跳到主要內容

臺灣博碩士論文加值系統

(44.220.255.141) 您好!臺灣時間:2024/11/04 04:16
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:曾心儀
研究生(外文):Hsin-I Tseng
論文名稱:山苦瓜萃取物降血糖活性物質之篩選及初步分子機制之研究
論文名稱(外文):Screening for hypoglycemic compounds in the extract of wild bitter melon and preliminary study of the molecular mechanism
指導教授:鄭雪玲鄭雪玲引用關係
指導教授(外文):Hsueh-Ling Cheng
學位類別:碩士
校院名稱:國立屏東科技大學
系所名稱:生物科技研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:73
中文關鍵詞:第二型糖尿病胰島素抗性花蓮2號山苦瓜果實AMPK
外文關鍵詞:type 2 diabetesinsulin resistancewild bitter melonAMPK
相關次數:
  • 被引用被引用:1
  • 點閱點閱:980
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:2
胰島素抗性(insulin resistance)是促成第二型糖尿病(type 2 diabetes)發病的主要因素。胰島素抗性是指原本對胰島素敏感的組織,如肌肉,肝臟,脂肪組織,對胰島素的敏感度降低,而減低了組織對葡萄糖的利用率,而造成高血糖的現象。因此若能治療胰島素抗性,將可以預防和改善第二型糖尿病。本實驗室過去已利用細胞株建立了一個篩選平台,可用以篩選「改善胰島素抗性」的活性物質,因此本研究亦利用此平台進行新品種山苦瓜花蓮2號之果實降血糖活性成分之篩選,並將篩選後認為有效的分液進行動物實驗以測驗其活體內的效果。以山苦瓜果實甲醇粗萃物進行細胞平台之葡萄糖吸收試驗,發現該甲醇粗萃物確能改善細胞的胰島素抗性而促進葡萄糖吸收。再將甲醇粗萃物進一步地分離成乙酸乙酯層、正丁醇層和水層,再進行葡萄糖吸收試驗,結果正丁醇層及水層皆能改善胰島素抗性細胞的葡萄糖吸收作用。再將正丁醇層進一步分成25個分液,發現分液7、12、16、19、21、23及24的活性最高,於較低濃度下,仍能恢復胰島素抗性細胞對葡萄糖的吸收。其中,分液16所含之天然物已進行純化,目前已獲得RA 2-10、RA 2-11及RA 2-19三個化合物。將此三個化合物進行分析,發現RA 2-19克服胰島素抗性的活性最明顯。進一步,發現RA 2-19可活化AMPK(AMP-activated protein kinase),暗示此天然物可能是經由活化AMPK而促進胰島素抗性細胞之葡萄糖吸收作用。再者,本研究亦發現RA 2-19可減少細胞之iNOS表現,但是RA2-19是否具有抗發炎的效果仍有待進一步驗證。此外,以分液15、21和23進行動物實驗,餵食具有高血糖症狀的小鼠,發現分液15於活體中降血糖效果不明顯,而分液21和23則有較明顯的降血糖效果,值得進ㄧ步分析純化其成分,以分離出更多具有降血糖效果的天然物。上述由山苦瓜果實中所純化出的降血糖活性成分,有潛力可開發成第二型糖尿病的治療藥物或保健食品。
Insulin resistance, the inability of insulin-responsive tissues mainly liver, muscles and adipose tissues to respond normally to circulating insulin, plays a key role in the development of type 2 diabetes. The reduced glucose utilzation by insulin-sensitive tissues results in hyperglycemia in organisms. Therefore, treatment of insulin resistance is an important strategy in preventing and improving type 2 diabetes. Previously, we have established a screening system using a mouse hepatic cell line to explore for compounds that can improve cellular insulin resistance. In this study, this system was used to screen for hypoglycemic compounds from the fruits of wild bitter melon. Meanwhile, animal tests were performed to test the in vivo effects of isolated fractions. The methanol extract from the fruits of wild bitter melon was shown to contain hypoglycemic compounds when tested using the screening system. The methanol extract was further partitioned into ethylacetate layer, butanol layer, and water layer. The butanol layer was further divided into twenty five fractions. It was found that fractions 16, 19, 21, 22, 23 and 24 had highest hypoglycemic activities, under the concentration. Compounds RA2-10, RA2-11 and RA2-19 were isolated from fraction 16. RA2-19 showed a hypoglycemic effect in insulin- resistant cells, and it was confirmed to activate AMPK (AMP-activated protein kinase). Furthermore, this research also discovered RA 2-19 may reduce iNOS of insulin- resistant cells but RA2-19 whether does have the anti-inflammation the effect still waited for further confirms. Meanwhile, the in vivo hyperglycemic effects of fractions 15, 21 and 23 were tested in animal models. Consequently, fraction 15 did not show obvious hypoglycemic effect, while fractions 21 and 23 showed more obvious hypoglycemic effects in the animal models. Thus, more bioactive compounds will be purified and identified from fractions 21 and 23. Purifies by wild bitter melon in hypoglycemic compounds, has the potential to become the anti-diabetic medicine or the health foods.
