齐墩果酸抗糖尿病作用及其机理研究
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摘要
糖尿病是世界范围内最常见的内分泌性疾病之一,其死亡率在发达国家仅次于心血管疾病、恶性肿瘤,成为第三位致死病因疾病。WHO调查材料显示,目前全世界至少有1.71亿糖尿病患者,预测到2030年将增至3.66亿,其发病率也将由目前的2.8%上升为4.4%。尽管有大量的降血糖药物在临床应用,但由于其副作用大、使用不便,疗效不稳定,目前仍未发现一种有效的治疗药物。胰岛素虽然是人类发现的有效降糖药物,但它只能缓解患者血糖的升高,并不能达到完全治愈的目的。天然抗糖尿病药物以其毒副作用小和不易产生耐药性普遍受到医学界的关注,西方发达国家正在加快天然药物开发,不断有源于天然产物的新药问世。女贞子是我国传统的中药,通常用来治疗癌症、肝炎等疾病。在降血糖研究中,尽管也有少量报道,但仍然缺乏较为系统的深入研究。有关女贞子治疗糖尿病的机理方面目前国际上仍未见相关的报道。
本研究采用多重结晶技术从植物女贞子中提取出活性物质——齐墩果酸(OA),通过分离、纯化,薄层色谱和质谱鉴定,进一步将其磨成粒径为200-700nm的粉末。以腹腔注射链尿佐菌素(STZ)和四氧嘧啶(Alloxan)构建大鼠和小鼠糖尿病模型,将其分为糖尿病对照组、齐墩果酸低剂量、高剂量治疗组和正常对照组。采用免疫组化、单细胞电泳、酶联免疫吸附、免疫印迹和RT-PCR等技术研究了齐墩果酸对糖类和脂类代谢相关基因PPARα、PPARγ、PKB和PKC的表达变化,以及对糖尿病鼠β细胞凋亡、抗氧化能力和糖代谢相关激素水平的影响,并获得如下研究结果。
糖尿病大鼠经OA处理40 d后,低、高剂量组血糖分别下降了32.4%和46.4%;高剂量治疗组TG、TC、LDL-c水平明显下降,HDL-c水平则升高(P <0.05, 0.01),表明其具有显著的降脂功能。治疗组大鼠血清ALP、AST和ALT水平均接近于正常,揭示OA对肝脏具有明显的保护作用。此外,OA也升高了SOD和GSH-px水平(P <0.05, 0.01),增强了机体的抗氧化能力。
采用HE染色、急毒性试验和单细胞电泳技术(SCGE)对OA的毒副作用进行检测,结果表明,OA能使胰岛数量及胰岛内细胞数量增加;同时它能够修复STZ诱导的糖尿病鼠的肝和肾的损伤。在急毒性试验中,小鼠灌服OA 1000 mg·kg-1剂量时,未见出现死亡。SCGE结果揭示,OA对淋巴细胞的DNA没有损伤。
通过对糖尿病大鼠胰岛素和甲状腺素水平分析表明,OA能够明显增加糖尿病大鼠的胰岛素分泌(P <0.05),但对血清T3、T4和TSH水平没有明显影响。此外,OA对糖尿病大鼠的肝脏、肺、胰腺和肾脏等器官的重量没有明显影响,但能够显著增加胸腺的重量(P <0.05),这可能是OA通过作用于胸腺而增强机体的免疫功能。
通过对细胞凋亡影响的研究表明,OA处理后,小鼠胰腺、肾组织的Bax mRNA表达均减少,而Bcl-2表达增加,Bcl-2/Bax比值接近正常对照组,与糖尿病组存在明显差异(P <0.05, 0.01)。说明OA对胰腺和肾脏细胞的凋亡可能具有明显的抑制作用。免疫组化分析表明,OA也改善了肝脏中Bax和Bcl-2蛋白的表达,恢复肝细胞的正常的糖、脂代谢功能,避免糖尿病并发症的发生。
通过对细胞因子的表达进行分析,结果表明经OA治疗8 w后,糖尿病鼠的PPARα表达上调,但与对照组没有明显的不同(P >0.05);OA明显刺激了胰腺、肾脏PPARγmRNA的表达水平(P <0.05)。通过Westhern Blot分析表明,OA治疗的糖尿病鼠肾组织中PKB蛋白含量明显增加(P <0.05)。这些结果揭示OA降血糖和血脂作用可能是通过PKB/PPAR途径完成,即OA刺激胰岛素分泌,修复肝、肾和胰腺的损伤,而发挥作用。此外,OA对肝、肾组织PKC的表达未发生显著影响(P >0.05)。
本文较系统地研究了女贞子提取物——齐墩果酸对糖尿病鼠的治疗作用,并从糖类和脂类相关激素和基因水平初步探讨了其作用机制。该研究为OA降糖作用与机理的进一步深入研究提供了科学依据和手段。
Diabetes mellitus (DM) is one of the most common endocrine diseases. The mortality is only inferior to cardiovascular disease and malignancy in the developed country, and becoming the third fatal pathogeny. The World Health Organization has estimated that the total number of diabetic patients is not less than 171 million presently, and expected that it will rise to 366 million in 2030. The incidence of diabetes will be increased to 4.4% in 2030 from 2.8% presently. In despite of the application of plentiful hypoglycemic agents in clinic, there is not effective drug for diabetes due to the severe toxicity and side effects, inconvenience and instable efficacy. Insulin is an effective hypoglycemic drug, but it only alleviates hyperglycemia of diabetic patient. And diabetes can not be cured completely by insulin. Natural anti-diabetic pharmaceutical are attracting attention in the medicinal field by the less toxicity and no-drug-resistance. The natural drugs are exploited rapidly in the developed country. Some new agents that were rooted in natural products frequently appeared. Ligustrum lucidum Ait has been used in traditional Chinese medicine due to its antitumor and hepatoprotective properties. There are a few reports on hypoglycemia of Ligustrum lucidum Ait. However, the treated mechanisms of Ligustrum lucidum Ait in diabetes are not reported yet. In order to develop new anti-diabetic pharmaceutical, the systematic and deep research on hypoglycemia of Ligustrum lucidum Ait is highly desired.
In this paper, the principal active compound-oleanolic acid (OA) was extracted from Ligustrum lucidum Ait by multi-crystal method. The extract was isolated, purified and analyzed by thin layer chromatography (TLC) and mass spectra (MS) technology. OA was ground to powder with 200-700 nm diameters. Diabetic rats and mice were induced with STZ or alloxan intraperitoneally. Diabetic animals were randomly divided into normal control group (NC), diabetic control group (DM), DM+OA low dose group (DM+OA LD) and DM+OA high dose group (DM+OA HD). The genes of PPARα, PPARγ, PKB and PKC were relative with metabolizing of saccharide and lipid. The expression of PPARα, PPARγ, PKB and PKC in the OA-treated animals was analyzed by immunohistochemical stain, single cell gel electrophoresis, ELISA, Westhern Blot and RT-PCR and so on. Meanwhile, the effect of OA was studied systematically on cell apoptosis, antioxidant ability and hormone level which are related with saccharide metabolizing. The results were listed as follows.
When diabetic rats were treated with OA for 40 days, the decreasing rates of the plasma glucose levels were 32.4% (in DM+OA LD group) and 46.4% (in DM+OA HD group), respectively. The levels of TG, TC, LDL-c in DM+OA HD group were significantly lower, while their level of HDL-c increased significantly (P <0.05, 0.01), which implied that OA has the function of hypolipidemia. The levels of serum ALP, AST and ALT of OA-treated rats approached to normal value. The results indicated that OA could protect the liver of the diabetic rats. Furthermore, OA also strengthened the antioxidant ability by increasing the activities of SOD and GSH-px.
The toxicity and side effect of OA was examined by HE stain, acute toxic test and single cell gel electrophoresis. Results showed that OA could increase the quantity of the pancreatic islets and the cells in pancreatic islet; OA has the ability to amend the impairment on liver and kidney of STZ-induced diabetic rats. In acute toxic test, the mice were fed OA 1000 mg/kg, as a result, there is not death of mouse. Moreover, the result of single cell gel electrophoresis indicated that OA did not destroy DNA of the lymphocytes basically.
The levels of insulin and thyroid hormones of the diabetic rats were analyzed, and the results indicated that OA could increase significantly the insulin secretion of diabetic rats (P <0.05), but the changes of serum T3, T4 and TSH levels were insignificant. Furthermore, OA did not affect significantly the weight of liver, lung, kidney and pancreas of the diabetic rats (P >0.05), but the weight of the thymus was significantly higher (P < 0.05). It is tempting to speculate that OA might stimulate the growth of thymus, consequently increasing the immune function of animals.
Effect of OA on apoptosis was studied; the results showed that expression of Bax mRNA in pancreas and kidney tissues was reduced after OA-treated, while expression of Bcl-2 was enhanced. The ratio of Bcl-2/Bax approached to normal level, and there was significant difference with diabetes control mice (P <0.05, 0.01). The research indicated that OA might restrain the apoptosis of pancreas and kidney. By immunohistochemical analysis, the results implied that OA also ameliorated expression of Bax and Bcl-2 protein in liver, and restore the function of saccharide and lipid metabolizing, consequently, which avoid diabetic complication.
The mechanisms of OA on anti-diabetes were investigated by determining expression of some cytokines. The results indicated that PPARαlevel was up-regulated in pancreas and kidney of OA-treated diabetic mice after OA treatment for 8 weeks, but the difference was insignificant with control mice (P >0.05). The expression of PPARγmRNA was significantly up-regulated in OA-treated diabetic mice kidney and pancreas tissue (P >0.05). Westhern Blot determining indicated that the expression of PKB protein was increased significantly in OA-treated diabetic mice kidney (P <0.05). The present study provided further evidence in support of OA on stimulating secretion of insulin, amending the impairment on liver, kidney and pancreas of STZ-induced diabetic rats, hypoglycemic and hypolipidemic activity. The study also found that OA did not affect the expression of PKC in diabetic mice liver and kidney (P >0.05).
In the study, the effects of extract of Ligustrum lucidum Ait-oleanolic acid on diabetic rats were investigated systematically, and the action mechanisms were discussed on hormone, protein and molecule levels. It will provide a scientific proof for development of Ligustrum lucidum Ait as a suitable natural anti-diabetic agent.
