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研究生:李家慧
研究生(外文):Lee Chia Hui
論文名稱:嚼食檳榔在胰島素抗性及內皮細胞功能異常中扮演的角色-探討檳榔鹼對人類內皮細胞中胰島素訊息傳遞的影響
論文名稱(外文):A Possible Role of Betel-quid Chewing in Insulin Resistance and Endothelial Dysfunction-Effects of Arecoline on Insulin Signaling in Human Endothelial Cells
指導教授:謝義興李建興李建興引用關係
口試委員:謝義興
口試日期:2012-12-28
學位類別:碩士
校院名稱:國防醫學院
系所名稱:牙醫科學研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:53
中文關鍵詞:檳榔鹼
外文關鍵詞:Arecoline
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背景:嚼食檳榔在亞洲各國是一種普遍的現象。而檳榔當中的檳榔鹼(Arecoline)已證實會經由增加細胞當中活性氧(Reactive oxygen species ROS)的產生造成細胞與動物產生細胞毒性(cytotoxic)以及基因毒性 (genotoxic)。近幾年的研究也指出ROS與心血管疾病及糖尿病的生成有關。除此之外,更有文獻證實嚼食檳榔與心血管疾病及糖尿病的死亡率有關,但其中的機制還不是很明確。在2011年的研究發現給予脂肪細胞檳榔鹼(Arecoline)的刺激,會影響脂肪細胞當中胰島素的敏感性及胰島素訊息傳遞,進而降低葡萄糖的攝取。經由以上的研究,我們認為嚼食檳榔惡化糖尿病及心血管疾病的原因,可能是由於檳榔當中的檳榔鹼(Arecoline)增加血管內皮細胞ROS的產生,進而影響胰島素的訊息傳遞,並造成血管內皮細胞的功能異常。
方法:利用檳榔鹼(Arecoline)去處理人類血管內皮細胞。觀察檳榔鹼(Arecoline)對血管內皮細胞中ROS的變化,及血管內皮細胞中黏附因子的表現和胰島素訊息傳遞路徑中蛋白的變化。並進一步利用氧化還原劑(NAC)和胰島素增敏劑Rosiglitazone的處理,觀察血管內皮細胞的改變。
結果:結果顯示人類血管內皮細胞(HMEC-1)產生ROS的情形會隨著檳榔鹼(Arecoline)的濃度及給予的時間而增加。另外HMEC-1的ICAM-1及VCAM-1表現量,也因為給予檳榔鹼後表現量有增加的情形。在內皮細胞與單核球細胞(monocyte THP-1)的黏附實驗中,結果顯示給予檳榔鹼的HMEC-1與THP-1黏附的細胞數明顯高於對照組。進一步檢測檳榔鹼對於胰島素訊息傳遞的影響,檳榔鹼的刺激會使得胰島素訊息傳遞路徑相關蛋白IRS-1及Akt的表現量下降,並且IRS-1的上游蛋白JNK的磷酸化也受到檳榔鹼的影響而上升。接著我們利用N-acetylcysteine(NAC)氧化還原劑觀察到NAC確實可以降低檳榔鹼(Arecoline)導致的ROS生成,並且使得ICAM-1及VCAM-1的表現量隨之降低及回復了原本被檳榔鹼(Arecoline)影響的磷酸化JNK、磷酸化IRS-1及Akt的表現量。最後在胰島素增敏劑Rosiglitazone的實驗,結果顯示Rosiglitazone也可以降低檳榔鹼(Arecoline)造成的ROS生成,Rosiglitazone同時降低了ICAM-1及VCAM-1的表現量,最後也發現Rosiglitazone回復了檳榔鹼(Arecoline)對於磷酸化JNK、磷酸化IRS-1及Akt的影響。
結論:由以上可知,檳榔鹼(Arecoline)確實會增加內皮細胞ROS的生成,進一步增加細胞表面ICAM-1及VCAM-1的表現量,而使得內皮細胞黏附單核細胞的數目增加,另外檳榔鹼(Arecoline)還會影響血管內皮細胞胰島素訊息的傳遞路徑;而氧化還原劑NAC及胰島素增敏劑Rosiglitazone的確可以回復檳榔鹼(Arecoline)對於血管內皮細胞的影響。本研究亦證實嚼食檳榔對胰島素抗性及血管內皮細胞通能之影響,進一步可能造成心血管疾病及糖尿病。

Background :
Betel nut is the most widely used addictive substance in the world , and betel quid chewing is a common oral habit in South Asia and Taiwan. Being a major alkaloid in betel nut , arecoline has long been considered a potential carcinogen. Several reports showed that arecoline can increase reactive oxygen species (ROS) to produce cytotoxicity and genotoxicity . Recent reports indicate that betel quid chewing also increase the risk of atherosclerosis and diabetes. However, the detail mechanism remains unknown. Most recently, arecoline have diabetogenic potential on adipocytes that may result in insulin resistance and diabetes at least in part via the obstruction of insulin signaling and the blockage of lipid storage. In this study, we try to investigate the possible mechanisms of arecoline induced insulin resistance and endothelial dysfunction.
Methods :
Human dermal microvascular endothelial cell (HMEC-1) were treated in different arecoline concentrations and tested the ROS levels and the expression of adhesion molecules, insulin signaling pathways and cell adhesion function. Then N-acetylcysteine (NAC) and Rosiglitazone were added to exam the effect on arecoline-induced endothelial dysfunction.
Results :
Our data showed that the ROS levels and adhesion molecules (ICAM-1, VCAM-1) significantly increased after arecoline treatment and along with increased adhesion ability between HMEC-1 and monocyte. The results also revealed that increased phosphorylation of JNK then downregulated insulin signaling pathways through IRS-1 and AKT after arecoline treatment. With the use of reducing agent NAC and Rosiglitazone in the arecoline-induced endothelial cell dysfunction, these cell dysfunctions and downstream signalings were found to be diminished and recovered.
Conclusions :
Our present study explore the influence of betel nut extract - arecoline on insulin signaling and endothelial dysfunction and partially explain the increased risk of insulin resistance and cardiovascular disease from betel nut chewing . In addition, our data showed Rosiglitazone reduced arecoline-induced endothelial dysfunction and insulin resistance including of reducing ICAM-1 and VCAM-1 expression and monocyte adhesion by modulating the JNK-IRS-1-PI3K/AKT signaling pathway in endothelial cells.