目錄
中文摘要....................................................I
英文摘要..................................................III
謝誌.......................................................V
目錄......................................................VI
圖表目錄...................................................XI
第1章 前言..................................................1
第2章 文獻回顧..............................................2
2.1 糖尿病的分類............................................2
2.1.2 第二型糖尿病..........................................3
2.1.3 妊娠糖尿病............................................3
2.1.4 葡萄糖耐受性異常.......................................3
2.2 胰島素與生理恆定之維持...................................4
2.2.1 胰島素與血糖的調控.....................................4
2.2.2 胰島素訊息傳遞路徑.....................................5
2.2.3 胰島素抗性............................................8
2.2.4 發炎與胰島素抗性.......................................8
2.2.4.1 TNF-α與胰島素抗性..................................10
2.2.4.2 NF-κB與IκB........................................10
2.2.4.3 iNOS..............................................11
2.2.5 改善胰島素抗性的藥物及其分子機制........................12
2.3 AMPK的功能............................................13
2.3.1 AMPK的調控..........................................13
2.3.2 AMPK與細胞新陳代謝之調節..............................14
2.4 高血糖動物模型之建立....................................15
2.5 苦瓜降血糖效果之研究....................................16
2.6 研究目的...............................................17
第3章 材料與方法...........................................18
3.1 實驗材料...............................................18
3.1.1 小鼠細胞株...........................................18
3.1.2 細胞培養基...........................................18
3.1.3 試劑及緩衝溶液.......................................18
3.1.3.1 葡萄糖濃度檢驗試劑組................................18
3.1.3.2 牛的胰島素溶液.....................................19
3.1.3.3 小鼠腫瘤壞死因子....................................19
3.1.3.4 Troglitazone藥物..................................19
3.1.3.5 山苦瓜花蓮2號......................................19
3.1.3.6 山苦瓜萃取物溶液之製備..............................20
3.1.4 蛋白質分析用試劑......................................20
3.1.5 蛋白質電泳分析之膠體..................................22
3.1.6 抗體................................................23
3.1.7 動物實驗使用材料與試劑................................24
3.1.7.1 小鼠品系...........................................24
3.1.7.2 檸檬酸鈉...........................................24
3.1.7.3 streptozotocin....................................24
3.1.7.4 甲基纖維素.........................................24
3.1.7.5 其他材料...........................................25
3.1.8 主要儀器及設備.......................................25
3.1.9 其他化學藥品.........................................26
3.2 實驗方法...............................................27
3.2.1 細胞培養與冷凍保存....................................27
3.2.1.1 FL83B小鼠肝臟細胞之活化.............................27
3.2.1.2 FL83B小鼠肝臟細胞之繼代培養.........................27
3.2.1.3 FL83B小鼠肝臟細胞的冷凍保存.........................27
3.2.2 苦瓜天然物促進細胞葡萄糖吸收之分析......................28
3.2.3 苦瓜天然物之細胞毒性分析...............................28
