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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 劉興華 | |
| dc.contributor.author | Wei-Chung Lee | en |
| dc.contributor.author | 李為中 | zh_TW |
| dc.date.accessioned | 2021-06-08T04:16:44Z | - |
| dc.date.copyright | 2010-09-09 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-08-01 | |
| dc.identifier.citation | Ali, A., Hoeflich, K.P., and Woodgett, J.R. (2001). Glycogen synthase kinase-3: properties, functions, and regulation. Chem Rev 101, 2527-2540.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22388 | - |
| dc.description.abstract | 二型糖尿病是目前常見的代謝疾病之一，主要和胰島素阻抗有關。當外源性或內源性胰島素對細胞的刺激不足時，細胞會無法有效的利用胰島素，造成血糖無法進入細胞被利用而滯留在循環中，此時胰島β細胞會代償性增加胰島素的分泌量以便能提高對循環中糖分的處理，當血糖在此機制下長期都無法完全達到正常血糖控制時，會造成胰島素濃度較正常人為高，也就是耐糖障礙的產生，長期惡性循環之下，便產生胰島素阻抗；此階段可能維持數年之久，直到胰島β細胞出現疲乏，細胞功能逐漸衰退，血糖值也會越來越高，即進入所謂第二型糖尿病階段。在進入第二型糖尿病階段前，動物體內葡萄糖的含量漸高，會產生梅納反應，也就是還原糖的羰基(carbonyl group)和蛋白質上的一級胺基 (primary amino group) 進行非酵素性縮合反應，而產生後期糖化終產物 (advanced glycation end products, AGEs)，而N-ε-carboxymethyl-lysine (CML) 則是AGEs中的一種。但是目前AGEs和CML與胰島的代償作用機制尚不清楚，因此本實驗目的在主要是探討葡萄糖及胰島素在高濃度時對胰島β細胞所產生的影響，而在高血糖狀態下大量產生的AGEs，是否也是透過誘發RAGE/P38/MAPK/NF-κB以及IRS2/AKT的訊息途徑，繼而造成胰島肥大的因子之一，最後形成胰島β細胞的功能異常而導致胰島素阻抗的產生。
吾人進行的實驗首先是採用糖尿病之對照組小鼠六隻（三隻公的及三隻母的），；糖尿病實驗組則是採用40-50g、8-12周（2∼3月齡）之db/db小鼠四隻（二隻公的及二隻母的）。觀察小鼠的胰島在經過生理上的代償作用後，發現有胰島肥大的現象發生，吾人接著利用葡萄糖濃度值2.8mM、11.1mM及30mM之培養基模擬血糖之狀態，以及外加2nM之胰島素加入培養基中，模擬胰島β細胞周圍含有高濃度胰島素的情形。培養胰島β細胞株（RIN-m5f）後收取細胞總蛋白質（total protein），並利用西方墨點法（western blot）觀察發現，在IRS2/AKT訊息途徑上主要的幾個磷酸化蛋白包括：P-IRS2、P-PDK、P-AKT、P-P70s6k及P-GSK3α/β，皆會隨著葡萄糖及胰島素而造成磷酸化的反應增加；由此結果推測，葡萄糖及胰島素在胰島β細胞的生理環境中，有可能會透過IRS2/AKT之訊息傳遞路徑繼而影響胰島β細胞的增生作用。另外藉由對照組的五隻母小鼠及實驗組五隻db/db母的小鼠犧牲之後取出胰臟組織，經過包埋及切片過程後，使用AGEs及CML antibody進行免疫組織化學染色的結果顯示，AGEs及CML在胰島中有表現增加的趨勢，同樣的採用CML濃度為0、0.1、1、5、20μg/ml進行western blot分析，也發現CML會增加IRS2/AKT的活化作用，最後利用免疫組織化學染色也發現胰島中IRS2/AKT有增加的趨勢，因此判斷這條代償作用的相關路徑可能是經由IRS2的磷酸化作用，活化PI3K、AKT，並抑制GSK-3β，促進cyclin D1的表現而產生。因此推測AGEs及CML在db/db小鼠中，可能是經由IRS2/AKT訊息路徑會造成GSK-3β在細胞中的活性降低，可能會導致cyclin D1的表現增加，進而增加細胞周期的運作而促進細胞的活性，造成胰島的肥大。 | zh_TW |
| dc.description.abstract | Type 2 diabetes is characterized by hyperglycemia due to insulin resistance in peripheral tissues and deficient insulin secretion by pancreatic islet β-cells. Hyperglycemia also fosters the endogenous nonenzymatic glycoxidation of proteins, lipids, and nucleic acids, and results in the accumulation of heterogeneous molecules known as advanced glycation end products (AGEs). Nε-(carboxymethyl)lysine (CML) were modified proteins have been identified as major AGEs. Compelling evidence implicates this accumulation of AGEs in the pathogenesis of diabetic complications. However, their role in β-cell dysfunction is less clear. It has been found that the compensation involves expansion of β cell mass and enhanced insulin biosynthesis in type 2 diabetes mice. In this study, CML treatment of pancreatic β cell line (RIN-m5f) was not arrest proliferation, and highly expressed phosphor IRS2/phosphor AKT, RAGE, and