm M, Kawano Y, Lehtihet M, etal.Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activety in skeletal muscle from NIDDM subject s after in vivo insulin stimulation1 Diabetes,1997, 46:524-527.
[124]Ishizuka T, Miura A, Kajita K, et al. Alterations in insulin induced post receptor signaling in adipocytes of t he Ot suka Long-Evans Tokushima fatty rat strain1 J Endocrinol,1998,156:1-13.
[125]Miura A,Ishizuka T,Kanoh Y. Effect of tumor necrosis factor-alpha on insulin signal transduction in rat adipocytes:relation to PKC beta and zeta translocation [J].Biochem Biophys Acta,1999,1449:227-238.
[126]杨永宗.动脉粥样硬化性心血管病基础与临床[M].北京：科学出版社,2004,619-620
[127]Fulvio Morello, Alessia Perino, Emilio Hirsch. Phosphoinositide 3-kinase signaling in the vascular system [J].Cardiovascular Research,2008,18,1-11
[128]Young LH, Ikeda Y, Scalia R, Lefer AM. Wortmannin, a potent antineutrophil agent, exerts cardioprotective effects in myocardial ischemia/reperfusion. J Pharmacol Exp Ther 2000;295:37-43
[129]Mourani PM, Garl PJ, Wenzlau JM, Carpenter TC, Stenmark KR, Weiser-Evans MCM. Unique, highly proliferative growth phenotype expressed by embryonic and neointimal smooth muscle cells is driven by constitutive Akt, mTOR, and p70S6K signaling and is actively repressed by PTEN. Circulation 2004;109:1299-1306.
[130]Sousa JE, Costa MA, Abizaid A, Abizaid AS, Feres F, Pinto IMF et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries:A Quantitative Coronary Angiography and Three-Dimensional Intravascular Ultrasound Study. Circulation 2001; 103:192-195.
[131]Poon M, Badimon JJ, Fuster V. Overcoming restenosis with sirolimus:from alphabet soup to clinical reality. Lancet 2002;359:619-622.
[132]王新,闻勤生,黄裕新.L-NAME对肝硬化大鼠胃肠道中一氧化氮合酶亚型表达的影响[J].第四军医大学学报,2001,22(9)：
[133]Li J P, De Fea K, Roth R A. Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an Akt/phosphatidy linositol 3-kinase pathway. J Biol Chem, 1999,274:9351～9356.
[1]王芬,何华亮,张红敏,等.参芪复方对GK大鼠脂代谢异常的实验研究[J].天津中医药,2007,24(6)：507-508
[2]谢毅强,李军茹,张红敏等.参芪复方治疗2型糖尿病胰岛素抵抗的临床研究[J].中华实用中西医杂志,2005,18(17)：844-846
[3]张红敏,陈世伟,谢春光等.参芪复方对GK大鼠白色脂肪组织脂联素基因表达的影响[J].中成药,2006,28(7)：996-1001
[4]张红敏,陈世伟,谢春光等.参芪复方抗自发性糖尿病GK大鼠早期动脉粥样硬化的作用机制[J].中国中药杂志,2006,31(15)：1272-1276
[5]许曼音,陆广华,陈名道.糖尿病学[M].上海科学技术出版社,上海：2003,365-366
[6]Vuksan V, Sievenpiper J L, Koo VYY, etc.American Crinseng (Panax quinquefolius L) reduces postprandial glycemia in nondiabetic subjects and subjects with type 2diabetes mellitus. Arch Intern Med.2000,160:1009-1013.
[7]Anoja S.Attele, Yun-Ping Zhou, Jing-Tian Xie, etc.Antidiabetic Effects of Panax ginseng Berry Extract and the Identification of an Effective Component.DIABETES.51 (7):1851-1858
[8]张树生,马长武主编.神农本草经贯通[M].中国医药科技出版社,北京：1996
[9]朴春梅.黄芪对糖尿病的药理机理研究近况[J].云南中医中药杂志,2005,26(2)：54-56
[10]李先荣,康永,程霞,等.注射用黄芪多糖药理作用的研究,对血糖及其肝糖原含量的影响[J].中成药,1989,11(9)：32-34.
[11]毛先晴,欧阳静萍,吴勇.中药黄芪多糖对糖尿病大鼠心肌GLUT4表达的影响[J].武汉大学学报(医学版),2005,26(4)：457-459.
[12]高美风,黄容,陈云芳.黄芪多糖的提取及其治疗糖尿病药理作用进展[J].辽宁中医药大学学报,2008,10(6)：38-40.
[13]吴勇,欧阳静萍,涂淑珍.黄芪多糖对糖尿病大鼠血管内皮细胞的影响[J].辽宁中医杂志,2002,29(1)：22-23.
[14]Haneda Ⅲ,Araki S,Togawa Ⅲ,et al.Mitogen-activated protein kinase cascade is activated in glomeruli of diabetic rats and glomerular mesangial cells cultured under high glucose conditions [J]. Diabetes,1997, (46):847～853.
[15]李英,张益民,吴文倩,等,野黄芪甙原对糖尿病肾脏蛋白激酶C活性作用的研究[J].中华肾脏病杂志,2000,16(2)：89-92.
[16]张汝学,周金黄,贾正平.地黄寡糖抗糖尿病药理作用及机制研究回顾[J].中药药理与临床,2003,19(2)：48-50
[17]于震,王军,李更生,等.地黄甙D滋阴补血和降血糖作用的实验研究[J].辽宁中医杂志,2001,28(4)：240-242.