3.2.4 動物實驗.............................................28
3.2.4.1 誘導高血糖前測量小鼠體重及血糖值......................28
3.2.4.2 以STZ誘導產生高血糖小鼠並測量血糖值...................29
3.2.4.3 餵食山苦瓜分液並測量血糖值...........................29
3.2.5 西方墨點法分析.......................................29
3.2.5.1 細胞蛋白質粗萃液之製備..............................29
3.2.5.2 蛋白質定量.........................................30
3.2.5.3 聚丙烯醯胺凝膠電泳..................................30
3.2.5.4 西方墨點法.........................................30
3.2.6 統計分析.............................................31
第4章 結果.................................................32
4.1 由山苦瓜果實萃取物中篩選出可改善胰島素抗性之天然物..........32
4.1.1 析甲醇粗萃物、乙酸乙酯層、正丁醇層及水層萃取物之活性......32
4.1.2 由正丁醇層萃取物中篩選活性物質.........................33
4.1.3 分析分液16中所含天然物RA2-10、RA2-11及RA2-19之活性.....34
4.2 初步分子機制之探討......................................35
4.2.1 分析山苦瓜萃取物是否活化AMPK...........................35
4.2.2 分析山苦瓜萃取物是否具有抗發炎的效果....................35
4.2.2.1 分析TNF-α是否造成細胞之發炎反應......................35
4.2.2.2 分析RA2-19是否可抑制TNF-α所誘導之發炎反應............36
4.3 分析山苦瓜分液於活體中之降血糖效果........................37
第5章 討論.................................................56
第6章 結論.................................................59
參考文獻...................................................60
作者簡介...................................................73


圖表目錄
圖1. 胰島素訊息傳遞路徑......................................7
圖2. AMPK調控GLUT4轉位作用.................................15
圖3. 山苦瓜果實成分之萃取分離流程圖...........................39
圖4. 分析甲醇粗萃物、乙酸乙酯層、正丁醇層及水層萃取物之活性........................................................40
圖5. 分析分液1~12之活性.....................................41
圖6. 分析分液13~25之活性....................................42
圖7. 分析正丁醇層分液於1 μg/ml濃度下之活性....................43
圖8. 分析正丁醇層分液於1 μg/ml濃度下之活性....................44
圖9. 分析正丁醇層分液於0.1 μg/ml濃度下之活性..................45
圖10. 三個天然物之化學結構圖.................................46
圖11. 分析RA2-10、RA2-11及RA2-19對胰島素抗性細胞葡萄糖吸收之影響........................................................47
圖12. 分析RA2-19之有效劑量..................................48
圖13. 分析troglitazone之有效劑量............................49
圖14. 分析RA2-10、RA2-11、RA2-19是否活化AMPK...............50
圖15. 分析TNF-α是否降低IκBα 之表達.........................51
圖16. 分析TNF-α是否增加iNOS之表達..........................52
圖17. 分析troglitazone是否可抑制iNOS之表達.................53
圖18. 分析RA2-19是否可抑制iNOS之表達.......................54
表1. 分析山苦瓜分液於活體中之降血糖效果......................55
Ahmed, I., E. Adeghate, E. Cummings, A. K. Sharma, and J. Singh. 2004. Beneficial effects and mechanism of action of Momordica charantia juice in the treatment of streptozotocin-induced diabetes mellitus in rat. Mol Cell Biochem 261:63-70.
del Aguila, L. F., K. P. Claffey, and J. P. Kirwan. 1999. TNF-alpha impairs insulin signaling and insulin stimulation of glucose uptake in C2C12 muscle cells. Am J Physiol 276:E849-55.
Baron, V., P. Kaliman, N. Gautier, and E. Van Obberghen. 1992. The insulin receptor activation process involves localized conformational changes. J Biol Chem 267:23290-4.
Bhattacharya, S., D. Dey, and S. S. Roy. 2007. Molecular mechanism of insulin resistance. J Biosci 32:405-13.