本研究采用多重结晶技术从植物女贞子中提取出活性物质——齐墩果酸(OA),通过分离、纯化,薄层色谱和质谱鉴定,进一步将其磨成粒径为200-700nm的粉末。以腹腔注射链尿佐菌素(STZ)和四氧嘧啶(Alloxan)构建大鼠和小鼠糖尿病模型,将其分为糖尿病对照组、齐墩果酸低剂量、高剂量治疗组和正常对照组。采用免疫组化、单细胞电泳、酶联免疫吸附、免疫印迹和RT-PCR等技术研究了齐墩果酸对糖类和脂类代谢相关基因PPARα、PPARγ、PKB和PKC的表达变化,以及对糖尿病鼠β细胞凋亡、抗氧化能力和糖代谢相关激素水平的影响,并获得如下研究结果。
糖尿病大鼠经OA处理40 d后,低、高剂量组血糖分别下降了32.4%和46.4%;高剂量治疗组TG、TC、LDL-c水平明显下降,HDL-c水平则升高(P <0.05, 0.01),表明其具有显著的降脂功能。治疗组大鼠血清ALP、AST和ALT水平均接近于正常,揭示OA对肝脏具有明显的保护作用。此外,OA也升高了SOD和GSH-px水平(P <0.05, 0.01),增强了机体的抗氧化能力。
采用HE染色、急毒性试验和单细胞电泳技术(SCGE)对OA的毒副作用进行检测,结果表明,OA能使胰岛数量及胰岛内细胞数量增加;同时它能够修复STZ诱导的糖尿病鼠的肝和肾的损伤。在急毒性试验中,小鼠灌服OA 1000 mg·kg-1剂量时,未见出现死亡。SCGE结果揭示,OA对淋巴细胞的DNA没有损伤。
通过对糖尿病大鼠胰岛素和甲状腺素水平分析表明,OA能够明显增加糖尿病大鼠的胰岛素分泌(P <0.05),但对血清T3、T4和TSH水平没有明显影响。此外,OA对糖尿病大鼠的肝脏、肺、胰腺和肾脏等器官的重量没有明显影响,但能够显著增加胸腺的重量(P <0.05),这可能是OA通过作用于胸腺而增强机体的免疫功能。
通过对细胞凋亡影响的研究表明,OA处理后,小鼠胰腺、肾组织的Bax mRNA表达均减少,而Bcl-2表达增加,Bcl-2/Bax比值接近正常对照组,与糖尿病组存在明显差异(P <0.05, 0.01)。说明OA对胰腺和肾脏细胞的凋亡可能具有明显的抑制作用。免疫组化分析表明,OA也改善了肝脏中Bax和Bcl-2蛋白的表达,恢复肝细胞的正常的糖、脂代谢功能,避免糖尿病并发症的发生。
通过对细胞因子的表达进行分析,结果表明经OA治疗8 w后,糖尿病鼠的PPARα表达上调,但与对照组没有明显的不同(P >0.05);OA明显刺激了胰腺、肾脏PPARγmRNA的表达水平(P <0.05)。通过Westhern Blot分析表明,OA治疗的糖尿病鼠肾组织中PKB蛋白含量明显增加(P <0.05)。这些结果揭示OA降血糖和血脂作用可能是通过PKB/PPAR途径完成,即OA刺激胰岛素分泌,修复肝、肾和胰腺的损伤,而发挥作用。此外,OA对肝、肾组织PKC的表达未发生显著影响(P >0.05)。
本文较系统地研究了女贞子提取物——齐墩果酸对糖尿病鼠的治疗作用,并从糖类和脂类相关激素和基因水平初步探讨了其作用机制。该研究为OA降糖作用与机理的进一步深入研究提供了科学依据和手段。
Diabetes mellitus (DM) is one of the most common endocrine diseases. The mortality is only inferior to cardiovascular disease and malignancy in the developed country, and becoming the third fatal pathogeny. The World Health Organization has estimated that the total number of diabetic patients is not less than 171 million presently, and expected that it will rise to 366 million in 2030. The incidence of diabetes will be increased to 4.4% in 2030 from 2.8% presently. In despite of the application of plentiful hypoglycemic agents in clinic, there is not effective drug for diabetes due to the severe toxicity and side effects, inconvenience and instable efficacy. Insulin is an effective hypoglycemic drug, but it only alleviates hyperglycemia of diabetic patient. And diabetes can not be cured completely by insulin. Natural anti-diabetic pharmaceutical are attracting attention in the medicinal field by the less toxicity and no-drug-resistance. The natural drugs are exploited rapidly in the developed country. Some new agents that were rooted in natural products frequently appeared. Ligustrum lucidum Ait has been used in traditional Chinese medicine due to its antitumor and hepatoprotective properties. There are a few reports on hypoglycemia of Ligustrum lucidum Ait. However, the treated mechanisms of Ligustrum lucidum Ait in diabetes are not reported yet. In order to develop new anti-diabetic pharmaceutical, the systematic and deep research on hypoglycemia of Ligustrum lucidum Ait is highly desired.
In this paper, the principal active compound-oleanolic acid (OA) was extracted from Ligustrum lucidum Ait by multi-crystal method. The extract was isolated, purified and analyzed by thin layer chromatography (TLC) and mass spectra (MS) technology. OA was ground to powder with 200-700 nm diameters. Diabetic rats and mice were induced with STZ or alloxan intraperitoneally. Diabetic animals were randomly divided into normal control group (NC), diabetic control group (DM), DM+OA low dose group (DM+OA LD) and DM+OA high dose group (DM+OA HD). The genes of PPARα, PPARγ, PKB and PKC were relative with metabolizing of saccharide and lipid. The expression of PPARα, PPARγ, PKB and PKC in the OA-treated animals was analyzed by immunohistochemical stain, single cell gel electrophoresis, ELISA, Westhern Blot and RT-PCR and so on. Meanwhile, the effect of OA was studied systematically on cell apoptosis, antioxidant ability and hormone level which are related with saccharide metabolizing. The results were listed as follows.
When diabetic rats were treated with OA for 40 days, the decreasing rates of the plasma glucose levels were 32.4% (in DM+OA LD group) and 46.4% (in DM+OA HD group), respectively. The levels of TG, TC, LDL-c in DM+OA HD group were significantly lower, while their level of HDL-c increased significantly (P <0.05, 0.01), which implied that OA has the function of hypolipidemia. The levels of serum ALP, AST and ALT of OA-treated rats approached to normal value. The results indicated that OA could protect the liver of the diabetic rats. Furthermore, OA also strengthened the antioxidant ability by increasing the activities of SOD and GSH-px.
The toxicity and side effect of OA was examined by HE stain, acute toxic test and single cell gel electrophoresis. Results showed that OA could increase the quantity of the pancreatic islets and the cells in pancreatic islet; OA has the ability to amend the impairment on liver and kidney of STZ-induced diabetic rats. In acute toxic test, the mice were fed OA 1000 mg/kg, as a result, there is not death of mouse. Moreover, the result of single cell gel electrophoresis indicated that OA did not destroy DNA of the lymphocytes basically.
The levels of insulin and thyroid hormones of the diabetic rats were analyzed, and the results indicated that OA could increase significantly the insulin secretion of diabetic rats (P <0.05), but the changes of serum T3, T4 and TSH levels were insignificant. Furthermore, OA did not affect significantly the weight of liver, lung, kidney and pancreas of the diabetic rats (P >0.05), but the weight of the thymus was significantly higher (P < 0.05). It is tempting to speculate that OA might stimulate the growth of thymus, consequently increasing the immune function of animals.
Effect of OA on apoptosis was studied; the results showed that expression of Bax mRNA in pancreas and kidney tissues was reduced after OA-treated, while expression of Bcl-2 was enhanced. The ratio of Bcl-2/Bax approached to normal level, and there was significant difference with diabetes control mice (P <0.05, 0.01). The research indicated that OA might restrain the apoptosis of pancreas and kidney. By immunohistochemical analysis, the results implied that OA also ameliorated expression of Bax and Bcl-2 protein in liver, and restore the function of saccharide and lipid metabolizing, consequently, which avoid diabetic complication.
The mechanisms of OA on anti-diabetes were investigated by determining expression of some cytokines. The results indicated that PPARαlevel was up-regulated in pancreas and kidney of OA-treated diabetic mice after OA treatment for 8 weeks, but the difference was insignificant with control mice (P >0.05). The expression of PPARγmRNA was significantly up-regulated in OA-treated diabetic mice kidney and pancreas tissue (P >0.05). Westhern Blot determining indicated that the expression of PKB protein was increased significantly in OA-treated diabetic mice kidney (P <0.05). The present study provided further evidence in support of OA on stimulating secretion of insulin, amending the impairment on liver, kidney and pancreas of STZ-induced diabetic rats, hypoglycemic and hypolipidemic activity. The study also found that OA did not affect the expression of PKC in diabetic mice liver and kidney (P >0.05).
In the study, the effects of extract of Ligustrum lucidum Ait-oleanolic acid on diabetic rats were investigated systematically, and the action mechanisms were discussed on hormone, protein and molecule levels. It will provide a scientific proof for development of Ligustrum lucidum Ait as a suitable natural anti-diabetic agent.
引文
1 A.J. Scheen. From Obesity to Diabetes: Why, When and Who? Acta Clin. Belg, 2000,55:9-15
2 J.C. Seidell. Obesity, Insulin Resistance and Diabetes-a Worldwide Epidemic. Br. J. Nutr, 2000, 83: 5-8
3 M.C. Corti, J.M. Guralnik and M.E. Salive, et al. HDL Cholesterol Predicts Coronary Heart Disease Mortality in Older Persons. JAMA, 1995, 274:539-544
4 K. Ravi, B. Ramachandran, S. Subramanian. Protective Effect of Eugenia Jambolana Seed Kernel on Tissue Antioxidants in Streptozotocin Induced Diabetic Rats. Biological and Pharmaceutical Bulletin, 2004, 27:1212-1217
5 Y.J. Li, H.X. XU. Research Progress on Anti-diabetic Chinese Medicine. J. Chin. Med. Mat, 2006, 29(6): 621-624
6 A.J. Krentz, C. Bailey. Oral Antidiabetic Agents: Current Role in Type 2 Diabetes Mellitus. Drugs, 2005, 65(3):385
7 D.G. Maggs, M. Fineman, J. Kornstein. Pramlintide Reduces Postprandial Glucose Excursions when Added to Insulin Lispro in Subjects with Type 2 Diabetes: a Dose-timing Study. Diabetes Metab Res Rev, 2004, 20(1):55-60