誌謝……………………………………..………………….………….Ⅰ
目錄……………………………………..………………….………….Ⅱ
圖目錄…………………………………………..………….………….Ⅲ
附錄目錄…………………………………………………………….. Ⅵ
中文摘要………………………………………………..…….……….Ⅴ
英文摘要………………………………………………..…….………. Ⅵ

第一章 緒論………………………………………………….……...01
第一節 檳榔與口腔疾病……………………………….………. .01
第二節 檳榔鹼與糖尿病、心血管疾病…………………….…...04
第三節 檳榔鹼與胰島素抗性、內皮細胞功能異常……………05
第四節 胰島素增敏劑.…………………………………….….….08
研究動機…………….………………………………………………...10
第二章 實驗材料與方法……………………………………….…...11
第一節 實驗材料 ……………………………………………....11
第二節 實驗方法 ……………………………………………....13
第三章 結果………………………………………………………....19
第一節 Arecoline對HMEC-1的細胞的影響……………………… 19
Arecoline對HMEC-1的細胞毒性測試
Arecoline對HMEC-1的細胞產生ROS的變化
Arecoline造成HMEC-1細胞產生ICAM-1和VCAM-1的表現
Arecoline 造成 THP-1 黏附到 HMEC-1細胞上的表現
Arecoline對HMEC-1細胞內胰島素訊息傳遞路徑的影響
第二節 氧化還原劑N-acetylcysteine(NAC)對Arecoline造成
HMEC-1細胞的影響…………………………………………20
氧化還原劑 (NAC)對Arecoline造成HMEC-1細胞產生ROS的變化
氧化還原劑(NAC)對Arecoline造成HMEC-1細胞產生ICAM-1和VCAM-1的表現
氧化還原劑(NAC)對Arecoline 造成THP-1 黏附到 HMEC-1細胞上的表現
氧化還原劑(NAC)對Arecoline造成HMEC-1細胞內胰
島素訊息傳遞路徑變化之影響
第三節 胰島素增敏劑Rosiglitazone 對Arecoline造成HMEC-1
細胞的影響……………………………………………… 22
Rosiglitazone 對Arecoline造成HMEC-1細胞產生ROS變化
Rosiglitazone 對Arecoline對HMEC-1細胞產生ICAM-1
和VCAM-1的表現
Rosiglitazone對Arecoline造成THP-1 黏附到 HMEC-1細胞上的表現
Rosiglitazone Arecoline影響HMEC-1細胞內胰島素訊息傳遞路徑變化之影響
第四章 討論…………………………………………………………27
第五章 結論…………………………………………………………29
參考文獻………………………………………………………………30
圖表……………………………………………………………………34

圖目錄
圖一 Arecoline對HMEC-1的細胞毒性測試……………………34
圖二 Arecoline對HMEC-1的細胞產生ROS的變化……………35
圖三 Arecoline造成HMEC-1細胞產生ICAM-1和VCAM-1的表
現……………………………………………………………36
圖四 Arecoline 造成 THP-1 黏附到 HMEC-1細胞上的表現..37
圖五 Arecoline對HMEC-1細胞內胰島素訊息傳遞路徑的影
響…………………………………………………………… 38
圖六 氧化還原劑 (NAC)對Arecoline造成HMEC-1細胞產生ROS的
影響…………………………………………………………39
圖七 氧化還原劑(NAC)對Arecoline造成HMEC-1細胞功能損害之
影響…………………………………………………………40
圖八 氧化還原劑(NAC)對Arecoline造成HMEC-1。細胞黏附功能
之影響………………………………………………………41
圖九 氧化還原劑(NAC)對Arecoline影響HMEC-1細胞內胰島素訊
息傳遞路徑變化之影響……………………………………42
圖十 Rosiglitazone 對Arecoline造成HMEC-1細胞產生的ROS的
影響…………………………………………………………43
圖十一 Rosiglitazone 對Arecoline對HMEC-1細胞功能損害之影
響………………………………………………………………44
圖十二 Rosiglitazone對Arecoline造成HMEC-1細胞黏附功能影
響………………………………………………………………45
圖十三 Rosiglitazone Arecoline影響HMEC-1細胞內胰島素訊息傳
遞路徑變化之影響……………………………………………46














附錄目錄
附錄一 : 全球盛行嚼食檳榔地區……………………………………47
附錄二 : ROS的產生對細胞的影響………………………………… 48
附錄三 : 代謝疾病與心血管疾病的致病機轉……………………… 49
附錄四 : 對胰島素敏感的細胞中胰島素傳遞路徑………………….50
附錄五 : NF-κB傳導與脂肪酸產生的炎症和胰島素抵抗的關係…51
附錄六:高血糖影響B-cell的胰島素訊息傳遞路徑……………… 52
附錄七 :血管內皮細胞中PPAR的路徑的活化…………………… 53


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