Boden, G., and L. H. Carnell. 2003. Nutritional effects of fat on carbohydrate metabolism. Best Pract Res Clin Endocrinol Metab 17:399-410.
Bonizzi, G., and M. Karin. 2004. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25:280-8.
Bouzakri, K., and J. R. Zierath. 2007. MAP4K4 gene silencing in human skeletal muscle prevents tumor necrosis factor-alpha-induced insulin resistance. J Biol Chem 282:7783-9.
Carter, S. K., L. Broder, and M. Friedman. 1971. Streptozotocin and metastatic insulinoma. Ann Intern Med 74:445-6.
Carvalho-Filho, M. A., M. Ueno, J. B. Carvalheira, L. A. Velloso, and M. J. Saad. 2006. Targeted disruption of iNOS prevents LPS-induced S-nitrosation of IRbeta/IRS-1 and Akt and insulin resistance in muscle of mice. Am J Physiol Endocrinol Metab 291:E476-82.
Carvalho-Filho, M. A., M. Ueno, S. M. Hirabara, A. B. Seabra, J. B. Carvalheira, M. G. de Oliveira, L. A. Velloso, R. Curi, and M. J. Saad. 2005. S-nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt: a novel mechanism of insulin resistance. Diabetes 54:959-67.
Chan, A. Y., and J. R. Dyck. 2005. Activation of AMP-activated protein kinase (AMPK) inhibits protein synthesis: a potential strategy to prevent the development of cardiac hypertrophy. Can J Physiol Pharmacol 83:24-8.
Chao-Pin, L., Y. Guy, and O. Seung Joon. 2002. Type 2 diabetes--delivery approaches for novel therapeutics. Adv Drug Deliv Rev 54:1161-3.
Cheatham, B., and C. R. Kahn. 1995. Insulin action and the insulin signaling network. Endocr Rev 16:117-42.
Chen, H. 2006. Cellular inflammatory responses: novel insights for obesity and insulin resistance. Pharmacol Res 53:469-77.
Cheng, H. L., H. K. Huang, C. I. Chang, C. P. Tsai, and C. H , Chou. 2008. A cell-based screening identifies compounds from the stem of Momordica charantia that overcome insulin resistance and activate AMP-activated protein kinase. J Agric Food Chem. in press.
Choi, S. E., H. L. Noh, H. M. Kim, J. W. Yoon, and Y. Kang. 2002. Streptozotocin upregulates GAD67 expression in MIN6N8a mouse beta cells. J Autoimmun 19:1-8.
Conrad, B., E. Weidmann, G. Trucco, W. A. Rudert, R. Behboo, C. Ricordi, H. Rodriquez-Rilo, D. Finegold, and M. Trucco. 1994. Evidence for superantigen involvement in insulin-dependent diabetes mellitus aetiology. Nature 371:351-5.
Dandona, P., A. Aljada, and A. Bandyopadhyay. 2004. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25:4-7.
DeFronzo, R. A. 1988. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37:667-87.
Dresner, A., D. Laurent, M. Marcucci, M. E. Griffin, S. Dufour, G. W. Cline, L. A. Slezak, D. K. Andersen, R. S. Hundal, D. L. Rothman, K. F. Petersen, and G. I. Shulman. 1999. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 103:253-9.
Dunne, F. 2005. Type 2 diabetes and pregnancy. Semin Fetal Neonatal Med 10:333-9.
Eisenbarth, G. S. 1986. Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med 314:1360-8.
Fisher, J. S., J. Gao, D. H. Han, J. O. Holloszy, and L. A. Nolte. 2002. Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin. Am J Physiol Endocrinol Metab 282:E18-23.
Fujii, N., N. Jessen, and L. J. Goodyear. 2006. AMP-activated protein kinase and the regulation of glucose transport. Am J Physiol Endocrinol Metab 291:E867-77.
Fujimoto, M., N. Shimizu, K. Kunii, J. A. Martyn, K. Ueki, and M. Kaneki. 2005. A role for iNOS in fasting hyperglycemia and impaired insulin signaling in the liver of obese diabetic mice. Diabetes 54:1340-8.