8 T.W. Kurtz, M. Pravenec. Antidiabetic Mechanisms of Angiotensin-converting Enzyme Inhibitors and AngiotensinⅡReceptor Antagonists: Beyond the Rennin-angiotensin System. J Hypertens, 2004, 22(12):2253-2261
9 E. Toorisaka, M. Hashida, N. Kamiya. An Enteric-coated Dry Emulsion Formulation for Oral Insulin Delivery. Control Release, 2005, 107(1):91-96
10 J.F. Mouser. New Drugs for Management of Diabetes: Insulin Analogues, Inhaled Insulin, Pramllntide, and Novel Peptides. Nutr Clin Pract, 2004, 19(2):172-180
11 G. Camejo. PPAR Agonists in the Treatment of Insulin Resistance and Associated Arterial Disease. Int J CIin Pract Suppl, 2003, 3(134):36-44
12 G.L. Plosker, D.P. Figgitt. Repaglinide:a Pharmacoeconomic Review of Its Use in Type 2 Diabetes Mellitus. Pharmacoeconomics, 2004,22(6):389-411
13 W.A. Scherbaum. Unlocking the Opportunity of Tight Glycaemic Control. Diabetes Obes Metab,2005, 7(Suppl 1):S9-13
14 T.K. Mandal. Inhaled Insulin for Diabetes Mellitus. Am J Health Syst Pharm, 2005, 62(13): 1359-1364
15王天志,杜蕾蕾,柏川.金果榄研究进展.中药材,2002,25(4):292-294
16袁干军,田育望,王志琪.海南五层龙根乙醇提取物的降血糖作用.中药新药与临床药理, 2005, 16(4): 253-256
17王先远,金宏.苦瓜皂甙降血糖作用及其机制初探.氨基酸和生物资源, 2001,23(3):42-45
18 P.A. Hollander, P. Levy, M.S. Fineman. Pramlintide as an Adjunct to Insulin Therapy Improves Long-term Glyeemie and Weight Control in Patients with Type 2 Diabetes: a 1-year Randomized Controlled Trial. Diabetes Care, 2003,26(3):784 -790
19戴岳,杭秉茜,盂庆玉,等.女贞子的抗炎作用.中国中药杂志,1989,14(7):431-433
20彭小英,李晴宇,饶芳,等.复方女贞子降血糖作用的实验研究.上海实验动物科学, 2001,21(2): 103-105
21丁安伟,孟丽.女贞子多糖的免疫调节作用研究.中药药理与临床, 2001,17(2):11-12
22阮红.女贞子多糖免疫调节作用研究.中国中药杂志, 1999,24(11):693-696
23张鹏霞,赵蕾,王昭,等.女贞子血清药理对Hela细胞凋亡的影响.肿瘤, 2006,26(12):1136-1140
24张东方,黄炜,黄济群,等.齐墩果酸抗人肺癌细胞增殖、侵袭和诱导细胞凋亡的研究.肿瘤防治研究, 2003,30(3):180-183
25孟静岩.黄芪女贞子汤抗癌转移作用的离体实验研究.天津中医学院学报, 2001,20(3):32-34
26范秦鹤,侯雅玲,朱爱华,等.女贞子不同炮制品升高白细胞耐缺氧作用及毒性比较.西北药学杂志, 2004,19(1):20-22
27李磷,丁安伟,盂丽.女贞子多糖的免疫调节作用研究.中药药理与临床, 2001,17(2):11-12
28 E. Sezik, M. Aslan, E. Yesilada, et al. Hypoglycaemic Activity of Gentiana Olivieri and Isolation of the Active Constituent through Bioassay-directed Fractionation Techniques. Life Sci, 2005,76: 1223-1238
29 S.B. Sharma, A. Nasir, K.M. Prabhu, et al. Hypoglycaemic and Hypolipidemic Effect of Ethanolic Extract of Seeds of Eugenia Jambolana in Alloxan-induced Diabetic Rabbits. J.Ethnopharmacol, 2003,85:201-206
30 A.C. Maritim, R.A. Sanders, J.B. Watkins. Diabetes, Oxidative Stress and Antioxidants:a Review. J Bioehem Mol Toxicol, 2003,17(1):24-38
31 R.P. Robertson, J. Harmon, P.O. Tran. Glucose Toxicity in Beta-cells: Type 2 Diabetes, Good Radicals Gone Bad, and the Glutathione connection. Diabetes. 2003,52(3):581-587
32 M. Brownlee. The Pathobiology of Diabetic Complications: a Unifying Mechanism. Diabetes, 2005, 54:1615-1625
33 S. Idris, R.Gray. Donnelly. Protein Kinase C Activation: Isozyme-specific Effects on Metabolism and Cardiovascular Complications in Diabetes. Diabetologia, 2001,44:659-673
34 D. Koya, M. Haneda, H. Nakagawa. Amelioration of Accelerated Diabetic Mesangial Expansion by Treatment with a PKC-βInhibitor in Diabetic db/db mice, a Rodent Model for Type 2 Diabetes. FASEB J, 2000,14:439-447
35 P. Holander, D.G. Maggs, Jh. Ruggles. Effect of Pram1intide on Weight in Overweight and Obese Insulin-treated Type 2 Diabetes Patients. Obes Res, 2004,12(4):661-668
36 P. Ritch, C.M. Rudin, J.D. Bitran, et al. Phase II study of PKC-alpha antisense oligonucleotide aprinocarsen in combination with gemcitabine and carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer. 2006,52(2):173-180
37 B. Ahren, R. Gomis, E. Standl. Twelve-and 52-week Efficacy of the Dipeptidyl Peptidase-IV Inhibitor LAF237 in Metfonnin-treated Patients with Type 2 Diabetes. Diabetes Care, 2004,27 (12): 2874-2880
38 B. Ahren, G. Pacini, J.E. Foley. Improved Meal-related Beta-cell Function and Insulin Sensitivity by the Dipeptidy PeptidaseⅣInhibitor Vildagliptin in Metformin-treated Patients with Type 2 Diabetes over 1 Year. Diabetes Care, 2005,28(8):1936-1940
39 R.E. Routh, J.H. Johnson, K.J. McCarthy. Troglitazone Suppresses the Secretion of Type I Collagen by Mesangial Cells in Vitro. Kidney Int., 2002,61:1365-1376
40 S.P. Staal. Molecular Cloning of the Akt Oncogene and its Human Homologues Akt1 and AKT2: Amplification of AKT1 in a Primary Human Gastric Adenocarcinoma. Proc Natl Acad Sci USA, 1987,84:5034-5037
41 S.P. Staal, J.W. Hartley. Thymic Lymphoma Induction by the AKT8 Murine Retrovirus. J Exp Med, 1988,167:1259-1264
42 O.G. Koherman, J.B. Buse, M.S. Fineman,et al. Synthetic Exendin-4 (exenatide) Significantly Reduces Postprandial and Fasting Plasma Glucose in Subjects with Type 2 Diabetes. J Clin Endocrinol Metab, 2003,88(7):3082-3089
43 K. Raslova, M. Bogoev, I. Raz, et al. Insulin Detemir and Insulin Aspart: a Promising Basal-bolus Regimen for Type 2 Diabetes. Diabetes Res Clin Pract, 2004,66(2):193-20
44 C. Weyer, A. Gottlieb, D.D. Kim, et al. Pramlintide Reduces Postprandial Glucose Excursions when Added to Regular Insulin or Insulin Lispro in Subjects with Type 1 Diabetes: a Dose-timing Study. Diabates Care, 2003,26(11):3074-3079
45 H. Cho, J. Mu, J.K. Kim, et al. Insulin Resistance and a Diabetes Mellitus-like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKB beta). Science. 200l, 292:1728-1731
46 H. Cho, J.L. Thorvaldsen, Q. Chu, et al. Aktl/PKB Alpha is Required for Normal Growth but Dispens- able for Maintenance of Glucose Homeostasis in Mice. J Biol Chem, 2001,276: 38349- 38352
47 J.S. Elmendorf, J.E. Pessin. Insulin Signaling Regulating the Trafficking and Plasma Membrane Fusion of GLUT4-containing Intracellular Vesicles. Exp Cell Res, 1999, 253:55-62
48 E. Hajduch, D.R. Alessi, B.A. Hemmings, et al. Constitutive Activation of Protein Kinase B Alpha by Membrane Targeting Promotes Glucose and System A Amino Acid Transport, Protein Synthesis, and Inactivation of Glycogen Synthase Kinase 3 in L6 Muscle Cells. Diabetes,1998, 47:l006-1013
49 A. Barthel, S.T. Okino, J. Liao, et al. Regulation of GLUTl Gene Transcription by the Serine/threonine Kinase Akt1. J Biol Chem, 1999,274:20281-20286
50 N. Nakashima, P.M. Sharma, T. Imalmra, et al. The Tumor Suppressor PTEN Negatively Regulates Insulin Signaling in 3T3-L1 Adipocytes. J Biol Chem, 2000,275:12889-12895
51 V.A. Mosser, Y.H. Li, M.J. Quon, et al. PTEN does not Modulate GLUT 4 Translocation in Rat Adipose Cells Under Physiologlcal Conditions. Biochem Biophys Res Commun, 2001,88: 1011-1017
52 J. Deprez, D. Vertomrnen, D.R. Alessi, et al. Phosphorylation and Activation of Heart 6-phosphofructo-2-kinase by Prorein Kinase B and Other Protein Kinases of the Insulin Signa1ing Cascades. J Biol Chem, 1997,272:17269-17275
53 M.R. Pozuelo, M. Peggie, B.H. Wong, et al. Regulate Fructose-2, 6-bisphosphate Levels by Binding to PKB-phosphorylated Cardiac Fructose-2,6-bisphosphate Kinase/phosphatase. EMBO J, 2003, 22: 3514-3523
54 M.Z. Mehdi, A.K. Srivastava. Organo-vanadium Compounds are Potent Activators of the ProteinKinase B Signaling Pathway and Protein Tyrosine Phosphorylation: Mechanism of Insulinomimesis. Arch Biochem Biophys, 2005,440(2):158-164
55 I. Briaud, L.M. Dickson, M.K. Lingohr, et al. Insulin Receptor Substrate-2 Proteasomal Degradation Mediated by a Mammalian Target of Rapamycin (mTOR)-induced Negative Feedback Down-regulates Protein Kinase B-mediated Signaling Pathway in Beta-cells. J Biol Chem, 2005, 280(3): 2282-2293
56 E. Kurosaki, R. Nakano, A. Shimaya, et al. Differential Effects of YM440 a Hypoglycemic Agent on Binding to a Peroxisome Roliferator-activated Receptor Gamma and its Transactivation. Bio Chem Pharmacol, 2003,65:795-805
57 J.C. Fruchart, P. Durriez, B. Staels, et al. Peroxisome Proliferator-activated Receptor-alpha Activators Regulate Genes Governing Lipoprotein Metabolism. Vascular Inflammation and Atherosclerosis. Cur Opin Lipidol, 1999,10:245-257
58 R. Carroll, D.L. Severson. Peroxisome Proliforator-activated Receptor-alpha Ligands Inhibit Cardiac Lipoprotein Lipase Activity. Am J Physiol Heart Circ Physiol, 2001,281:H888-894
59 M.C. Sugden, K. Bulmer, G.F. Gibbons, et al. Peroxisome-proliferators-activated Receptor-alpha (PPARalpha) Deficiency Leads to Dysregulation of Hepatic Lipid and Carbohydrate Metabolism by Fatty Acids and Insulin. Biochem J, 2002,364:361-368
60 G. Boden. Fatty Acids and Insulin Resistance. Diabetes Care, 1996,19:394-395
