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系統識別號 U0026-0812200914264125
論文名稱(中文) 胍(Guanidine)在糖尿病鼠上對血糖調控之研究
論文名稱(英文) The effect of guanidine on plasma glucose in diabetic animals
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 96
學期 2
出版年 97
研究生(中文) 黃詩芸
研究生(英文) Shih-Yun Huang
電子信箱 s2695110@mail.ncku.edu.tw
學號 S2695110
學位類別 碩士
語文別 中文
論文頁數 76頁
口試委員 口試委員-徐鳳麟
口試委員-劉怡旻
指導教授-鄭瑞棠
中文關鍵字 咪唑啉    腺苷單磷酸-活性蛋白質激酶 
英文關鍵字 guanidine  AMP-activated protein kinase  imidazoline 
學科別分類
中文摘要 胍(guanidine)是由法國丁香(Galega officinalis)這種植物中萃取出來的主要成分。胍是咪唑啉第二亞型受體(imidazoline-I2 receptor, I2R)的配位體(ligand),具有降血糖的效果。先前研究指出,活化第1型糖尿病鼠腎上腺的I2R會增加腎上腺腦內啡(β-endorphin)的釋放,進而活化嗎啡μ型受體(opioid-μ receptor),達到降血糖效果。然而,胍可能的降血糖機轉目前仍不清楚,首先本研究在第1型糖尿病鼠上,發現胍降血糖的現象呈現劑量相關性。此結果會被I2R拮抗劑(BU224)所抑制,但卻不被嗎啡受體拮抗劑(naloxone)和嗎啡μ型受體拮抗劑(naloxonazine)所抑制。顯示胍的降血糖作用並非透過嗎啡μ型受體。此外,胍可增加正常大白鼠離體骨骼肌對葡萄糖的攝入能力,而此現象亦可被BU224所抑制。文獻指出,胍的衍生物會活化調節體內能量平衡的蛋白腺苷單磷酸-活性蛋白質激酶(AMP-activated protein kinase, AMPK)。當AMPK被活化後,會促進下游葡萄糖運送蛋白第四亞型(glucose transporter subtype 4, Glut4)蛋白的表現量,而導致骨骼肌攝入葡萄糖的能力增加,達到降血糖效果。在西方點墨法實驗中觀察到,guanidine會促進C2C12骨骼肌細胞AMPK的磷酸化,Glut4蛋白表現量以及葡萄糖的攝入能力,而這些結果皆會被BU224所抑制,但不受I2AR拮抗劑(amiloride)所影響。進一步,亦發現胍可以透過I2R以外的路徑來促進第1型糖尿病鼠的胰島素敏感性。綜合上述結果顯示本研究首度發現,胍可以藉由活化骨骼肌細胞上的I2BR來增加AMPK的磷酸化、Glut4蛋白表現量以及葡萄糖的攝入能力,進而達到降血糖的效果。
英文摘要 Guanidine is an active ingredient extracted from Galega officinalis. It is thought to be an endogenous ligand for imidazoline I2 receptor (I2R) and possesses a blood glucose-lowering effect. Previous studies have been shown that an activation of I2R in adrenal gland lowered plasma glucose by releasing β-endorphin, which act the opioid-μ receptor in streptozotocin-induced diabetic rats (STZ rats). However, the possible mechanism of guanidine for hypoglycemic action remains unclear. In this study, we found that guanidine exerted a dose-related hypoglycemic effect in STZ rats, which was blocked by I2R antagonist (BU224) but not by opioid receptor antagonist (naloxone) and opioid-μ receptor antagonist (naloxonazine). These results indicated that the effect of guanidine on hypoglycemia was not through opioid-μ receptor. In addition, the increased effect of guanidine on glucose uptake in skeletal muscle from Wistar rats was observed, whereas this effect was abolished by BU224. It also has been reported that guanidines activated AMP-activated protein kinase (AMPK). AMPK played a regulatory role of energy homeostasis, which was related to increased phosphorylation of AMPK, glucose transporter subtype 4 (Glut4) expression and glucose uptake, leading to hypoglycemia. In Western blotting analysis, we observed that guanidine significantly increased the phosphorylation of AMPK, total Glut4 expression and glucose uptake in C2C12 skeletal muscle fibroblast cells, whereas these effects were also blocked by BU224 but not by an I2AR antagonist (amiloride). Furthermore, we also found that guanidine enhanced insulin sensitivity which was not blocked by BU224 but through an unknown pathway in STZ rats. These results, we have shown for the first time suggested that guanidine decreased plasma glucose via an activation of I2BR to increase glucose uptake, which is related to phosphorylation of AMPK and Glut4 expression in skeletal muscle.
論文目次 中文摘要…………………………………………………………………I
英文摘要 ………………………………………………………………IV
縮寫表…………………………………………………………………VII
第一章 緒論…………………………………………………………1
第二章 實驗材料與方法……………………………………………7
第三章 實驗結果……………………………………………………27
第四章 討論…………………………………………………………36
第五章 結論…………………………………………………………41
參考文獻 ………………………………………………………………43
附圖 ……………………………………………………………………53
自述 ……………………………………………………………………76
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