phosphor GSK-3β/cyclin D1, on the protein level when analyzed by Western blotting. Islets exhibited an increased frequency of these proteins staining, indicating a potential role for β-cell differentiation. Moreover we also found that the expansion of islet mass, increased insulin biosynthesis, and IRS2/AKT, and GSK-3β/cyclin D1 expressions in islets of db/db-diabetic mice. Thus, several adaptive mechanisms account for the compensatory growth of β-cells, a combination of enhanced survival and neogenesis as a potential mediator in these processes. It might be suggested that AGEs have identified a key role for the potential regulatory mechanisms whereby IRS2/AKT signaling promotes enhanced β-cell mass in an animal that develops severe insulin resistance in adulthood. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T04:16:44Z (GMT). No. of bitstreams: 1 ntu-99-R97447007-1.pdf: 4466715 bytes, checksum: df1e9643600a1da0ce5cf005882a2cb4 (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | 口試委員會審定書…………………………………………………….II
目錄………………………………….…………………………..….III 縮寫表……………………………………………………………..….IV 中文摘要……………………………………………………………….1 英文摘要……………………………………………………………….3 第一章 導論………………………………………………………….4 第一節 糖尿病的簡介……………..………………………..…...4 第二節 胰島β 細胞之功能及相關機制……………………………6 第三節 胰島β 細胞與二型糖尿病之關係………..………...….10 第四節 二型糖尿病之後期糖化終產物之生成及影響……………….15 第二章 研究目的………………………………………………...…19 第三章 材料與方法…………………………………………..…….20 第一節 實驗材料………………………..……………………..….20 第二節 實驗方法………………………………………………….…26 第四章 實驗結果…………………………………………………...40 第一節 觀察胰島素及葡萄糖分泌情形與胰島形態……………….40 第二節 觀察胰島素及葡萄糖對胰島β 細胞之影響……………….41 第三節 觀察AGEs 及CML 在胰島之表現及其影響………………..42 第四節 正常小鼠及db/db 小鼠之胰島組織學訊息傳遞路徑之觀察..44 第五章 結果討論…………………………………………………...45 第一節 研究動機…………………………………………………….45 第二節 參考依據…………………………………………….………45 第三節 IRS-2/AKT 與GSK-3β 在胰島β 細胞中的功能探討…….46 第四節 AGEs 及CML 在胰島之表現及其功能探討…………………47 第五節 組織學的染色觀察並探討相關蛋白在胰島中的表現…….....48 第六節 結論……………………………………………....……….50 圖次…………………………………………………………………...52 參考文獻…………………………………………………………...72 | |
| dc.language.iso | zh-TW | |
| dc.subject | 胰島肥大作用 | zh_TW |
| dc.subject | 二型糖尿病 | zh_TW |
| dc.subject | 胰島素阻抗 | zh_TW |
| dc.subject | IRS2/AKT 的訊息途徑 | zh_TW |
| dc.subject | 後期糖化終產物 | zh_TW |
| dc.subject | compensatory growth of β-cells | en |
| dc.subject | Type 2 diabetes | en |
| dc.subject | insulin resistance | en |
| dc.subject | IRS2/AKT signaling | en |
| dc.subject | advanced glycation end products | en |
| dc.title | 探討糖尿病對於胰島β細胞成長及功能之影響 | zh_TW |
| dc.title | The effects of diabetes in growth and function of islet β cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 蕭水銀,楊榮森 | |
| dc.subject.keyword | 二型糖尿病,胰島素阻抗,IRS2/AKT 的訊息途徑,後期糖化終產物,胰島肥大作用, | zh_TW |
| dc.subject.keyword | Type 2 diabetes,insulin resistance,IRS2/AKT signaling,advanced glycation end products,compensatory growth of β-cells, | en |
| dc.relation.page | 80 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2010-08-02 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
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