61 L. Rebecca, Z.P. Shen, R. Melissah, et al. Long Term Treatment with Rosiglitazone and Metformin Reduces the Extent of, but not Prevent, Islet Amyloid Deposition in Mice Expressing the Gene for Human Islet Amyloid Polypetide.Diabetes, 2005,21(11):2235-2444
62 A.E. Butler, J. Janson, S. Bonner-Weir, et al.β-cell Deficit and Increasedβ-cell Apoptosis in Humans with Type 2 Diabetes. Diabetes, 2003,52:102-110
63 A.E. Butler, J. Jang, T. Gurlo, et al. Diabetes Due to a Progressive Defect in Beta-cell Mass in Rats Transgenic for Human Islet Amyloid Polypeptide (HIP Rat):a New Model for Type 2 Diabetes. Diabetes, 2004,53:1509-1516
64 M. Federici, M. Hribal, L. Perego, et al. High Glucose Causes Apoptosis in Cultured Human Pancreatic Islets of Langerhans. Diabetes, 2001,50:1290-1301
65 K. Maedler, P. Sergeev, F. Ris, et al. Glucose-induced beta-cell Production of IL-IβContributes to Glucotoxicity in Human Pancreas Poatic Islets.J Clin Invest, 2002,110:851-860
66边晓丽,王晓理,李金娜. 6种抗衰老中药清除自由基和抗脂质过氧化作用的影响.西北药学杂志, 2001, 16(2):68-69
67黄婉,杨耀芳.女贞子及其有效成分的药理及临床研究进展.现代中西医结合杂志, 2003,12(7):772-774
68马忠先,蒲家志,孙志勇.女贞子中提取齐墩果酸的实验方法.遵义医学院学报, 2003,26(5): 474-475
69 Y.Z. Deng, J. Henion, J.J. Li, et al. Chip-based Capillary Electrophoresis/Mass Spectrometry Determination of Carnitines in Human Urine. Anal Chem, 2001,73(3):639 -646
70 M. Trotta, F. Pattarino, T. Ignoni, et al. Stability of Drug-carrier Emulsions Containing Phosphatidyl Choline Mixtures. Eur J Pharm Biopharm, 2002,53(4):203-208
71 Y. Nishioka, H. Yoshino. Lymphatic Targeting with Nanoparticulate System. Adv Drug Del Rev, 2002,47:55-64
72 C. Jacobs, O. Kayser, R.H. Müller, et al. Nanosuspensions as a New Approach for the Formulation for the Poorly Soluble Drug Tarazepide. Int J Pharm, 2000,196:161-164
73 G.C. Liversidege, K.C. Cundy. Particle Size Reduction for Improvement of Oral Bioavailability of Hydrophobic Drugs. I. Absolute Oral Bioavailability of Nanocrystalline Ddanazole in Beagle Dogs. Int Pharm, 2005,127:91-97
74刘产明,杨洪元.不同粉碎度三七体外溶出试验.中成药, 1998,20(2):17-19
75杜晓敏,郭琪,何煜.中成药传统制剂与超细微粉制剂的药效学比较.中成药. 2000,2(4):307-309
76杜晓敏,刘璐,何煜.原生药材超细微粉制剂的药效学研究.中草药,1999,30(9):680
77吕文少,邱福军,王作明.炮制与超微粉碎对水蛭药效影响的初步实验研究.中国中药杂志, 2001,26(4): 241-244
78 L.M. Juliana, C.P. Roberto, J. Lima, et al. Oleanolic Acid, a Pentacyclic Triterpene Attenuates Capsaicin-induced Nociception in Mice: Possible Mechanisms. Pharmacological Res.,2006,54: 282-286
79 G.C. Liversideg, P. Conzentino. Drug Particle Size Reduction for Decreasing Gastric Irritancy and Enhancing Absorption of Naproxen in Rats. Int J Pharm, 2005,125:309-313
80 S. Wild, G. Roqlic, A. Green, et al. Global Prevalence of Diabetes Estimates for the Year 2000 and Projections for 2030.Diabetes Care, 2004,27(5):1047-1053
81 H. Mansour, A. Newairy, M. Yousef, et al. Biochemical Study on the Effects of Some EgyptianHerbs in Alloxan-induced Diabetic Rats. Toxicology, 2002,170:221-228
82 J. Ojewole. Antinociceptive, Anti-inflammatory and Antidiabetic Effects of Bryophyllum Pinnatum (Crassulaceae) Leaf Aqueous Extract. J Ethnopharmacol, 2005,99:13-19
83 P. Trinder. Determination of Blood Glucose Using an Oxidase-peroxidase System with a Non-carcinogenic Chromogen. J Clin Pathol, 1969,22:158-161
84 M. Bradford. A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-dye Binding. Anal Biochem, 1976,72:248-254
85 N. Takasu, I. Komiya, T Asawa, et al. Streptozocin and Alloxan-induced H202 Generation and DNA Fragmentation in Pancreatic Islets. Diabetes, 1991,40(9):1141-1145
86 A.R. Collins, M. Dusinska. Oxidation of Cellular DNA Measured with the Comet Aassay. Meth. Mol. Biol, 2002,6:147-159
87 T. Sakatani, T. Shirayama, Y. Suzaki, et al. The Association between Cholesterol and Mortality in Heart Failure. Comparison between Patients with and without Coronary Artery Disease. Int Heart J, 2005,46:619-629
88 S.B. Sharma, A. Nasir, K.M. Prabhu, et al. Hypoglycaemic and Hypolipidemic Effect of Ethanolic Extract of Seeds of Eugenia Jambolana in Alloxan-induced Diabetic Rabbits. J Ethnopharmacol, 2003,85:201-206
89 S. Aida. Alkaline Phosphatase Isoenzyme Activities in Rheumatoid Arthritis: Hepatobiliary Enzyme Dissociation and Relation to Disease Activity. Ann Rheum Dis. J, 1993,52:511-516
90 D. Rajdl, J. Raceki, A. Steinerova, et al. Markers of Oxidative Stress in Diabetic Mothers and Their Infants during Delivery. Physiol Res, 2005,54:429-436
91 J. V. Ovska, J. Racek, F. Stozicky, et al. Parameters of Oxidative Stress in Children with Type 1 Diabetes Mellitus and Their Relatives. J Diabetes Complications, 2003,17:7-10
92 J.V. Ovská, J. Racek, R. ?tetina, et al. Aspects of Oxidative Stress in Children with Type 1 Diabetes Mellitus. Bio. Pharma, 2004,58:539-545
93 N. Aksoy, H. Vural , T. Sabuncu, et al. Effects of Melatonin on Oxidative-antioxidative Status of Tissues in Streptozotocin-induced Diabetic Rats. Cell Biochem Funct, 2003,21:121-125
94 F.L. Hu , H.R. Hepburn, H. Xuan, et al. Effects of Propolis on Blood Glucose, Blood Lipid and Free Radicals in Rats with Diabetes Mellitus. Pharmacol Res, 2005,51:147-152.
95 M. Aragno, R. Mastrocola, M.G. Catalano, et al. Oxidative Stress Impairs Skeletal Muscle Repairin Diabetic Rats. Diabetes, 2004,53:1082-1088
96 Y. Tanaka, P.O. Tran, J. Harmon, et al. A Role for Glutathione Peroxidase in Protecting PancreaticβCells against Oxidative Stress in a Model of Glucose Toxicity. Proc. Natl. Acad. Sci. U. S. A, 2002,99:12363-12368
97 D.A. Slatter, C.H. Bolton, A.J. Bailey. The Importance of Lipid-derived Malondialdehyde in Diabetes Mellitus. Diabetologia, 2000,43:550-557
98 O. Ozsoy-Sacan, O. Karabulut-Bulan , S. Bolkent, et al. Effects of Chard (Beta vulgaris L. var cicla) on the Liver of the Diabetic Rats: a Morphological and Biochemical Study. Biosci Biotechnol Biochem, 2004,68:1640-1648
99 R.P. Robertson. Chronic Oxidative Stress as a Central Mechanism for Glucose Toxicity in Pancreatic Islet Bbeta Cells in Diabetes. J Biol Chem, 2004,279:42351-42354
100 M. Aragno, R. Mastrocola, M.G. Catalano, et al. Oxidative Stress Impairs Skeletal Muscle Repair in Diabetic Rats. Diabetes, 2004,53:1082-1088
101 N.P. Singh, M.T. McCoy, R.R. Tice, et al. A Simple Technique for Quantitation of Low Levels of DNA Damage in Individual Cells. Exp. Cell Res., 1988,175:184-191.
102 M.H. Fraser, A. Cuerrier, P.S. Haddad, et al. Medicinal plants of Cree communities (Québec, Canada): antioxidant activity of plants used to treat type 2 diabetes symptoms. Can J Physiol Pharmacol. 2007,85(11):1200-1214
103 K. Ravi, B. Ramachandran, S. Subramanian. Protective Effect of Eugenia Jambolana Seed Kernel on Tissue Antioxidants in Streptozotocin Induced Diabetic Rats. Biol Pharma Bulletin, 2004,27: 1212-1217
104 M. Latha, L. Pari. Modulatory Effect of Scoparia Dulcis in Oxidative Stress-induced Lipid Peroxidation in Streptozocin Diabetic Rats. J. Med. Food, 2003,6:379-386
105 H.G. Nijs, J.K. Radder, M. Foolich, et al. Increased Insulin Action and Clearance in Hyperthyroid Newly Diagnosed IDDM Patient. Restoration to Normal with Antithyroid Treatment. Diabetes Care, 1989,12:319-324
106 J. Machackova, J. Barta, N.S. Dhalla. Molecular Defects in Cardiac Myfibrillar Proteins Due to Thyroid Hormone Imbalance and Diabeties. Can. J. Physiol. Pharmacol., 2005,83:1071-1091
107 S.W. Moon, J.R. Hahm, G.W. Lee, et al. A Case of Hyperglycemic Hyperosmolar State Associated with Graves' Hyperthyroidism : A Case Report J. Korean Med Sci, 2006,21:765-767
108 A. Bhattacharyya, P.G. Wile. Diabetic Ketocidosis Precipitated by Thyrotoxicosis. Postgrad Med J, 1999,75:291-292
109 S.B. Sharma, A. Nasir, K.M. Prabhu, et al. Hypoglycaemic and Hypolipidemic Effect of Ethanolic Extract of Seeds of Eugenia Jambolana in Alloxan-induced Diabetic Rabbits. J. Ethnopharmacol, 2003,85:201-206
110 G. Assmann, P. Cullen, J. Erbey, et al. Plasma Sitosterol Elevations are Associated with an Increased Incidence of Coronary Events in Men: Results of a Nested Case-control Analysis of the Prospective Cardiovascular Munster (PROCAM) Study. Nutr Metab Cardiovasc Dia, 2006, 16:13-21
111 M. Antonio, J.R. Gotto. Low High-density Lipoprotein Cholesterol as a Risk Factor in Coronary Heart Disease. Circulation, 2001,103:2213-2218
112 M.R. Taskinen. Diabetic dyslipidemia. Atherosclerosis, 2002,3:47-51
113 H.B. Rubins, S.J. Robins, D. Collins, et al. Department of Veterans Affairs HDL Intervention Trial Study Group. Distribution of Lipids in 8500 Men with Coronary Artery Disease. Am J Cardiol, 1995,75:1196-1201
