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系統識別號 U0026-0812200915242569
論文名稱(中文) 氨基胍對血糖恆定調控之研究
論文名稱(英文) Effect of Aminoguanidine on Glucose Homeostasis
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 97
學期 2
出版年 98
研究生(中文) 陳昱均
研究生(英文) Yu-chung Chen
電子信箱 wacamamachun@yahoo.com.tw
學號 S2696410
學位類別 碩士
語文別 中文
論文頁數 67頁
口試委員 口試委員-許朝添
指導教授-鄭瑞棠
口試委員-劉怡旻
中文關鍵字 糖尿病  氨基胍 
英文關鍵字 aminoguanidine  diabetes 
學科別分類
中文摘要 糖尿病是ㄧ種代謝疾病,臨床特徵是血糖無法有效被體內組織器官利用儲存,因此導致高血糖且造成多項糖尿病併發症產生。文獻曾報導氨基胍(aminoguanidine)能透過抑制醣化最終產物形成,進而改善糖尿病併發症的發生。但是目前對於氨基胍是否能直接影響體內血糖恆定,仍不清楚。本研究結果顯示,於正常大鼠和streptozotocin誘導之第一型糖尿病大鼠注射給予氨基胍後,可觀察到降血糖作用。另一面,氨基胍能增加正常大鼠的葡萄糖耐受性,這結果表示氨基胍降血糖效果可能透過增加血中胰島素濃度和葡萄糖的利用率。本研究發現氨基胍能增加大鼠的胰島釋放量,然而氨基胍並不會影響小鼠肌纖維母細胞株(C2C12)的葡萄糖攝取能力,且loperamide 對細胞所增加的葡萄糖攝取能力會因氨基胍處理而抑制。因此氨基胍在正常大鼠和糖尿病大鼠產生的降血糖效果可能是透過氨基胍代謝產物。文獻指出,氨基胍代謝產物可作為菸鹼型膽鹼性受體致效劑。活化菸鹼型膽鹼性受體後,可能誘導乙醯膽鹼釋放,進而活化蕈毒型膽鹼性受體,且研究指出第一亞型蕈毒型膽鹼性受體對於小鼠肌纖維母細胞的葡糖糖攝取能力和胰島素釋放也扮演相關角色。我們發現,氨基胍所引起降血糖作用和胰島素的釋放,會被菸鹼型膽鹼性受體阻斷劑(hexamethonium)、蕈毒型膽鹼性受體阻斷劑(atropine 或pirenzepine)所阻斷。於正常大鼠與糖尿病大鼠也觀察到physostigmine在能達到抑制膽鹼酯酶作用的濃度,也能加強氨基胍的降血糖作用。綜合上述實驗,本研究發現氨基胍具有降血糖作用,可能是透過氨基胍代謝產物所影響的膽鹼性神經傳導。
英文摘要 Diabetes is a metabolic disorder, characterized by impaired glucose utilization and high plasma glucose, lots of complications might be developed by diabetes. It was reported that aminoguanidine (AMG) inhibited advanced glycation end product formation to improve the development of diabetic complications. However, the direct effect of AMG on glucose homeostasis remains unclear. In this study, hypoglycemic effect was observed in Wistar rats and streptozotocin-induced type I diabetic rats (STZ-diabetic rats) after AMG injection. On the other hand, AMG treatment increased glucose tolerance in Wistar rats, indicating that the glucose-lowering action of AMG might increase plasma insulin levels or glucose utility. In the present study, the plasma insulin level of Wistar rats was increased after AMG treatment, whereas AMG had no effect on glucose uptake in mouse myoblast cells (C2C12). Also, the loperamide-induced glucose uptake was inhibited by AMG treatment in vitro. Thus, the hypoglycemic effect of AMG in STZ-diabetic rats and Wistar rats seems through the AMG metabolites. Previous studies had been shown that AMG metabolites act as agonists at the nicotinic cholinoceptor. Activation of nicotinic cholinoceptor might induce acetylcholine release and further activated muscarinic cholinoceptor and several studies had shown that muscarinic M1 recepter plays a role of glucose uptake into C2C12 cells and insulin secretion. We found that the hypoglycemic action and insulinotropic effect of AMG in experimental rats was blocked by nicotinic cholinoceptor antagonist (hexamethonium) and muscarinic cholinoceptor antagonist (atropine or pirenzepine). Physostigmine at concentration sufficient to inhibit acetylcholinesterase enhanced the hypoglycemic action of AMG in Wistar rats and STZ-diabetic rats. Taken together, these results suggest that AMG has an ability to decrease blood glucose in diabetic rats and normal rats, probably through AMG metabolites to activate cholinergic neurotransmission.
論文目次 英文摘要.........................................................................................Ⅰ

中文摘要........................................................................................ III

縮寫表............................................................................................ VI

第一章 緒論....................................................................................1

第二章 實驗方法與材料................................................................7

第三章 實驗結果...........................................................................25

第四章 討論...................................................................................34

第五章 結論...................................................................................42

參考文獻.........................................................................................44

附圖.................................................................................................51