Gao, Z., D. Hwang, F. Bataille, M. Lefevre, D. York, M. J. Quon, and J. Ye. 2002. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 277:48115-21.
Garcia-Puig, J., L. M. Ruilope, M. Luque, J. Fernandez, R. Ortega, and R. Dal-Re. 2006. Glucose metabolism in patients with essential hypertension. Am J Med 119:318-26.
Gerich, J. E. 2003. Contributions of insulin-resistance and insulin-secretory defects to the pathogenesis of type 2 diabetes mellitus. Mayo Clin Proc 78:447-56.
Goldstein, B. J. 2002. Insulin resistance as the core defect in type 2 diabetes mellitus. Am J Cardiol 90:3-10.
Graham, D. J., L. Green, J. R. Senior, and P. Nourjah. 2003. Troglitazone-induced liver failure: a case study. Am J Med 114:299-306.
Greenfield, J. R., and L. V. Campbell. 2004. Insulin resistance and obesity. Clin Dermatol 22:289-95.
Gual, P., Y. Le Marchand-Brustel, and J. F. Tanti. 2005. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 87:99-109.
Hanada, T., and A. Yoshimura. 2002. Regulation of cytokine signaling and inflammation. Cytokine Growth Factor Rev 13:413-21.
Hanley, A. J., K. Williams, M. P. Stern, and S. M. Haffner. 2002. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care 25:1177-84.
Hardie, D. G. 2004. The AMP-activated protein kinase pathway--new players upstream and downstream. J Cell Sci 117:5479-87.
Harinantenaina, L., M. Tanaka, S. Takaoka, M. Oda, O. Mogami, M. Uchida, and Y. Asakawa. 2006. Momordica charantia constituents and antidiabetic screening of the isolated major compounds. Chem Pharm Bull (Tokyo) 54:1017-21.
Herrera, R., and O. M. Rosen. 1986. Autophosphorylation of the insulin receptor in vitro. Designation of phosphorylation sites and correlation with receptor kinase activation. J Biol Chem 261:11980-5.
Hevener, A. L., D. Reichart, A. Janez, and J. Olefsky. 2001. Thiazolidinedione treatment prevents free fatty acid-induced insulin resistance in male wistar rats. Diabetes 50:2316-22.
Hou, J. C., and J. E. Pessin. 2007. Ins (endocytosis) and outs (exocytosis) of GLUT4 trafficking. Curr Opin Cell Biol 19:466-73.
Huang, S., and M. P. Czech. 2007. The GLUT4 glucose transporter. Cell Metab 5:237-52.
Isomaa, B., P. Almgren, T. Tuomi, B. Forsen, K. Lahti, M. Nissen, M. R. Taskinen, and L. Groop. 2001. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24:683-9.
Iwata, M., T. Haruta, I. Usui, Y. Takata, A. Takano, T. Uno, J. Kawahara, E. Ueno, T. Sasaoka, and M. Ishibayashi. 2001. Pioglitazone ameliorates tumor necrosis factor-α-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferators-activated receptor-γ. Diabetes 50: 1083-1092.
Janjic, D., P. Maechler, N. Sekine, C. Bartley, A. S. Annen, and C. B. Wolheim. 1999. Free radical modulation of insulin release in INS-1 cells exposed to alloxan. Biochem Pharmacol 57:639-48.
Junod, A., A. E. Lambert, W. Stauffacher, and A. E. Renold. 1969. Diabetogenic action of streptozotocin: relationship of dose to metabolic response. J Clin Invest 48:2129-39.
Kahn, B. B., T. Alquier, D. Carling, and D. G. Hardie. 2005. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1:15-25.
Kahn, B. B., and J. S. Flier. 2000. Obesity and insulin resistance. J Clin Invest 106:473-81.
Kanzaki, M., and J. E. Pessin. 2001. Signal integration and the specificity of insulin action. Cell Biochem Biophys 35:191-209.