114 E.J. Whitney, R.A. Krasuski, B.E. Personius, et al. A Randomized Trial of a Strategy for Increasing High Density Lipoprotein Cholesterol Levels: Effects on Progression of Coronary Heart Disease and Clinical Events. Ann Intern Med, 2005,142:45-104
115 S.S. Pertsov. Effect of Melatonin on the Thymus, Adrenal Glands, and Spleen in Rats during Acute Stress. Bull Exp Biol Med, 2006,141:292-295
116 E. Sezik, M. Aslan, E. Yesilada, et al. Hypoglycaemic Activity of Gentiana Olivieri and Isolation of the Active Constituent through Bioassay-directed Fractionation Techniques. Life Sci, 2005,76: 1223-1238
117 M. Benwahhoud, H. Jouad, M. Eddouks, et al. Hypoglycemic Effect of Suaeda Fruticosa in Streptozotocin Induced Diabetic Rats. J Ethnopharmacol, 2001,76:35-38
118 G.D. Dimitriadis, S.A. Raptis. Thyroid Hormone Excess and Glucose Intolerance. Exp Clin Endocrinol Diabetes, 2001,2:225-239
119 Bhattacharyya, P.G. Wiles. Diabetic Ketoacidosis Precipitated by Thyrotoxicosis. Postgrad. Med J, 1999,75:291-292
120 Q.H. Fan, Y.L. Hou, A.H. Zhu, et al. Comparising the Effects of Different Preparations ofFructus Ligustri Lucid on Enhancing White Blood Cell and Anti-hypoxia Ability. Northwest Pharmaceutical J, 2004,19:20-22
121 Z. Bacová, M. Orecná, R. Hafko, et al. Cell Swelling-induced Signaling for Insulin Secretion Bypasses Steps Involving G Proteins and PLA2 and is N-ethylmaleimide Insensitive. Cell Physiol Biochem, 2007,20(5):387-396
122 H. Takahashi, Y. Kurose, M. Sakaida, et al. Ghrelin Differentially Modulates Glucose-induced Insulin Secretion according to Feeding Status in Sheep. J Endocrinol, 2007,194(3):621-625
123 Andrade-Cetto, H. Wiedenfeld. Hypoglycemic Effect of Cecropia Obtusifolia on Streptozotocin Diabetic Rats. J Ethnopharmacol, 2001,78:145-149
124 C. Ricci, V. Pastukh, M. Mozaffari, et al. Insulin Withdrawal Induces Apoptosis via a Free Radical-mediated Mechanism. Can J Physiol Pharmacol., 2007,85(3-4):455-464
125 A. Ortiz, F.N. Ziyadeh, G.E. Neilson. Expression of Apoptosis Regulatory Genes in Renal Proximal Tubular Epithelial Cells Exposed to High Ambient Glucose and in Diabetic Kidneys. J Invest Med, 1997,45:50-56
126 D. Kumar, J. Zimpelmann, S. Robertson, et al. Tubular and Interstitial Cell Apoptosis in the Streptozotocin-diabetic Rat Kidney. Nephron Exp Nephrol, 2004,96(3):77-88
127 J. Chen, F.M. Couto, A.H. Minn, et al. Exenatide Inhibits Beta-cell Apoptosis by Decreasing Thioredoxin-interacting Protein. Biochem Biophys Res Commun, 2006,346(3):1067-1074
128薛耀明,罗仁,朱波,等.六味地黄丸对OLETF大鼠胰腺凋亡相关基因Bcl-2和Bax表达的影响.中西医结合学报,2005,3(6):455-458
129 Q. Huang, S. Bu, Y. Yu, et al. Diazoxide Prevents Diabetes through Inhibiting Pancreatic Beta- cells from Apoptosis via Bcl-2/Bax Rate and p38-beta Mitogen-activated Protein Kinase. J Endocrinology, 2007,148(1):81-91
130 W.H. Kim, J.W. Lee, Y.H. Suh, et al. Exposure to Chronic High Glucose Induces Beta-cell Apoptosis through Decreased Interaction of Glucokinase with Mitochondria: Downregulation of Glucokinase in Pancreatic Beta-cells. Diabetes, 2005,54(9):2602-2611
131 R.W. Vander Meer, M. Diamant, J.J. Westenberg, et al. Magnetic Resonance Assessment of Aortic Pulse Wave Velocity, Aortic Distensibility, and Cardiac Function in Uncomplicated Type 2 Diabetes Mellitus. J Cardiovasc Magn Reson, 2007,9(4):645-651
132 H. Li, S. Télémaque, R.E. Miller, et al. High Glucose Inhibits Apoptosis Induced by SerumDeprivation in Vascular Smooth Muscle Cells via Upregulation of Bcl-2 and Bcl-xl. Diabetes,2005, 54(2):540-545
133 Q. Huang, S. Bu, Y. Yu, et al. Diazoxide prevents diabetes through inhibiting pancreatic beta-cells from apoptosis via Bcl-2/Bax rate and p38-beta mitogen-activated protein kinase. Endocrinology. 2007,148(1):81-91
134 Z.G. Li, M. Britton, A.A. Sima, et al. Diabetes enhances apoptosis induced by cerebral ischemia. Life Sci, 2004,76(3):249-262
135 S. Srinivasan, M. Stevens, J.W. Wiley. Diabetic Peripheral Neuropathr Evidence for Apoptosis and Associated Mitochondrial Dysfunction. Diabetes, 2000,49:1932-1938
136 L.M. Blanco, A. Villa, M. Ortego. 3-Hydroxy-3-methyl-glutaryl Coenzyme A Reduetase Inhibitors, Atorvastatin and Simvastatin, Induce Apoptosis of Vascular Smooth Muscle Cells by Downregulation of Bcl-2 expression and Rho Aprenylation. Atherosclerosis, 2002,161(1):17-26
137 H. Cho, J. Mu, J.K. Kim, et al. Insulin Resistance and a Diabetes Mellitus-like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKB beta). Science, 200l,292:1728-1731
138 D. Koya, M.R. Jirousek, Y.W. Lin et al. Characterization of Protein Kinase C-βIsoform Activation on the Gene Expression of Transforming Growth Factor-β, Extracellular Matrix Components, and Prostanoids in the Glomeruli of Diabetic Rats. J Clin Invest, 1997,100:115-125
139 E.J. Tisdale. Rab2 Purification and Interaction with Pprotein Kinase C Iota/lambda and Glyceraldehyde-3-phosphate Dehydrogenase. Methods Enzymol, 2005,403:381-391
140 N. Takahashia, T. Kawada, T. Gotoa, et al. Dual Action of Isoprenols from Herbal Medicines on both PPARαand PPARγin 3T3-L1 Adipocytes and HepG2 Hepatocytes. FEBS Letters, 2002, 514:315-322
141 L. Malerod, M. Sporstol, L.K. Juvet et al. Hepatic Scavenger Receptor Class B. Type I is Stimulated by Peroxisome Proliferator Activated Receptor Gamma and Hepatocyte Nuclear Factor 4 Alpha. Biochem Biophys Res Commun, 2003,305(3):557-565
142 N. Strakova , J. Ehrmann , J. Bartos, et al. Peroxisome Proliferator-activated Receptors (PPAR) Agonists Affect Cell Viability, Apoptosis and Expression of Cell Cycle Related Proteins in Cell Lines of Glial Brain Tumors. Neoplasma, 2005,52(2):126-136
143 M.Y. Park, K.S. Lee, M.K. Sung, et al.. Effects of Dietary Mulberry, Korean Red Ginseng, and Banana on Glucose Homeostasis in Relation to PPAR-a, PPAR-γ, and LPL mRNA Expressions.Life Sciences, 2005,77: 3344-3354
144 O. Ludovico, F. Pellegrini, R.D. Paola, et al. Heterogeneous Effect of Peroxisome Proliferator -activated Receptor Gamma2 Ala12 Variant on Type 2 Diabetes Risk. Obesity (Silver Spring), 2007,15(5):1076-1081
145 L. Gelman, J.N. Feige, B. Desvergne. Molecular Basis of Selective PPAR gamma Modulation for the Treatment of Type 2 Diabetes. Biochim Biophys Acta, 2007, 1771(8):1094-1107
146 R. Meshkani, M. Taghikhani, B. Larijani, et al. Pro12Ala Polymorphism of the Peroxisome Proliferator-activated Receptor-gamma2 (PPARgamma-2) Gene is Associated with Greater Insulin Sensitivity and Decreased Risk of Type 2 Diabetes in an Iranian Population. Clin Chem Lab Med, 2007,45(4):477-482
147 S. Samuelsson, S. Johansson, S. Halldórsdóttir, et al. Food does not Affect the Pharmacokinetics
148 B. Fagerberg, S. Edwards, T. Halmos, et al. Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia. 2005, 48(9):1716-1725.
149 H.J. Atherton, N.J. Bailey, W. Zhang, et al. A Combined 1H-NMR Spectroscopy- and Mass Spectrometry-based Metabolomic Study of the PPAR-alpha Null Mutant Mouse Defines Profound Systemic Changes in Metabolism Linked to the Metabolic Syndrome. Physiol Genomics, 2006,27(2):178-186
150 P. Gervois, J.C. Fruchart, B. Staels. Inflammation, Dyslipidaemia, Diabetes and PPARs: Pharmacological Interest of Dual PPARalpha and PPARgamma Agonists. Int J Clin Pract Suppl., 2004,(143):22-29
151 B.C. Lee, H.J. Lee, J.H. Chung. Peroxisome Proliferator-activated Receptor-gamma 2 Pro12Ala Polymorphism is Associated with Reduced Risk for Ischemic Stroke with Type 2 Diabetes. Neurosci Lett, 2006,410(2):141-145
152 M. Scarsi, M. Podvinec, A. Roth, et al. Sulfonylureas and Glinides Exhibit Peroxisome Proliferators-activated Receptor Gamma Activity: A Combined Virtual Screening and Biological Assay Approach. Mol Pharmacol, 2007,71(2):398-406
153 J.S. Moyers, T.L. Shiyanova, F. Mehrbod, et al. Molecular Determinants of FGF-21 Activity-synergy and Cross-talk with PPARgamma Signaling. J Cell Physiol, 2007, 210(1):1-6
154 C.B. Patel, J.A. De Lemos, K.L. Wyne, et al Thiazolidinediones and Risk for Atherosclerosis: Pleiotropic Effects of PPAR Gamma Agonism. Diab Vasc Dis Res, 2006,3(2):65-71.
155 A. Munteanu, M. Taddei, I. Tamburini, et al.Antagonistic Effects of Oxidized Low Density Lipoprotein and-Tocopherol on CD36 Scavenger Receptor Expression in Monocytes Involvement of Protein Kinase B and Peroxisome Proliferator-Activated Receptor. J Biological Chemistry, 2006,281(10):6489-6497
156 Z.F. Yang, J.L. Yi, X. Li. et al. Correlation between Loss of PTEN Expression and PKB/AKT Phosph0rylati0n in Hepatocellular Carcinoma. J Huazhong University Science and Technology, 2005, 25(1):45-47.
