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研究生:呂蘭英
研究生(外文):Lan-Ying Lu
論文名稱:補充生物素對產生胰島素阻抗性的第2型糖尿病KK小鼠骨骼肌中IRS-1、IRS-2的蛋白質表現與酪胺酸磷酸化,及其與PI3-kinase連結的影響
論文名稱(外文):Effect of Biotin Supplementation on Protein Expression, Tyrosine Phosphorylation and Association with PI 3-kinase in Skeletal Muscle of Insulin-Resistant Type 2 Diabetic KK Mice
指導教授:張毓芬張毓芬引用關係
學位類別:碩士
校院名稱:中國醫藥大學
系所名稱:營養學系碩士班
學門:醫藥衛生學門
學類:營養學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:107
中文關鍵詞:生物素IRS-1 (Insulin receptor substrate-1)IRS-2(Insulin receptor substrate-2)PI 3-kinase (Phosphatidylinositol 3-kinase)
外文關鍵詞:biotinIRS-1IRS-2IRS-1 tyrosine phosphorylationIRS-2 tyrosine phosphorylationPI 3-kinase
相關次數:
  • 被引用被引用:1
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中文摘要
本研究室先前的研究發現,長期給予第2型糖尿病KK小鼠補充生物素可改善空腹血糖、葡萄糖耐受異常和胰島素阻抗性,並且可顯著增加骨骼肌細胞中中葡萄糖轉運蛋白4(GLUT4)的表現量和位移情形。胰島素阻抗性主要發生在骨骼肌,近年有很多研究在探討胰島素訊息傳導和胰島素阻抗性的關係。過去研究認為,初步胰島素訊息傳導的改變是構成胰島素阻抗的重要因素。所以本研究欲進一步探討補充生物素對改善骨骼肌中葡萄糖轉運是否經由影響胰島素傳導路徑中IRS-1 (Insulin receptor substrate-1)、IRS-2(Insulin receptor substrate-2) 的蛋白質表現與酪胺酸磷酸化(tyrosine phosphorylation),及其與PI 3-kinase (Phosphatidylinositol 3-kinase) 連結的影響。第2型糖尿病雄性KK小鼠先以高脂飲食誘導糖尿病症狀後,分別給予不同劑量的生物素補充(生理水、3mg或6 mg生物素/Kg of body wt/day),為期四週。補充期結束時,胰島素誘導組在犧牲前30分鐘給予腹膜內注射4U/100g regular insulin。犧牲後取得骨骼肌樣品,以免疫沉澱法和免疫墨點法分析IRS-1,2、IRS-1,2 tyrosine phosphorylation及與IRS連結的PI 3-kinase蛋白質表現量。結果顯示,在沒有胰島素的刺激下,3mg和6mg的生物素組,骨骼肌中IRS-1與IRS-2的蛋白質總表現量均顯著高於生理水組,但IRS-1的總蛋白質表現量3mg和6mg組之間沒有顯著差異,IRS-2則以6mg組顯著高於3mg組;而有胰島素刺激下,IRS-1與IRS-2的總蛋白質表現以6mg組最高,3mg組次之,生理水組最低,其中只有6mg組在有或無胰島素情況之間有顯著性差異。在沒有胰島素刺激的情況下(即為基礎狀態下),生理水組的IRS-1酪胺酸磷酸化型式的蛋白質和補充生物素3mg組和6mg組之間沒有顯著差異,但補充生物素3mg組比6mg組較高 (p<0.05);然而在有胰島素的刺激之下,生理水組顯著低於補充生物素3mg及6mg組 (p<0.05),但補充生物素6mg和3mg組之間沒有顯著差異。IRS-2酪胺酸磷酸化型式的蛋白質表現量在沒有胰島素刺激的情況下為6mg組最高、3mg組次之而生理水組最低 (p<0.05);然而在有胰島素的刺激之下,其蛋白質表現量亦為補充生物素6mg組最高、3mg組次之而生理水組最低(p<0.05)。與IRS-1 連結的PI 3-kinase之蛋白質表現,在有或沒有胰島素刺激下,都是6mg組最高,3mg組次之,生理水組最低,其中生理水組和3mg組在有或無胰島素情況之間有顯著性差異。與IRS-2連結的PI 3-kinase之蛋白質表現,在沒有胰島素的刺激下,6mg組顯著高於生理水組但與3mg組沒有顯著差異;在有胰島素刺激下6mg組顯著高於生理水組。由本研究結果推論,補充生物素可經由增加骨骼肌細胞中IRS-1與IRS-2的蛋白質表現量及與IRS-1、IRS-2連結的PI 3-kinase蛋白質表現量,而改善了骨骼肌細胞對葡萄糖的利用。