[18]张汝学,正萍,景文,等.老年大鼠糖代谢变化及地黄寡糖对其的改善作用[J].中国老年学杂志,2002,22(5)：408～409.
[19]Zhang R, Zhou J, J IA Z, Zhang Y, GU G..Hypoglycemic effect of Rehmannia glutino sa oligo saccharide in hyperglycemic and alloxan2induced diabetic rats and its mechanism [J].J Ethnopharmaco 1,2004,90 (1):39～43.
[20]王晓莉,张汝学,贾正平.地黄寡糖灌胃对糖尿病大鼠的降糖作用及对肠道菌群的影响[J].西北国防医学杂志,2003,24(2)：121-123.
[21]张汝学,贾正平,周金黄.地黄寡糖抗糖尿病药理作用及机制研究[J].中医药学刊,2003,21(12)：3012-3014.
[22]李振红,陆阳,刘晶星.天花粉化学成分与药理活性[J].国外医药植物药分册,2003,18(1)：1-4.
[23]李振红,陆阳,刘晶星.天花粉化学成分与药理活性[J].国外医药植物药分册,2003,18(1)：1-4.
[24]姚宏兵,吴伸,董贻诚.天花粉蛋白Y14F／R22L定点突变及其活性研究[J].中国生物化学与分子生物学报,1998,14(3)：264-268
[25]张聪,金德章.山茱萸的研究进展[J].上海医药,2008,29(10)：464-468
[26]刘宝林,朱丹妮,禹志颖,等.山茱萸醇提物对实验动物血糖、血脂和血小板聚集的影响[J].中国药科大学学报,1992,23(1)：19—21.
[27]刘洪,许惠琴,时艳.山茱萸环烯醚萜总苷对2型糖尿病心脏病变大鼠胰岛素抵抗及血脂含量的影响[J].中药药理与临床,2007,23(3)：36-40.
[28]许惠琴,刘洪,郝海平.山茱萸环烯醚萜总苷对糖尿病大鼠胸主动脉血管内皮的保护作用[J].中国药理学通报,2003,19(6)：713-715.
[29]郝海平,许惠琴,朱荃.山茱萸环烯醚萜总苷对由链脲佐菌素诱导的糖尿病血管并发症大鼠血清Sicam-1、TNF-a的影响[J].中药药理与临床,2002,18(4)：13-14.
[30]皮文霞,蔡宝昌,许惠琴.山茱萸环烯醚萜总苷对糖尿病血管并发症模型大鼠血清SOD的影响[J].中药新药与临床药理,2003,14(1)：23-24.
[31]黄桂东,钟先锋,易军鹏.山药的研究概况[J].农产品加工·学刊,2006,7：55-57
[32]李锋涛,陈毓.山药的研究进展[J].海峡药学,2008,20(10)：19-21.
[33]郜红利,肖本见,梁文梅.山药多糖对糖尿病小鼠降血糖作用[J].中国公共卫生,2006,22(7)：804-805
[34]胡国强,杨保华,张忠泉.山药多糖对大鼠血糖及胰岛释放的影响[J-].山东中医杂志,2004,23(4)：230-231.
[35]唐涛,郭伟强,王珏,等.丹参酮Ⅱ 2A在RAW264.7细胞系中的抗炎症作用机制[J].生物技术通讯,2007,18(1)：51-53.
[36]卢志坤,陈一平.酚妥拉明联合丹参酮治疗糖尿病周围神经病变临床观察[J].浙江临床医学,2007,9(4)：30.
[37]林英辉,黄小琪.阿伐他汀联合丹参酮II A磺酸钠对糖尿病肾病患者TGF-β1、CTGF表达水平的影响[J].医学临床研究,2007,24(12)：2049-2051.
[38]杨泽平,蔡景英.丹参酮ⅡA磺酸钠治疗对2型糖尿病患者血管性假血友病因子和超敏C反应蛋白的影响[J].中国医师杂志,2007,9(11)：1559-1560.
[39]李志刚,王章阳,刘松青.大黄素对家兔离体主动脉平滑肌细胞增殖影响的可能途径[J].中国临床康复,2005,9(27)：135
[40]王苑铭,田林红,张娟.大黄多糖对糖尿病动脉粥样硬化大鼠血糖、血脂、肝脂酶活性的影响[J].中国现代医药杂志,2008,10(4)：6-10.
[41]刘志红,郑敬民,吴义超,等.db／db糖尿病肾病小鼠肾脏基因表达谱及大黄酸对其的影响(J).肾脏病与透析肾移植杂志,2002,11(3)：201-205
[42]刘志红,朱加明,黄海东,等.大黄酸对转化生长因子诱导内皮细胞纤溶酶原激活物抑制物1表达的影响[J].中华肾脏病杂志,2002,18(5)：337～341.
[43]郭啸华,刘志红,戴春笋,等.大黄酸抑制TGF-β1诱导的肾小管上皮细胞肥大及细胞外基质产生[J].肾脏病与透析肾移植杂志,2001,10(2)：101～105
[44]刘凯,郑海生.大黄酸的药理作用研究述略[J].中医药学刊,2004,22(9)：1732-1736.
[45]田风胜,李振彬,王元松,等.大黄对糖尿病大鼠血管病变保护机制的研究[J].中国中药杂志.2008,33(6)：673-677.