臺灣博碩士論文加值系統

第二型糖尿病的發生被認為肇因於身體組織產生胰島素抗性。本實驗室於前期研究中，由白蓮苦瓜莖材篩選出三萜類化合物CH63及CH93，證明這些化合物於具有胰島素抗性的細胞中，可以促進細胞的葡萄糖吸收，並且可以活化胰島素訊息傳遞路徑，而且可以活化AMP-activated protein kinase(AMPK)，故認為這些化合物具有降血糖的功能。本研究的目的是更進一步探討CH63與CH93降血糖的分子機制。實驗結果顯示CH63及CH93可以促進FL83B小鼠肝臟細胞的第四型葡萄糖運送蛋白(GLUT4)移動至細胞膜上，這可能是這些化合物促進細胞葡萄糖吸收的重要機制。同時，研究證實AMPK的活化對於CH63及CH93 的降血糖功效扮演著關鍵的角色，並證實CH63及CH93活化AMPK，可能是經由LKB1。本研究更進一步提出CH63及CH93可能同時具有胰島素增敏劑及胰島素取代劑的功能。

The occurrence of type 2 diabetes is closely associated with the development of insulin resistance. Previously, two triterpenes, CH63 and CH93, were isolated from the extract of the stem of Momordica charantia. They were proved to promote glucose uptake, activate the insulin signaling pathway and AMP-activated protein kinase (AMPK) in insulin-resistant cells. Therefore, CH63 and CH93 were considered to be hypoglycemic molecules. The purpose of this study is to further explore the molecular mechanisms underlying the hypoglycemic activitise of CH63 and CH93. In this study, it was shown that CH63 and CH93 can promote the translocation of glucose transporter 4 (GLUT4) to the cell membrane in FL83B cells, which is likely an important mechanism for their hypoglycemic effects. Meanwhile, the data suggested that the activation of AMPK plays a key role for the hypoglycemic effects of CH63 and CH93. Furthermore, the data indicated that the activation of AMPK by CH63 and CH93 was likely mediated by LKB1. Based on the data presented in this study, CH63 and CH93 were proposed to work as both insulin sensitizers and insulin substitutes.

中文摘要 I
ABSTRACT II
誌謝 III
目錄 IV
圖表目錄 VII
第1章 前言 1
第2章 文獻回顧 2
2.1 第二型糖尿病 2
2.2 胰島素訊息傳遞路徑 2
2.3 胰島素抗性 4
2.4 改善胰島素抗性的藥物 5
2.5 AMPK的功能及調控路徑 6
2.6 苦瓜的降血糖活性研究 8
2.7 以細胞快速篩選降血糖分子的方法 9
2.8研究目的及架構 11
第3章 材料與方法 13
3.1 實驗材料 13
3.1.1 細胞株 13
3.1.2 細胞培養基 13
3.1.3試劑及緩衝溶液 14
3.1.3.1 Compound C (AMPK Inhibitor) 14
3.1.3.2牛胰島素溶液(bovine insulin solution) 14
3.1.3.3 小鼠腫瘤壞死因子 14
3.1.3.4 Troglitazone 14
3.1.3.5白蓮苦瓜莖材萃取物溶液之製備 14
3.1.3.6 葡萄糖濃度檢測試劑 15
3.1.3.7 蛋白質分析用試劑 15
3.1.4 蛋白質電泳分析之膠體 17
3.1.5 蛋白質分子量標記 18
3.1.6 抗體 18
3.1.6.1 一級抗體 18
3.1.6.2 二級抗體 19
3.1.7其它化學藥品 19
3.1.8 主要儀器及設備 19
3.2 實驗方法 21
3.2.1 細胞培養 21
3.2.1.1 FL83B小鼠肝臟細胞之冷凍活化 21
3.2.1.2 FL83B細胞之繼代培養 (Subculture) 21
3.2.2以共軛焦顯微鏡觀察GLUT4的轉位情形 21
3.2.3細胞葡萄糖吸收的測試 22
3.2.4 西方墨點法分析 (Western blot analysis) 23
3.2.4.1 細胞蛋白質粗萃液製備 23
3.2.4.2蛋白質定量 24
3.2.4.3聚丙烯醯胺凝膠電泳 24
3.2.4.4 蛋白質轉漬及抗體分析 24
3.2.5 實驗數據統計分析 25
第4章 結果 26
4.1檢驗CH63及CH93是否促進FL83B細胞中的GLUT4轉移到細胞膜上 26
4.2 CH63與CH93的降血糖活性是否為胰島素依賴 26
4.3 分析AMPK的活化是否為重要機制 :抑制AMPK後對CH63與CH93降血糖相關活性之影響 28
4.3.1 測試compound C的適當濃度 28
4.3.2 使用compound C後，CH63及CH93的降血糖活性 29
4.3.3 使用compound C後，CH63及CH93是否仍能活化胰島素訊息傳遞路徑 29
4.3.4 以compound C處理後，CH63及CH93是否仍能提升glucokinase的表達 29
4.4初步探討CH63及CH93活化AMPK的機制 30
第5章 討論 41
第6章結論 45
參考文獻 46
作者簡介 59
圖表目錄

圖 2-1 細胞葡萄糖吸收與代謝之分子機制………………………….....4
圖 2-2 CH63與CH93的化學結構………………………………………9
圖 2-3 以細胞快速篩選降血糖分子的方法…………………………...10
圖 2-4 實驗架構圖………………………………...…………………....12
圖 4-1 以共軛焦顯微鏡檢驗CH63及CH93是否促進FL83B細胞中的GLUT4轉移到細胞膜上………………………………………..31
圖 4-2 檢驗CH63及CH93活化Akt是否需要胰島素的存在………32
圖 4-3 檢驗CH63及CH93活化AMPK是否需要胰島素的存在……33
圖 4-4 分析CH63及CH93在無胰島素及compound C 20 μM處理下對細胞葡萄糖吸收的影響………………………………………...34
圖 4-5 測試compound C的適當使用濃度………………………….....35
圖 4-6 檢驗加了compound C 後CH63及CH93是否仍能促進AMPK的磷酸化………………………………………………………...36
圖 4-7 檢驗加了compound C後CH63及CH93是否仍能促進AS160的磷酸化………………………………………………………...37
圖 4-8 檢驗加了compound C後CH63及CH93是否仍能增加glucokinase的表達量…………………………………………...38
圖 4-9 檢驗CH63及CH93 是否活化LKB1…………………………39
圖 4-10 CH63及CH93是否活化PKCζ/λ………………………………40
圖 5-1 CH63及CH93具有胰島素增敏劑及胰島素取代劑的功能….44

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