自述.................................................................................................67
參考文獻 1. He A, Liu X, Liu L, Chang Y, Fang F: How many signals impinge on GLUT4 activation by insulin? Cell Signal 19:1-7, 2007

2. Harris MI, Hadden WC, Knowler WC, Bennett PH: Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged 20-74 yr. Diabetes 36:523-534, 1987

3. Bate KL, Jerums G: 3: Preventing complications of diabetes. Med J Aust 179:498-503, 2003

4. Eizirik DL, Sandler S, Palmer JP: Repair of pancreatic beta-cells. A relevant phenomenon in early IDDM? Diabetes 42:1383-1391, 1993

5. Rodger W: Insulin-dependent (type I) diabetes mellitus. Can.Med. Assoc. J 145:1227-1237, 1991

6. Thornalley PJ: Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts. Arch Biochem Biophys 419:31-40, 2003

7. Wang GY, Ji B, Wang X, Gu JH: Anti-cancer effect of iNOS inhibitor and its correlation with angiogenesis in gastric cancer. World J Gastroenterol 11:3830-3833, 2005

8. Yeh DY, Feng NH, Chen CF, Lin HI, Wang D: Inducible nitric oxide synthase expressions in different lung injury models and the protective effect of aminoguanidine. Transplant Proc 40:2178-2181, 2008

9. Corman B, Duriez M, Poitevin P, Heudes D, Bruneval P, Tedgui A, Levy BI: Aminoguanidine prevents age-related arterial stiffening and cardiac hypertrophy. Proc Natl Acad Sci U S A 95:1301-1306, 1998


10. Mohamad NA, Cricco GP, Sambuco LA, Croci M, Medina VA, Gutierrez AS, Bergoc RM, Rivera ES, Martin GA: Aminoguanidine impedes human pancreatic tumor growth and metastasis development in nude mice. World J Gastroenterol 15:1065-1071, 2009

11. Yamagishi S, Nakamura K, Matsui T: Advanced glycation end products (AGEs) and their receptor (RAGE) system in diabetic retinopathy. Curr Drug Discov Technol 3:83-88, 2006

12. Ford KA, Casida JE: Unique and common metabolites of thiamethoxam, clothianidin, and dinotefuran in mice. Chem Res Toxicol 19:1549-1556, 2006

13. Tomizawa M, Casida JE: Neonicotinoid insecticide toxicology: mechanisms of selective action. Annu Rev Pharmacol Toxicol 45:247-268, 2005

14. Kanne DB, Dick RA, Tomizawa M, Casida JE: Neonicotinoid nitroguanidine insecticide metabolites: synthesis and nicotinic receptor potency of guanidines, aminoguanidines, and their derivatives. Chem Res Toxicol 18:1479-1484, 2005

15. Bender T, Nagy G, Barna I, Tefner I, Kadas E, Geher P: The effect of physical therapy on beta-endorphin levels. Eur J Appl Physiol 100:371-382, 2007

16. Curry DL, Bennett LL, Li CH: Stimulation of insulin secretion by beta-endorphins (1-27 & 1-31). Life Sci 40:2053-2058, 1987

17. Yu BC, Chang CK, Su CF, Cheng JT: Mediation of beta-endorphin in andrographolide-induced plasma glucose-lowering action in type I diabetes-like animals. Naunyn Schmiedebergs Arch Pharmacol 377:529-540, 2008

18. Liu IM, Chi TC, Chen YC, Lu FH, Cheng JT: Activation of opioid mu-receptor by loperamide to lower plasma glucose in streptozotocin-induced diabetic rats. Neurosci Lett 265:183-186, 1999

19. Cheng JT, Huang CC, Liu IM, Tzeng TF, Chang CJ: Novel mechanism for plasma glucose-lowering action of metformin in streptozotocin-induced diabetic rats. Diabetes 55:819-825, 2006

20. Teff KL: Visceral nerves: vagal and sympathetic innervation. JPEN J Parenter Enteral Nutr 32:569-571, 2008

21. Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, Aguilar-Bryan L, Rossetti L: Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434:1026-1031, 2005

22. Stagner JI, Samols E: Modulation of insulin secretion by pancreatic ganglionic nicotinic receptors. Diabetes 35:849-854, 1986

23. Renuka TR, Robinson R, Paulose CS: Increased insulin secretion by muscarinic M1 and M3 receptor function from rat pancreatic islets in vitro. Neurochem Res 31:313-320, 2006

24. Miguel JC, Abdel-Wahab YH, Mathias PC, Flatt PR: Muscarinic receptor subtypes mediate stimulatory and paradoxical inhibitory effects on an insulin-secreting beta cell line. Biochim Biophys Acta 15:1-3, 2002

25. Liu TP, Yu PC, Liu IM, Tzeng TF, Cheng JT: Activation of muscarinic M1 receptors by acetylcholine to increase glucose uptake into cultured C2C12 cells. Auton Neurosci 96:113-118, 2002

26. El Shazly AH, Mahmoud AM, Darwish NS: Potential prophylactic role of aminoguanidine in diabetic retinopathy and nephropathy in experimental animals. Acta Pharm 59:67-73, 2009