157 A. Mora, C. Lipina, F. Tronche, et al. Deficiency of PDK1 in Liver Results in Glucose Intolerance, Impairment of Insulin-regulated Gene Expression and Liver Failure. Biochem J. 2005,385(Pt 3):639-648
158 F.S. Walton, A.W. Harmon, D.S. Paul, et al. Inhibition of Insulin-dependent Glucose Uptake by Trivalent Arsenicals: Possible Mechanism of Arsenic-induced Diabetes. Toxicol Appl Pharmacol, 2004,198(3):424-33
159 V. Sancho, M.V. Trigo, N. Gonzalez, et al. Effects of Glucagon-like Peptide-1 and Exendins on Kinase Activity, Glucose Transport and Lipid Metabolism in Adipocytes from Normal and Type-2 Diabetic Rats. J Mol Endocrinol, 2005,35(1):27-38
160 D.D. Sarbasaov, D.A. Guerfin, S.M. Ali. Phosphorylation and Regulation of Akt/PKB by the Rrictor—mTOR Complex. Science, 2005, 307(5712):1098-1101
161 E.A. Schwartz , P.D. Reaven. Molecular and signaling mechanisms of atherosclerosis in insulin resistance. Endocrinol Metab Clin North Am. 2006, 35(3):525-549
2 J.C. Seidell. Obesity, Insulin Resistance and Diabetes-a Worldwide Epidemic. Br. J. Nutr, 2000, 83: 5-8
3 M.C. Corti, J.M. Guralnik and M.E. Salive, et al. HDL Cholesterol Predicts Coronary Heart Disease Mortality in Older Persons. JAMA, 1995, 274:539-544
4 K. Ravi, B. Ramachandran, S. Subramanian. Protective Effect of Eugenia Jambolana Seed Kernel on Tissue Antioxidants in Streptozotocin Induced Diabetic Rats. Biological and Pharmaceutical Bulletin, 2004, 27:1212-1217
5 Y.J. Li, H.X. XU. Research Progress on Anti-diabetic Chinese Medicine. J. Chin. Med. Mat, 2006, 29(6): 621-624
6 A.J. Krentz, C. Bailey. Oral Antidiabetic Agents: Current Role in Type 2 Diabetes Mellitus. Drugs, 2005, 65(3):385
7 D.G. Maggs, M. Fineman, J. Kornstein. Pramlintide Reduces Postprandial Glucose Excursions when Added to Insulin Lispro in Subjects with Type 2 Diabetes: a Dose-timing Study. Diabetes Metab Res Rev, 2004, 20(1):55-60
8 T.W. Kurtz, M. Pravenec. Antidiabetic Mechanisms of Angiotensin-converting Enzyme Inhibitors and AngiotensinⅡReceptor Antagonists: Beyond the Rennin-angiotensin System. J Hypertens, 2004, 22(12):2253-2261
9 E. Toorisaka, M. Hashida, N. Kamiya. An Enteric-coated Dry Emulsion Formulation for Oral Insulin Delivery. Control Release, 2005, 107(1):91-96
10 J.F. Mouser. New Drugs for Management of Diabetes: Insulin Analogues, Inhaled Insulin, Pramllntide, and Novel Peptides. Nutr Clin Pract, 2004, 19(2):172-180
11 G. Camejo. PPAR Agonists in the Treatment of Insulin Resistance and Associated Arterial Disease. Int J CIin Pract Suppl, 2003, 3(134):36-44
12 G.L. Plosker, D.P. Figgitt. Repaglinide:a Pharmacoeconomic Review of Its Use in Type 2 Diabetes Mellitus. Pharmacoeconomics, 2004,22(6):389-411
13 W.A. Scherbaum. Unlocking the Opportunity of Tight Glycaemic Control. Diabetes Obes Metab,2005, 7(Suppl 1):S9-13
14 T.K. Mandal. Inhaled Insulin for Diabetes Mellitus. Am J Health Syst Pharm, 2005, 62(13): 1359-1364
15王天志,杜蕾蕾,柏川.金果榄研究进展.中药材,2002,25(4):292-294
16袁干军,田育望,王志琪.海南五层龙根乙醇提取物的降血糖作用.中药新药与临床药理, 2005, 16(4): 253-256
17王先远,金宏.苦瓜皂甙降血糖作用及其机制初探.氨基酸和生物资源, 2001,23(3):42-45
18 P.A. Hollander, P. Levy, M.S. Fineman. Pramlintide as an Adjunct to Insulin Therapy Improves Long-term Glyeemie and Weight Control in Patients with Type 2 Diabetes: a 1-year Randomized Controlled Trial. Diabetes Care, 2003,26(3):784 -790
19戴岳,杭秉茜,盂庆玉,等.女贞子的抗炎作用.中国中药杂志,1989,14(7):431-433
20彭小英,李晴宇,饶芳,等.复方女贞子降血糖作用的实验研究.上海实验动物科学, 2001,21(2): 103-105
21丁安伟,孟丽.女贞子多糖的免疫调节作用研究.中药药理与临床, 2001,17(2):11-12
22阮红.女贞子多糖免疫调节作用研究.中国中药杂志, 1999,24(11):693-696
23张鹏霞,赵蕾,王昭,等.女贞子血清药理对Hela细胞凋亡的影响.肿瘤, 2006,26(12):1136-1140
24张东方,黄炜,黄济群,等.齐墩果酸抗人肺癌细胞增殖、侵袭和诱导细胞凋亡的研究.肿瘤防治研究, 2003,30(3):180-183
25孟静岩.黄芪女贞子汤抗癌转移作用的离体实验研究.天津中医学院学报, 2001,20(3):32-34
26范秦鹤,侯雅玲,朱爱华,等.女贞子不同炮制品升高白细胞耐缺氧作用及毒性比较.西北药学杂志, 2004,19(1):20-22
27李磷,丁安伟,盂丽.女贞子多糖的免疫调节作用研究.中药药理与临床, 2001,17(2):11-12
28 E. Sezik, M. Aslan, E. Yesilada, et al. Hypoglycaemic Activity of Gentiana Olivieri and Isolation of the Active Constituent through Bioassay-directed Fractionation Techniques. Life Sci, 2005,76: 1223-1238
29 S.B. Sharma, A. Nasir, K.M. Prabhu, et al. Hypoglycaemic and Hypolipidemic Effect of Ethanolic Extract of Seeds of Eugenia Jambolana in Alloxan-induced Diabetic Rabbits. J.Ethnopharmacol, 2003,85:201-206
30 A.C. Maritim, R.A. Sanders, J.B. Watkins. Diabetes, Oxidative Stress and Antioxidants:a Review. J Bioehem Mol Toxicol, 2003,17(1):24-38
31 R.P. Robertson, J. Harmon, P.O. Tran. Glucose Toxicity in Beta-cells: Type 2 Diabetes, Good Radicals Gone Bad, and the Glutathione connection. Diabetes. 2003,52(3):581-587
32 M. Brownlee. The Pathobiology of Diabetic Complications: a Unifying Mechanism. Diabetes, 2005, 54:1615-1625
33 S. Idris, R.Gray. Donnelly. Protein Kinase C Activation: Isozyme-specific Effects on Metabolism and Cardiovascular Complications in Diabetes. Diabetologia, 2001,44:659-673
34 D. Koya, M. Haneda, H. Nakagawa. Amelioration of Accelerated Diabetic Mesangial Expansion by Treatment with a PKC-βInhibitor in Diabetic db/db mice, a Rodent Model for Type 2 Diabetes. FASEB J, 2000,14:439-447
35 P. Holander, D.G. Maggs, Jh. Ruggles. Effect of Pram1intide on Weight in Overweight and Obese Insulin-treated Type 2 Diabetes Patients. Obes Res, 2004,12(4):661-668
36 P. Ritch, C.M. Rudin, J.D. Bitran, et al. Phase II study of PKC-alpha antisense oligonucleotide aprinocarsen in combination with gemcitabine and carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer. 2006,52(2):173-180
37 B. Ahren, R. Gomis, E. Standl. Twelve-and 52-week Efficacy of the Dipeptidyl Peptidase-IV Inhibitor LAF237 in Metfonnin-treated Patients with Type 2 Diabetes. Diabetes Care, 2004,27 (12): 2874-2880
38 B. Ahren, G. Pacini, J.E. Foley. Improved Meal-related Beta-cell Function and Insulin Sensitivity by the Dipeptidy PeptidaseⅣInhibitor Vildagliptin in Metformin-treated Patients with Type 2 Diabetes over 1 Year. Diabetes Care, 2005,28(8):1936-1940
39 R.E. Routh, J.H. Johnson, K.J. McCarthy. Troglitazone Suppresses the Secretion of Type I Collagen by Mesangial Cells in Vitro. Kidney Int., 2002,61:1365-1376
40 S.P. Staal. Molecular Cloning of the Akt Oncogene and its Human Homologues Akt1 and AKT2: Amplification of AKT1 in a Primary Human Gastric Adenocarcinoma. Proc Natl Acad Sci USA, 1987,84:5034-5037
41 S.P. Staal, J.W. Hartley. Thymic Lymphoma Induction by the AKT8 Murine Retrovirus. J Exp Med, 1988,167:1259-1264
42 O.G. Koherman, J.B. Buse, M.S. Fineman,et al. Synthetic Exendin-4 (exenatide) Significantly Reduces Postprandial and Fasting Plasma Glucose in Subjects with Type 2 Diabetes. J Clin Endocrinol Metab, 2003,88(7):3082-3089
43 K. Raslova, M. Bogoev, I. Raz, et al. Insulin Detemir and Insulin Aspart: a Promising Basal-bolus Regimen for Type 2 Diabetes. Diabetes Res Clin Pract, 2004,66(2):193-20
44 C. Weyer, A. Gottlieb, D.D. Kim, et al. Pramlintide Reduces Postprandial Glucose Excursions when Added to Regular Insulin or Insulin Lispro in Subjects with Type 1 Diabetes: a Dose-timing Study. Diabates Care, 2003,26(11):3074-3079
45 H. Cho, J. Mu, J.K. Kim, et al. Insulin Resistance and a Diabetes Mellitus-like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKB beta). Science. 200l, 292:1728-1731
46 H. Cho, J.L. Thorvaldsen, Q. Chu, et al. Aktl/PKB Alpha is Required for Normal Growth but Dispens- able for Maintenance of Glucose Homeostasis in Mice. J Biol Chem, 2001,276: 38349- 38352
47 J.S. Elmendorf, J.E. Pessin. Insulin Signaling Regulating the Trafficking and Plasma Membrane Fusion of GLUT4-containing Intracellular Vesicles. Exp Cell Res, 1999, 253:55-62
48 E. Hajduch, D.R. Alessi, B.A. Hemmings, et al. Constitutive Activation of Protein Kinase B Alpha by Membrane Targeting Promotes Glucose and System A Amino Acid Transport, Protein Synthesis, and Inactivation of Glycogen Synthase Kinase 3 in L6 Muscle Cells. Diabetes,1998, 47:l006-1013
49 A. Barthel, S.T. Okino, J. Liao, et al. Regulation of GLUTl Gene Transcription by the Serine/threonine Kinase Akt1. J Biol Chem, 1999,274:20281-20286
50 N. Nakashima, P.M. Sharma, T. Imalmra, et al. The Tumor Suppressor PTEN Negatively Regulates Insulin Signaling in 3T3-L1 Adipocytes. J Biol Chem, 2000,275:12889-12895
51 V.A. Mosser, Y.H. Li, M.J. Quon, et al. PTEN does not Modulate GLUT 4 Translocation in Rat Adipose Cells Under Physiologlcal Conditions. Biochem Biophys Res Commun, 2001,88: 1011-1017
52 J. Deprez, D. Vertomrnen, D.R. Alessi, et al. Phosphorylation and Activation of Heart 6-phosphofructo-2-kinase by Prorein Kinase B and Other Protein Kinases of the Insulin Signa1ing Cascades. J Biol Chem, 1997,272:17269-17275
53 M.R. Pozuelo, M. Peggie, B.H. Wong, et al. Regulate Fructose-2, 6-bisphosphate Levels by Binding to PKB-phosphorylated Cardiac Fructose-2,6-bisphosphate Kinase/phosphatase. EMBO J, 2003, 22: 3514-3523
54 M.Z. Mehdi, A.K. Srivastava. Organo-vanadium Compounds are Potent Activators of the ProteinKinase B Signaling Pathway and Protein Tyrosine Phosphorylation: Mechanism of Insulinomimesis. Arch Biochem Biophys, 2005,440(2):158-164
55 I. Briaud, L.M. Dickson, M.K. Lingohr, et al. Insulin Receptor Substrate-2 Proteasomal Degradation Mediated by a Mammalian Target of Rapamycin (mTOR)-induced Negative Feedback Down-regulates Protein Kinase B-mediated Signaling Pathway in Beta-cells. J Biol Chem, 2005, 280(3): 2282-2293