Khanna, P., S. C. Jain, A. Panagariya, and V. P. Dixit. 1981. Hypoglycemic activity of polypeptide-p from a plant source. J Nat Prod 44:648-55.
Kumar, N., and C. S. Dey. 2003. Development of insulin resistance and reversal by thiazolidinediones in C2C12 skeletal muscle cells. Biochem Pharmacol 65:249-57.
Langer, O., Y. Yogev, O. Most, and E. M. Xenakis. 2005. Gestational diabetes: the consequences of not treating. Am J Obstet Gynecol 192:989-97.
Lebovitz, H. E. 2001. Insulin resistance: definition and consequences. Exp Clin Endocrinol Diabetes 109 Suppl 2:S135-48.
Lebovitz, H. E. 2001. Oral therapies for diabetic hyperglycemia. Endocrinol Metab Clin North Am 30:909-33.
Lebovitz, H. E. 2002. Rationale for and role of thiazolidinediones in type 2 diabetes mellitus. Am J Cardiol 90:34-41.
Lebovitz, H. E., and M. A. Banerji. 2004. Treatment of insulin resistance in diabetes mellitus. Eur J Pharmacol 490:135-46.
Lehmann, J. M., L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison, T. M. Willson, and S. A. Kliewer. 1995. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 270:12953-6.
Lillioja, S., D. M. Mott, B. V. Howard, P. H. Bennett, H. Yki-Jarvinen, D. Freymond, B. L. Nyomba, F. Zurlo, B. Swinburn, and C. Bogardus. 1988. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. N Engl J Med 318:1217-25.
Lindsley, J. E., and J. Rutter. 2004. Nutrient sensing and metabolic decisions. Comp Biochem Physiol B Biochem Mol Biol 139:543-59.
Long, Y. C., and J. R. Zierath. 2006. AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest 116:1776-83.
de Luca, C., and J. M. Olefsky. 2008. Inflammation and insulin resistance. FEBS Lett 582:97-105.
Maresh, M. 2001. Diabetes in pregnancy. Curr Opin Obstet Gynecol 13:103-7.
McCarty, M. F. 2004. Does bitter melon contain an activator of AMP-activated kinase? Med Hypotheses 63:340-3.
McEvoy, G. K. 2005. Dose adjustment in renal impairment: response from AHFS Drug Information. Bmj 331:293.
Mlinar, B., J. Marc, A. Janez, and M. Pfeifer. 2007. Molecular mechanisms of insulin resistance and associated diseases. Clin Chim Acta 375:20-35.
Moule, S. K., and R. M. Denton. 1997. Multiple signaling pathways involved in the metabolic effects of insulin. Am J Cardiol 80:41A-49A.
Munoz, P., J. Chillaron, M. Camps, A. Castello, M. Furriols, X. Testar, M. Palacin, and A. Zorzano. 1996. Evidence for posttranscriptional regulation of GLUT4 expression in muscle and adipose tissue from streptozotocin-induced diabetic and benfluorex-treated rats. Biochem Pharmacol 52:1665-73.
Perreault, M., and A. Marette. 2001. Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat Med 7:1138-43.
Pessin, J. E., and A. R. Saltiel. 2000. Signaling pathways in insulin action: molecular targets of insulin resistance. J Clin Invest 106:165-9.
Pietropaolo, M. and D. L. Roith. 2002. Pathogenesis of diabetes: our current understanding. Diabetes 4: 1-16.
Proietto, J., and S. Andrikopoulos. 2004. Molecular mechanisms of increased glucose production: identifying potential therapeutic targets. J Investig Med 52:389-93.
Rakieten, N., M. L. Rakieten, and M. V. Nadkarni. 1963. Studies on the diabetogenic action of streptozotocin. Cancer Chemother Rep 29:91-8.
Rangwala, S. M., and M. A. Lazar. 2004. Peroxisome proliferator-activated receptor gamma in diabetes and metabolism. Trends Pharmacol Sci 25:331-6.