27. Kolta MG, Wallace LJ, Gerald MC: Streptozocin-induced diabetes affects rat urinary bladder response to autonomic agents. Diabetes 34:917-921, 1985

28. Godsland IF, Luzio S, Wynn V, Owens DR: Methodological issues in the application of the minimal model: effects of glucose dose, basal glucose concentration, test duration and modelling constraint. Diabetes Res 26:139-153, 1994

29. Porstmann T, Kiessig ST: Enzyme immunoassay techniques. An overview. J Immunol Methods 150:5-21, 1992

30. Gliemann J, Rees WD, Foley JA: The fate of labelled glucose molecules in the rat adipocyte. Dependence on glucose concentration. Biochim Biophys Acta 804:68-76, 1984

31. Davis RM, Richard JL: Production of [14C]rubratoxin B. Mycopathologia 67:35-38, 1979

32. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 193:265-275, 1951

33. Liu IM, Liou SS, Chen WC, Chen PF, Cheng JT: Signals in the activation of opioid mu-receptors by loperamide to enhance glucose uptake into cultured C2C12 cells. Horm Metab Res 36:210-214, 2004

34. Osicka TM, Yu Y, Panagiotopoulos S, Clavant SP, Kiriazis Z, Pike RN, Pratt LM, Russo LM, Kemp BE, Comper WD, Jerums G: Prevention of albuminuria by aminoguanidine or ramipril in streptozotocin-induced diabetic rats is associated with the normalization of glomerular protein kinase C. Diabetes 49:87-93, 2000

35. Heikkinen S, Argmann CA, Champy MF, Auwerx J: Evaluation of glucose homeostasis. Curr Protoc Mol Biol 29:3, 2007

36. Hwang SL, Liu IM, Tzeng TF, Cheng JT: Activation of imidazoline receptors in adrenal gland to lower plasma glucose in streptozotocin-induced diabetic rats. Diabetologia 48:767-775, 2005

37. Cheng JT, Liu IM, Tzeng TF, Tsai CC, Lai TY: Plasma glucose-lowering effect of beta-endorphin in streptozotocin-induced diabetic rats. Horm Metab Res 34:570-576, 2002

38. Liu XJ, He AB, Chang YS, Fang FD: Atypical protein kinase C in glucose metabolism. Cell Signal 18:2071-2076, 2006

39. Tasaka Y, Nakaya F, Matsumoto H, Omori Y: Effects of aminoguanidine on insulin release from pancreatic islets. Endocr J 41:309-313, 1994

40. Gur S, Kadowitz PJ, Hellstrom WJ: A critical appraisal of erectile function in animal models of diabetes mellitus. Int J Androl 32:93-114, 2009

41. Jove M, Planavila A, Laguna JC, Vazquez-Carrera M: Palmitate-induced interleukin 6 production is mediated by protein kinase C and nuclear-factor kappaB activation and leads to glucose transporter 4 down-regulation in skeletal muscle cells. Endocrinology 146:3087-3095, 2005

42. Zhao Z, Zhao C, Zhang XH, Zheng F, Cai W, Vlassara H, Ma ZA: Advanced glycation end products inhibit glucose-stimulated insulin secretion through nitric oxide-dependent inhibition of cytochrome c oxidase and adenosine triphosphate synthesis. Endocrinology 150:2569-2576, 2009

43. Yamabe N, Kang KS, Goto E, Tanaka T, Yokozawa T: Beneficial effect of Corni Fructus, a constituent of Hachimi-jio-gan, on advanced glycation end-product-mediated renal injury in Streptozotocin-treated diabetic rats. Biol Pharm Bull 30:520-526, 2007

44. Chang KC, Hsu KL, Tseng CD, Lin YD, Cho YL, Tseng YZ: Aminoguanidine prevents arterial stiffening and cardiac hypertrophy in streptozotocin-induced diabetes in rats. Br J Pharmacol 147:944-950, 2006

45. Lukivskaya O, Patsenker E, Lis R, Buko VU: Inhibition of inducible nitric oxide synthase activity prevents liver recovery in rat thioacetamide-induced fibrosis reversal. Eur J Clin Invest 38:317-325, 2008

46. Bolton WK, Cattran DC, Williams ME, Adler SG, Appel GB, Cartwright K, Foiles PG, Freedman BI, Raskin P, Ratner RE, Spinowitz BS, Whittier FC, Wuerth JP: Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol 24:32-40, 2004

47. Miyata T, van Ypersele de Strihou C: Angiotensin II receptor blockers and angiotensin converting enzyme inhibitors: implication of radical scavenging and transition metal chelation in inhibition of advanced glycation end product formation. Arch Biochem Biophys 419:50-54, 2003

48. Toso CF, Rodriguez RR, Renauld AR, Marquez AG, Linares LM: Adrenocorticotrophic hormone, cortisol and catecholamine concentrations during insulin hypoglycaemia in dogs anaesthetized with thiopentone. Can J Anaesth 40:1084-1091, 1993
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