目錄
目錄…………………………………………………………………Ⅰ
圖次.…………………………………………………………………Ⅴ
表次…………………………………………………………………Ⅶ
縮寫表…………………………………………………………Ⅸ
中文摘要…………………………………………………………Ⅹ
英文摘要……………………………………………………………ⅩⅢ
第一章、緒言……………………………………………………1
第二章、文獻整理……………………………………………………3
壹、糖尿病……………………………………………………….3
一、糖尿病………………………………………………3
二、糖尿病的分類 …………………………………………….4
三、糖尿病的診斷標準………………………………………...6
四、第2型糖尿病與胰島素阻抗性……………………………9
貳、胰島素訊息傳導………………………………………….11
一、簡介胰島素………………………………………………11
二、胰島素訊息傳遞路徑…………………………………….12
三、PI 3-kinase pathway的胰島素訊息傳遞路徑……………16
四、胰島素訊息傳導與胰島素阻抗性的關係……………….24
參、簡介生物素………………………………………………….26
一、生物素…………………………………………………..26
二、生物素對於代謝的影響………………………….……….31
三、生物素對於葡萄糖代謝於基因層面的影響……………...33
四、生物素對於糖尿病模式之葡萄糖代謝的影響…………...35
肆、本研究室先前的結果…………………………………………38
一、補充生物素對調控血糖的影響…………………38
二、生物素對骨骼肌中GLUT4蛋白質表現及位移的影響….44
第三章、研究目的…………………………………………………47
第四章、材料與方法……………………………………………….48
壹、試驗動物與飼養條件…………………………………..48
一、試驗動物模式………………………………………….48
二、飼料與墊料…………………………………………….50
三、飼料成分……………………………………………….50
四、飼養環境條件……………………………………………...52
五、生物素的補充…………………………………………..52
貳、試驗設計與分組……………………………………………53
參、試驗流程……………………………………………………..55
肆、測試項目…………………………………………………..56
一、空腹血糖值之測定………………………………………56
二、腹腔葡萄糖耐受性試驗…………………………………..56
三、血清胰島素濃度………………………………………..57
四、胰島素阻抗性…………………………………………..57
五、骨骼肌中總IRS-1、IRS-2;IRS-1、IRS-2酪胺酸磷酸化
形式及與其相連結的PI 3-kinase之蛋白質表現
量………………………….……………………………...58
伍、統計分析…………………………………………………...72
第五章、結果…………………………………………………………73
補充生物素對於骨骼肌中胰島素訊息傳遞上游路徑蛋白質表
現的影響……………………………73
一、總IRS-1蛋白質表現量……………………………73
二、總IRS-2蛋白質表現量..………………………….75
三、IRS-1酪胺酸磷酸化型式的蛋白質表現量………………77
四、IRS-2酪胺酸磷酸化型式的蛋白質表現量………………79
五、與IRS-1相連結的PI 3-kinase蛋白質表現量…………..81
六、與IRS-2相連結的PI 3-kinase蛋白質表現量…………..83
第六章、討論……………………………………………………85
壹、補充生物素對於空腹血糖、葡萄糖耐受性及胰島素阻抗性
的影響…………………………………………………….85
貳、補充生物素對胰島素訊息傳遞上游路徑的影響…………88
一、生物素對胰島素訊息傳遞路徑上游中IRS-1、IRS-2的影響…………………………………………………………….88
二、生物素對胰島素訊息傳遞路徑中與IRS-1、IRS-2相連結
的PI 3-kinase之影響……………………………………..92
第七章、結論………………………………………………………94
第八章、參考文獻…………………………………………………….96
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