Reaven, G. M. 1993. Role of insulin resistance in human disease (syndrome X): an expanded definition. Annu Rev Med 44:121-31.
Rendell, M. S., and L. Jovanovic. 2006. Targeting postprandial hyperglycemia. Metabolism 55:1263-81.
Roffey, B. W., A. S. Atwal, T. Johns, and S. Kubow. 2007. Water extracts from Momordica charantia increase glucose uptake and adiponectin secretion in 3T3-L1 adipose cells. J Ethnopharmacol 112:77-84.
Ruland, J., and T. W. Mak. 2003. From antigen to activation: specific signal transduction pathways linking antigen receptors to NF-kappaB. Semin Immunol 15:177-83.
Saha, A. K., P. R. Avilucea, J. M. Ye, M. M. Assifi, E. W. Kraegen, and N. B. Ruderman. 2004. Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo. Biochem Biophys Res Commun 314:580-5.
Sandler, S., and A. Andersson. 1985. Modulation of streptozotocin-induced insulitis and hyperglycaemia in the mouse. Acta Pathol Microbiol Immunol Scand [A] 93:93-8.
Sarkar, S., M. Pranava, and R. Marita. 1996. Demonstration of the hypoglycemic action of Momordica charantia in a validated animal model of diabetes. Pharmacol Res 33:1-4.
Sato, Y., N. Hotta, N. Sakamoto, S. Matsuoka, N. Ohishi, and K. Yagi. 1979. Lipid peroxide level in plasma of diabetic patients. Biochem Med 21:104-7.
Scollan-Koliopoulos, M., S. Guadagno, and E. A. Walker. 2006. Gestational diabetes management: guidelines to a healthy pregnancy. Nurse Pract 31:14-23; quiz 24-5.
Shepherd, P. R., and B. B. Kahn. 1999. Glucose transporters and insulin action--implications for insulin resistance and diabetes mellitus. N Engl J Med 341:248-57.
Shoelson, S. E., L. Herrero, and A. Naaz. 2007. Obesity, inflammation, and insulin resistance. Gastroenterology 132:2169-80.
Shulman, G. I. 2000. Cellular mechanisms of insulin resistance. J Clin Invest 106:171-6.
Shulman, G. I., D. L. Rothman, T. Jue, P. Stein, R. A. DeFronzo, and R. G. Shulman. 1990. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med 322:223-8.
Sitasawad, S. L., Y. Shewade, and R. Bhonde. 2000. Role of bittergourd fruit juice in stz-induced diabetic state in vivo and in vitro. J Ethnopharmacol 73:71-9.
Stein, M. P., J. Dong, and A. Wandinger-Ness. 2003. Rab proteins and endocytic trafficking: potential targets for therapeutic intervention. Adv Drug Deliv Rev 55:1421-37.
Stenmark, H., and V. M. Olkkonen. 2001. The Rab GTPase family. Genome Biol 2:reviews3007.1-3007.7
Strubbe, J. H., and A. B. Steffens. 1988. Hormonal modifications induced by food intake contribute to the regulation of the body weight and to metabolic variations. Ann Endocrinol (Paris) 49:105-12.
Tan, M. J., J. M. Ye, N. Turner, C. Hohnen-Behrens, C. Q. Ke, C. P. Tang, T. Chen, H. C. Weiss, E. R. Gesing, A. Rowland, D. E. James, and Y. Ye. 2008. Antidiabetic activities of triterpenoids isolated from bitter melon associated with activation of the AMPK pathway. Chem Biol 15:263-73.
Thong, F. S., P. J. Bilan, and A. Klip. 2007. The Rab GTPase-activating protein AS160 integrates Akt, protein kinase C, and AMP-activated protein kinase signals regulating GLUT4 traffic. Diabetes 56:414-23.
Tilg, H., and G. S. Hotamisligil. 2006. Nonalcoholic fatty liver disease: Cytokine-adipokine interplay and regulation of insulin resistance. Gastroenterology 131:934-45.