56 E. Kurosaki, R. Nakano, A. Shimaya, et al. Differential Effects of YM440 a Hypoglycemic Agent on Binding to a Peroxisome Roliferator-activated Receptor Gamma and its Transactivation. Bio Chem Pharmacol, 2003,65:795-805
57 J.C. Fruchart, P. Durriez, B. Staels, et al. Peroxisome Proliferator-activated Receptor-alpha Activators Regulate Genes Governing Lipoprotein Metabolism. Vascular Inflammation and Atherosclerosis. Cur Opin Lipidol, 1999,10:245-257
58 R. Carroll, D.L. Severson. Peroxisome Proliforator-activated Receptor-alpha Ligands Inhibit Cardiac Lipoprotein Lipase Activity. Am J Physiol Heart Circ Physiol, 2001,281:H888-894
59 M.C. Sugden, K. Bulmer, G.F. Gibbons, et al. Peroxisome-proliferators-activated Receptor-alpha (PPARalpha) Deficiency Leads to Dysregulation of Hepatic Lipid and Carbohydrate Metabolism by Fatty Acids and Insulin. Biochem J, 2002,364:361-368
60 G. Boden. Fatty Acids and Insulin Resistance. Diabetes Care, 1996,19:394-395
61 L. Rebecca, Z.P. Shen, R. Melissah, et al. Long Term Treatment with Rosiglitazone and Metformin Reduces the Extent of, but not Prevent, Islet Amyloid Deposition in Mice Expressing the Gene for Human Islet Amyloid Polypetide.Diabetes, 2005,21(11):2235-2444
62 A.E. Butler, J. Janson, S. Bonner-Weir, et al.β-cell Deficit and Increasedβ-cell Apoptosis in Humans with Type 2 Diabetes. Diabetes, 2003,52:102-110
63 A.E. Butler, J. Jang, T. Gurlo, et al. Diabetes Due to a Progressive Defect in Beta-cell Mass in Rats Transgenic for Human Islet Amyloid Polypeptide (HIP Rat):a New Model for Type 2 Diabetes. Diabetes, 2004,53:1509-1516
64 M. Federici, M. Hribal, L. Perego, et al. High Glucose Causes Apoptosis in Cultured Human Pancreatic Islets of Langerhans. Diabetes, 2001,50:1290-1301
65 K. Maedler, P. Sergeev, F. Ris, et al. Glucose-induced beta-cell Production of IL-IβContributes to Glucotoxicity in Human Pancreas Poatic Islets.J Clin Invest, 2002,110:851-860
66边晓丽,王晓理,李金娜. 6种抗衰老中药清除自由基和抗脂质过氧化作用的影响.西北药学杂志, 2001, 16(2):68-69
67黄婉,杨耀芳.女贞子及其有效成分的药理及临床研究进展.现代中西医结合杂志, 2003,12(7):772-774
68马忠先,蒲家志,孙志勇.女贞子中提取齐墩果酸的实验方法.遵义医学院学报, 2003,26(5): 474-475
69 Y.Z. Deng, J. Henion, J.J. Li, et al. Chip-based Capillary Electrophoresis/Mass Spectrometry Determination of Carnitines in Human Urine. Anal Chem, 2001,73(3):639 -646
70 M. Trotta, F. Pattarino, T. Ignoni, et al. Stability of Drug-carrier Emulsions Containing Phosphatidyl Choline Mixtures. Eur J Pharm Biopharm, 2002,53(4):203-208
71 Y. Nishioka, H. Yoshino. Lymphatic Targeting with Nanoparticulate System. Adv Drug Del Rev, 2002,47:55-64
72 C. Jacobs, O. Kayser, R.H. Müller, et al. Nanosuspensions as a New Approach for the Formulation for the Poorly Soluble Drug Tarazepide. Int J Pharm, 2000,196:161-164
73 G.C. Liversidege, K.C. Cundy. Particle Size Reduction for Improvement of Oral Bioavailability of Hydrophobic Drugs. I. Absolute Oral Bioavailability of Nanocrystalline Ddanazole in Beagle Dogs. Int Pharm, 2005,127:91-97
74刘产明,杨洪元.不同粉碎度三七体外溶出试验.中成药, 1998,20(2):17-19
75杜晓敏,郭琪,何煜.中成药传统制剂与超细微粉制剂的药效学比较.中成药. 2000,2(4):307-309
76杜晓敏,刘璐,何煜.原生药材超细微粉制剂的药效学研究.中草药,1999,30(9):680
77吕文少,邱福军,王作明.炮制与超微粉碎对水蛭药效影响的初步实验研究.中国中药杂志, 2001,26(4): 241-244
78 L.M. Juliana, C.P. Roberto, J. Lima, et al. Oleanolic Acid, a Pentacyclic Triterpene Attenuates Capsaicin-induced Nociception in Mice: Possible Mechanisms. Pharmacological Res.,2006,54: 282-286
79 G.C. Liversideg, P. Conzentino. Drug Particle Size Reduction for Decreasing Gastric Irritancy and Enhancing Absorption of Naproxen in Rats. Int J Pharm, 2005,125:309-313
80 S. Wild, G. Roqlic, A. Green, et al. Global Prevalence of Diabetes Estimates for the Year 2000 and Projections for 2030.Diabetes Care, 2004,27(5):1047-1053
81 H. Mansour, A. Newairy, M. Yousef, et al. Biochemical Study on the Effects of Some EgyptianHerbs in Alloxan-induced Diabetic Rats. Toxicology, 2002,170:221-228
82 J. Ojewole. Antinociceptive, Anti-inflammatory and Antidiabetic Effects of Bryophyllum Pinnatum (Crassulaceae) Leaf Aqueous Extract. J Ethnopharmacol, 2005,99:13-19
83 P. Trinder. Determination of Blood Glucose Using an Oxidase-peroxidase System with a Non-carcinogenic Chromogen. J Clin Pathol, 1969,22:158-161
84 M. Bradford. A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-dye Binding. Anal Biochem, 1976,72:248-254
85 N. Takasu, I. Komiya, T Asawa, et al. Streptozocin and Alloxan-induced H202 Generation and DNA Fragmentation in Pancreatic Islets. Diabetes, 1991,40(9):1141-1145
86 A.R. Collins, M. Dusinska. Oxidation of Cellular DNA Measured with the Comet Aassay. Meth. Mol. Biol, 2002,6:147-159
87 T. Sakatani, T. Shirayama, Y. Suzaki, et al. The Association between Cholesterol and Mortality in Heart Failure. Comparison between Patients with and without Coronary Artery Disease. Int Heart J, 2005,46:619-629
88 S.B. Sharma, A. Nasir, K.M. Prabhu, et al. Hypoglycaemic and Hypolipidemic Effect of Ethanolic Extract of Seeds of Eugenia Jambolana in Alloxan-induced Diabetic Rabbits. J Ethnopharmacol, 2003,85:201-206
89 S. Aida. Alkaline Phosphatase Isoenzyme Activities in Rheumatoid Arthritis: Hepatobiliary Enzyme Dissociation and Relation to Disease Activity. Ann Rheum Dis. J, 1993,52:511-516
90 D. Rajdl, J. Raceki, A. Steinerova, et al. Markers of Oxidative Stress in Diabetic Mothers and Their Infants during Delivery. Physiol Res, 2005,54:429-436
91 J. V. Ovska, J. Racek, F. Stozicky, et al. Parameters of Oxidative Stress in Children with Type 1 Diabetes Mellitus and Their Relatives. J Diabetes Complications, 2003,17:7-10
92 J.V. Ovská, J. Racek, R. ?tetina, et al. Aspects of Oxidative Stress in Children with Type 1 Diabetes Mellitus. Bio. Pharma, 2004,58:539-545
93 N. Aksoy, H. Vural , T. Sabuncu, et al. Effects of Melatonin on Oxidative-antioxidative Status of Tissues in Streptozotocin-induced Diabetic Rats. Cell Biochem Funct, 2003,21:121-125
94 F.L. Hu , H.R. Hepburn, H. Xuan, et al. Effects of Propolis on Blood Glucose, Blood Lipid and Free Radicals in Rats with Diabetes Mellitus. Pharmacol Res, 2005,51:147-152.
95 M. Aragno, R. Mastrocola, M.G. Catalano, et al. Oxidative Stress Impairs Skeletal Muscle Repairin Diabetic Rats. Diabetes, 2004,53:1082-1088
96 Y. Tanaka, P.O. Tran, J. Harmon, et al. A Role for Glutathione Peroxidase in Protecting PancreaticβCells against Oxidative Stress in a Model of Glucose Toxicity. Proc. Natl. Acad. Sci. U. S. A, 2002,99:12363-12368
97 D.A. Slatter, C.H. Bolton, A.J. Bailey. The Importance of Lipid-derived Malondialdehyde in Diabetes Mellitus. Diabetologia, 2000,43:550-557
98 O. Ozsoy-Sacan, O. Karabulut-Bulan , S. Bolkent, et al. Effects of Chard (Beta vulgaris L. var cicla) on the Liver of the Diabetic Rats: a Morphological and Biochemical Study. Biosci Biotechnol Biochem, 2004,68:1640-1648
99 R.P. Robertson. Chronic Oxidative Stress as a Central Mechanism for Glucose Toxicity in Pancreatic Islet Bbeta Cells in Diabetes. J Biol Chem, 2004,279:42351-42354
100 M. Aragno, R. Mastrocola, M.G. Catalano, et al. Oxidative Stress Impairs Skeletal Muscle Repair in Diabetic Rats. Diabetes, 2004,53:1082-1088
101 N.P. Singh, M.T. McCoy, R.R. Tice, et al. A Simple Technique for Quantitation of Low Levels of DNA Damage in Individual Cells. Exp. Cell Res., 1988,175:184-191.
102 M.H. Fraser, A. Cuerrier, P.S. Haddad, et al. Medicinal plants of Cree communities (Québec, Canada): antioxidant activity of plants used to treat type 2 diabetes symptoms. Can J Physiol Pharmacol. 2007,85(11):1200-1214
103 K. Ravi, B. Ramachandran, S. Subramanian. Protective Effect of Eugenia Jambolana Seed Kernel on Tissue Antioxidants in Streptozotocin Induced Diabetic Rats. Biol Pharma Bulletin, 2004,27: 1212-1217
104 M. Latha, L. Pari. Modulatory Effect of Scoparia Dulcis in Oxidative Stress-induced Lipid Peroxidation in Streptozocin Diabetic Rats. J. Med. Food, 2003,6:379-386
105 H.G. Nijs, J.K. Radder, M. Foolich, et al. Increased Insulin Action and Clearance in Hyperthyroid Newly Diagnosed IDDM Patient. Restoration to Normal with Antithyroid Treatment. Diabetes Care, 1989,12:319-324
106 J. Machackova, J. Barta, N.S. Dhalla. Molecular Defects in Cardiac Myfibrillar Proteins Due to Thyroid Hormone Imbalance and Diabeties. Can. J. Physiol. Pharmacol., 2005,83:1071-1091
107 S.W. Moon, J.R. Hahm, G.W. Lee, et al. A Case of Hyperglycemic Hyperosmolar State Associated with Graves' Hyperthyroidism : A Case Report J. Korean Med Sci, 2006,21:765-767
108 A. Bhattacharyya, P.G. Wile. Diabetic Ketocidosis Precipitated by Thyrotoxicosis. Postgrad Med J, 1999,75:291-292
109 S.B. Sharma, A. Nasir, K.M. Prabhu, et al. Hypoglycaemic and Hypolipidemic Effect of Ethanolic Extract of Seeds of Eugenia Jambolana in Alloxan-induced Diabetic Rabbits. J. Ethnopharmacol, 2003,85:201-206
110 G. Assmann, P. Cullen, J. Erbey, et al. Plasma Sitosterol Elevations are Associated with an Increased Incidence of Coronary Events in Men: Results of a Nested Case-control Analysis of the Prospective Cardiovascular Munster (PROCAM) Study. Nutr Metab Cardiovasc Dia, 2006, 16:13-21
111 M. Antonio, J.R. Gotto. Low High-density Lipoprotein Cholesterol as a Risk Factor in Coronary Heart Disease. Circulation, 2001,103:2213-2218
112 M.R. Taskinen. Diabetic dyslipidemia. Atherosclerosis, 2002,3:47-51
113 H.B. Rubins, S.J. Robins, D. Collins, et al. Department of Veterans Affairs HDL Intervention Trial Study Group. Distribution of Lipids in 8500 Men with Coronary Artery Disease. Am J Cardiol, 1995,75:1196-1201