Treebak, J. T., S. Glund, A. Deshmukh, D. K. Klein, Y. C. Long, T. E. Jensen, S. B. Jorgensen, B. Viollet, L. Andersson, D. Neumann, T. Wallimann, E. A. Richter, A. V. Chibalin, J. R. Zierath, and J. F. Wojtaszewski. 2006. AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on AMPK catalytic and regulatory subunits. Diabetes 55:2051-8.
Truglia, J. A., G. R. Hayes, and D. H. Lockwood. 1988. Intact adipocyte insulin-receptor phosphorylation and in vitro tyrosine kinase activity in animal models of insulin resistance. Diabetes 37:147-53.
van Haeften, T. W. 2002. Early disturbances in insulin secretion in the development of type 2 diabetes mellitus. Mol Cell Endocrinol 197:197-204.
Viollet, B., M. Foretz, B. Guigas, S. Horman, R. Dentin, L. Bertrand, L. Hue, and F. Andreelli. 2006. Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders. J Physiol 574:41-53.
Viollet, B., R. Mounier, J. Leclerc, A. Yazigi, M. Foretz, and F. Andreelli. 2007. Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders. Diabetes Metab 33:395-402.
Virdi, J., S. Sivakami, S. Shahani, A. C. Suthar, M. M. Banavalikar, and M. K. Biyani. 2003. Antihyperglycemic effects of three extracts from Momordica charantia. J Ethnopharmacol 88:107-11.
Wang, H. J., Y. X. Jin, W. Shen, J. Neng, T. Wu, Y. J. Li, and Z. W. Fu. 2007. Low dose streptozotocin (STZ) combined with high energy intake can effectively induce type 2 diabetes through altering the related gene expression. Asia Pac J Clin Nutr 16 Suppl 1:412-7.
Watson, R. T., M. Kanzaki, and J. E. Pessin. 2004. Regulated membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes. Endocr Rev 25:177-204.
Watson, R. T., and J. E. Pessin. 2006. Bridging the GAP between insulin signaling and GLUT4 translocation. Trends Biochem Sci 31:215-22.
Watson, R. T., and J. E. Pessin. 2007. GLUT4 translocation: the last 200 nanometers. Cell Signal 19:2209-17.
Weyer, C., C. Bogardus, D. M. Mott, and R. E. Pratley. 1999. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 104:787-94.
White, F. R. 1963. Streptozotocin. Cancer Chemother Rep 30:49-53.
Wilson, G. L., P. C. Hartig, N. J. Patton, and S. P. LeDoux. 1988. Mechanisms of nitrosourea-induced beta-cell damage. Activation of poly (ADP-ribose) synthetase and cellular distribution. Diabetes 37:213-6.
Wood, I. S., L. Hunter, and P. Trayhurn. 2003. Expression of Class III facilitative glucose transporter genes (GLUT-10 and GLUT-12) in mouse and human adipose tissues. Biochem Biophys Res Commun 308:43-9.
Worley, J. F., 3rd, M. S. McIntyre, B. Spencer, and I. D. Dukes. 1994. Depletion of intracellular Ca2+ stores activates a maitotoxin-sensitive nonselective cationic current in beta-cells. J Biol Chem 269:32055-8.
Wu, X., W. Li, V. Sharma, A. Godzik, and H. H. Freeze. 2002. Cloning and characterization of glucose transporter 11, a novel sugar transporter that is alternatively spliced in various tissues. Mol Genet Metab 76:37-45.
Wullaert, A., K. Heyninck, and R. Beyaert. 2006. Mechanisms of crosstalk between TNF-induced NF-kappaB and JNK activation in hepatocytes. Biochem Pharmacol 72:1090-101.
Yasukawa, T., E. Tokunaga, H. Ota, H. Sugita, J. A. Martyn, and M. Kaneki. 2005. S-nitrosylation-dependent inactivation of Akt/protein kinase B in insulin resistance. J Biol Chem 280:7511-8.
Zick, Y. 2001. Insulin resistance: a phosphorylation-based uncoupling of insulin signaling. Trends Cell Biol 11:437-41.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top