114 E.J. Whitney, R.A. Krasuski, B.E. Personius, et al. A Randomized Trial of a Strategy for Increasing High Density Lipoprotein Cholesterol Levels: Effects on Progression of Coronary Heart Disease and Clinical Events. Ann Intern Med, 2005,142:45-104
115 S.S. Pertsov. Effect of Melatonin on the Thymus, Adrenal Glands, and Spleen in Rats during Acute Stress. Bull Exp Biol Med, 2006,141:292-295
116 E. Sezik, M. Aslan, E. Yesilada, et al. Hypoglycaemic Activity of Gentiana Olivieri and Isolation of the Active Constituent through Bioassay-directed Fractionation Techniques. Life Sci, 2005,76: 1223-1238
117 M. Benwahhoud, H. Jouad, M. Eddouks, et al. Hypoglycemic Effect of Suaeda Fruticosa in Streptozotocin Induced Diabetic Rats. J Ethnopharmacol, 2001,76:35-38
118 G.D. Dimitriadis, S.A. Raptis. Thyroid Hormone Excess and Glucose Intolerance. Exp Clin Endocrinol Diabetes, 2001,2:225-239
119 Bhattacharyya, P.G. Wiles. Diabetic Ketoacidosis Precipitated by Thyrotoxicosis. Postgrad. Med J, 1999,75:291-292
120 Q.H. Fan, Y.L. Hou, A.H. Zhu, et al. Comparising the Effects of Different Preparations ofFructus Ligustri Lucid on Enhancing White Blood Cell and Anti-hypoxia Ability. Northwest Pharmaceutical J, 2004,19:20-22
121 Z. Bacová, M. Orecná, R. Hafko, et al. Cell Swelling-induced Signaling for Insulin Secretion Bypasses Steps Involving G Proteins and PLA2 and is N-ethylmaleimide Insensitive. Cell Physiol Biochem, 2007,20(5):387-396
122 H. Takahashi, Y. Kurose, M. Sakaida, et al. Ghrelin Differentially Modulates Glucose-induced Insulin Secretion according to Feeding Status in Sheep. J Endocrinol, 2007,194(3):621-625
123 Andrade-Cetto, H. Wiedenfeld. Hypoglycemic Effect of Cecropia Obtusifolia on Streptozotocin Diabetic Rats. J Ethnopharmacol, 2001,78:145-149
124 C. Ricci, V. Pastukh, M. Mozaffari, et al. Insulin Withdrawal Induces Apoptosis via a Free Radical-mediated Mechanism. Can J Physiol Pharmacol., 2007,85(3-4):455-464
125 A. Ortiz, F.N. Ziyadeh, G.E. Neilson. Expression of Apoptosis Regulatory Genes in Renal Proximal Tubular Epithelial Cells Exposed to High Ambient Glucose and in Diabetic Kidneys. J Invest Med, 1997,45:50-56
126 D. Kumar, J. Zimpelmann, S. Robertson, et al. Tubular and Interstitial Cell Apoptosis in the Streptozotocin-diabetic Rat Kidney. Nephron Exp Nephrol, 2004,96(3):77-88
127 J. Chen, F.M. Couto, A.H. Minn, et al. Exenatide Inhibits Beta-cell Apoptosis by Decreasing Thioredoxin-interacting Protein. Biochem Biophys Res Commun, 2006,346(3):1067-1074
128薛耀明,罗仁,朱波,等.六味地黄丸对OLETF大鼠胰腺凋亡相关基因Bcl-2和Bax表达的影响.中西医结合学报,2005,3(6):455-458
129 Q. Huang, S. Bu, Y. Yu, et al. Diazoxide Prevents Diabetes through Inhibiting Pancreatic Beta- cells from Apoptosis via Bcl-2/Bax Rate and p38-beta Mitogen-activated Protein Kinase. J Endocrinology, 2007,148(1):81-91
130 W.H. Kim, J.W. Lee, Y.H. Suh, et al. Exposure to Chronic High Glucose Induces Beta-cell Apoptosis through Decreased Interaction of Glucokinase with Mitochondria: Downregulation of Glucokinase in Pancreatic Beta-cells. Diabetes, 2005,54(9):2602-2611
131 R.W. Vander Meer, M. Diamant, J.J. Westenberg, et al. Magnetic Resonance Assessment of Aortic Pulse Wave Velocity, Aortic Distensibility, and Cardiac Function in Uncomplicated Type 2 Diabetes Mellitus. J Cardiovasc Magn Reson, 2007,9(4):645-651
132 H. Li, S. Télémaque, R.E. Miller, et al. High Glucose Inhibits Apoptosis Induced by SerumDeprivation in Vascular Smooth Muscle Cells via Upregulation of Bcl-2 and Bcl-xl. Diabetes,2005, 54(2):540-545
133 Q. Huang, S. Bu, Y. Yu, et al. Diazoxide prevents diabetes through inhibiting pancreatic beta-cells from apoptosis via Bcl-2/Bax rate and p38-beta mitogen-activated protein kinase. Endocrinology. 2007,148(1):81-91
134 Z.G. Li, M. Britton, A.A. Sima, et al. Diabetes enhances apoptosis induced by cerebral ischemia. Life Sci, 2004,76(3):249-262
135 S. Srinivasan, M. Stevens, J.W. Wiley. Diabetic Peripheral Neuropathr Evidence for Apoptosis and Associated Mitochondrial Dysfunction. Diabetes, 2000,49:1932-1938
136 L.M. Blanco, A. Villa, M. Ortego. 3-Hydroxy-3-methyl-glutaryl Coenzyme A Reduetase Inhibitors, Atorvastatin and Simvastatin, Induce Apoptosis of Vascular Smooth Muscle Cells by Downregulation of Bcl-2 expression and Rho Aprenylation. Atherosclerosis, 2002,161(1):17-26
137 H. Cho, J. Mu, J.K. Kim, et al. Insulin Resistance and a Diabetes Mellitus-like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKB beta). Science, 200l,292:1728-1731
138 D. Koya, M.R. Jirousek, Y.W. Lin et al. Characterization of Protein Kinase C-βIsoform Activation on the Gene Expression of Transforming Growth Factor-β, Extracellular Matrix Components, and Prostanoids in the Glomeruli of Diabetic Rats. J Clin Invest, 1997,100:115-125
139 E.J. Tisdale. Rab2 Purification and Interaction with Pprotein Kinase C Iota/lambda and Glyceraldehyde-3-phosphate Dehydrogenase. Methods Enzymol, 2005,403:381-391
140 N. Takahashia, T. Kawada, T. Gotoa, et al. Dual Action of Isoprenols from Herbal Medicines on both PPARαand PPARγin 3T3-L1 Adipocytes and HepG2 Hepatocytes. FEBS Letters, 2002, 514:315-322
141 L. Malerod, M. Sporstol, L.K. Juvet et al. Hepatic Scavenger Receptor Class B. Type I is Stimulated by Peroxisome Proliferator Activated Receptor Gamma and Hepatocyte Nuclear Factor 4 Alpha. Biochem Biophys Res Commun, 2003,305(3):557-565
142 N. Strakova , J. Ehrmann , J. Bartos, et al. Peroxisome Proliferator-activated Receptors (PPAR) Agonists Affect Cell Viability, Apoptosis and Expression of Cell Cycle Related Proteins in Cell Lines of Glial Brain Tumors. Neoplasma, 2005,52(2):126-136
143 M.Y. Park, K.S. Lee, M.K. Sung, et al.. Effects of Dietary Mulberry, Korean Red Ginseng, and Banana on Glucose Homeostasis in Relation to PPAR-a, PPAR-γ, and LPL mRNA Expressions.Life Sciences, 2005,77: 3344-3354
144 O. Ludovico, F. Pellegrini, R.D. Paola, et al. Heterogeneous Effect of Peroxisome Proliferator -activated Receptor Gamma2 Ala12 Variant on Type 2 Diabetes Risk. Obesity (Silver Spring), 2007,15(5):1076-1081
145 L. Gelman, J.N. Feige, B. Desvergne. Molecular Basis of Selective PPAR gamma Modulation for the Treatment of Type 2 Diabetes. Biochim Biophys Acta, 2007, 1771(8):1094-1107
146 R. Meshkani, M. Taghikhani, B. Larijani, et al. Pro12Ala Polymorphism of the Peroxisome Proliferator-activated Receptor-gamma2 (PPARgamma-2) Gene is Associated with Greater Insulin Sensitivity and Decreased Risk of Type 2 Diabetes in an Iranian Population. Clin Chem Lab Med, 2007,45(4):477-482
147 S. Samuelsson, S. Johansson, S. Halldórsdóttir, et al. Food does not Affect the Pharmacokinetics
148 B. Fagerberg, S. Edwards, T. Halmos, et al. Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia. 2005, 48(9):1716-1725.
149 H.J. Atherton, N.J. Bailey, W. Zhang, et al. A Combined 1H-NMR Spectroscopy- and Mass Spectrometry-based Metabolomic Study of the PPAR-alpha Null Mutant Mouse Defines Profound Systemic Changes in Metabolism Linked to the Metabolic Syndrome. Physiol Genomics, 2006,27(2):178-186
150 P. Gervois, J.C. Fruchart, B. Staels. Inflammation, Dyslipidaemia, Diabetes and PPARs: Pharmacological Interest of Dual PPARalpha and PPARgamma Agonists. Int J Clin Pract Suppl., 2004,(143):22-29
151 B.C. Lee, H.J. Lee, J.H. Chung. Peroxisome Proliferator-activated Receptor-gamma 2 Pro12Ala Polymorphism is Associated with Reduced Risk for Ischemic Stroke with Type 2 Diabetes. Neurosci Lett, 2006,410(2):141-145
152 M. Scarsi, M. Podvinec, A. Roth, et al. Sulfonylureas and Glinides Exhibit Peroxisome Proliferators-activated Receptor Gamma Activity: A Combined Virtual Screening and Biological Assay Approach. Mol Pharmacol, 2007,71(2):398-406
153 J.S. Moyers, T.L. Shiyanova, F. Mehrbod, et al. Molecular Determinants of FGF-21 Activity-synergy and Cross-talk with PPARgamma Signaling. J Cell Physiol, 2007, 210(1):1-6
154 C.B. Patel, J.A. De Lemos, K.L. Wyne, et al Thiazolidinediones and Risk for Atherosclerosis: Pleiotropic Effects of PPAR Gamma Agonism. Diab Vasc Dis Res, 2006,3(2):65-71.
155 A. Munteanu, M. Taddei, I. Tamburini, et al.Antagonistic Effects of Oxidized Low Density Lipoprotein and-Tocopherol on CD36 Scavenger Receptor Expression in Monocytes Involvement of Protein Kinase B and Peroxisome Proliferator-Activated Receptor. J Biological Chemistry, 2006,281(10):6489-6497
156 Z.F. Yang, J.L. Yi, X. Li. et al. Correlation between Loss of PTEN Expression and PKB/AKT Phosph0rylati0n in Hepatocellular Carcinoma. J Huazhong University Science and Technology, 2005, 25(1):45-47.
157 A. Mora, C. Lipina, F. Tronche, et al. Deficiency of PDK1 in Liver Results in Glucose Intolerance, Impairment of Insulin-regulated Gene Expression and Liver Failure. Biochem J. 2005,385(Pt 3):639-648
158 F.S. Walton, A.W. Harmon, D.S. Paul, et al. Inhibition of Insulin-dependent Glucose Uptake by Trivalent Arsenicals: Possible Mechanism of Arsenic-induced Diabetes. Toxicol Appl Pharmacol, 2004,198(3):424-33
159 V. Sancho, M.V. Trigo, N. Gonzalez, et al. Effects of Glucagon-like Peptide-1 and Exendins on Kinase Activity, Glucose Transport and Lipid Metabolism in Adipocytes from Normal and Type-2 Diabetic Rats. J Mol Endocrinol, 2005,35(1):27-38
160 D.D. Sarbasaov, D.A. Guerfin, S.M. Ali. Phosphorylation and Regulation of Akt/PKB by the Rrictor—mTOR Complex. Science, 2005, 307(5712):1098-1101
161 E.A. Schwartz , P.D. Reaven. Molecular and signaling mechanisms of atherosclerosis in insulin resistance. Endocrinol Metab Clin North Am. 2006, 35(3):525-549