臺灣博碩士論文加值系統

糖尿病患長期處於高血糖的環境下，容易引發葡萄糖自動氧化 (autoxidation)與蛋白質醣化 (glycation)。在糖尿病及老化的過程中，高度醣化終產物advanced glycation end products (AGEs) 被證實其扮演了抑制細胞生長、分化及機能的角色。AGEs是蛋白質或脂質經過非酵素參與之醣化作用 (non-enzymatic glycosylation) 及氧化作用，所形成的最終物質。以羧甲基離氨基酸(Nε-(carboxymethyl) lysine (CML)) 及羧乙基離氨基酸 (carboxyethyl lysine (CEL))為存在於生物體內的主要形式。當AGEs在人體組織內累積過量時，會產生較多的reactive oxygen species (ROS)，使得體內氧化壓力增加，進而促使脂質過氧化物增加，並促使血中脂蛋白的醣化及氧化，往往是造成罹患糖尿病、慢性腎病變、動脈硬化症等重要的因素。beta細胞是人體內主要分泌胰島素的場所，研究指出當粒線體功能缺損，ATP形成不足會影響胰島素的分泌。本研究的主旨為探討CML是否經由引發粒線體功能缺損而影響beta細胞功能進而降低分泌胰島素的功能。本實驗是利用大鼠胰島beta細胞 (RIN-m5F細胞株) 為細胞模式，由結果顯示當beta細胞經6 μM CML處理24小時後，發現造成細胞存活率明顯下降到70.4% ± 0.8% (p < 0.001)，ROS的產量比對照組增加29.9% ± 15.9% (p < 0.01)。進一步分析粒線體膜電位，發現CML處理可降低粒線體膜電位至13.9% ± 2.3% (p < 0.001)。β細胞經CML處理6小時後，分析細胞內ATP含量，ATP含量減少到對照組的55.9% ± 10.5% (p < 0.01)。此外，我們也發現CML會產生脂質過氧化及粒線體基因重組突變。此外，β細胞的胰島素釋放減少至69.1% ± 0.5% ( p < 0.001)。當以西方墨點法分析發現CML處理可以使粒線體內UCP2增加至112.4% ± 0.1%，而UCP2的增加可能與粒線體的氧化磷酸化作用及膜電位降低有關。本研究發現，CML造成粒線體功能缺損進而降低β細胞的胰島素的含量及分泌能力。我們推論CML可能在β細胞功能缺損，及β細胞mass減少扮演重要的角色。

Abstract
Diabetes is caused by progressive β cell dysfunction, insulin secretion deficiency and insulin resistance. Advanced glycation end products (AGEs) are nonenzymatically formed by reducing glucose, lipids, and/or certain amino acids on proteins, lipids, and nucleic acids. Nε-(carboxymethyl) lysine (CML) and carboxyethyl lysine (CEL) modified proteins have been identified as major AGEs. In this study, we investigated whethen CML might cause β cell malfunction via mitochondrial dysfunction. We examined the effects of CML-BSA on cell viability, insulin synthesis and secretion, and mitochondrial function in rat pancreatic β cells (RIN-m5F cells). Treatment of RIN-M5F cells with CML-BSA (6 μM) reduced the cell viability 70.4% ± 0.8% (p < 0.001) by dye exclusion assay. CML-BSA increased ROS generation as demonstrated in a time-dependent manner. Treatment of cells with CML-BSA (6 μM) reduced ATP production, mitochondrial membrane potential, and insulin secretion by 55.9% ± 10.5% (p < 0.01), 13.9% ± 2.3% (p < 0.001), 69.1% ± 0.5% (p < 0.001) respectively. Furthermore, 12.4% ± 0.1% increased of UCP2 were found in the CML-BSA treated cells. The increased UCP might contribute the declined mitochondrial respiratory activity and mitochondrial membrane potential. These results suggest that CML could attenuate insulin secretion via mitochondrial dysfunction of β cells. CML-BSA might play an important role in the progressive β cells dysfunction and loss of β cells.

縮寫表 1
摘要 3
Abstract 4
研究目的及動機 5
文獻回顧 6
一、糖尿病 (Diabetes Mellitus, DM) 6
二、 胰臟胰島內細胞 (pancreatic cells) 8
三、胰島素 (insulin) 8
四、Advanced glycation end products (AGEs) 9
五、Nε-(Carboxymethyl) lysine (CML) 10
六、粒線體 (mitochondria) 11
1. 粒線體外觀與構造 11
2. 粒線體功能 12
3. 粒線體DNA (mtDNA) 12
4. 粒線體去偶合蛋白家族 (uncoupling protein family) 13
七、氧化壓力 (oxidative stress) 14
八、實驗目的 15
實驗的材料與方法 17
藥品試劑 17
實驗方法 19
ㄧ、大鼠胰臟胰島內β細胞 ( Rattus Norvegicus pancreatic β-cell )培養 19
二、Nε-(carboxymethyl) lysine(CML)-BSA配製 19
三、細胞存活率 (Cell viability) 19
四、細胞蛋白質製備 (Preparation of cell lysate) 20
五、蛋白質定量法 (Protein assay) 20
六、西方墨點法 (Western blotting) 21
七、流式細胞儀分析 22
八、粒線體產生ATP能力測定 24
九、以Lowry方法進行蛋白分析 24
十二、細胞分泌胰島素的能力測定 25
十三、測定粒線體DNA突變 25
十四、分析細胞內相關基因的表現 27
十五、Real-time Quantitative PCR 28
十六、雷射共軛焦顯微鏡 28
十七、統計分析 29
實驗結果 30
一、CML造成β細胞的細胞存活率 (cell viability) 下降 30
二、CML引發β細胞中ROS增加 30
三、CML處理影響細胞粒線體膜電位改變 31
四、CML影響細胞粒線體內ATP的含量 31
五、CML影響β細胞內胰島素的分泌及合成 31
六、CML處理對β細胞內粒線體DNA的影響 32
1. 粒線體DNA copy number 32
2. CML所引發粒線體DNA突變、斷裂與斷損DNA序列分析 32
七、CML引發去偶合蛋白(UCP2)的表現 32
討論 33
參考文獻 39
實驗圖表 51
Table.1本論文所使用的寡核苷酸引子，用來分析Rat β細胞受CML處理後，粒線體 DNA(mtDNA)和基因表現量。 51
Fig. 1.醣化終產物(advanced glycation end products，AGEs)形成的機制 52
Fig. 2.Nε-carboxymethyllysine(CML)化學結構式 53
Fig. 3.CML對rat β 細胞存活率的影響 54
Fig. 4.CML造成rat β細胞存活率隨作用時間增加而下降 55
Fig. 5.CML引發β細胞內ROS增加. 56
Fig. 6.β細胞處理CML後粒線體膜電位的變化 57
Fig. 7.CML造成β細胞ATP含量減少 58
Fig. 8.β細胞處理CML後細胞內proinsulin的變化 59
Fig. 9.β細胞處理CML後降低細胞內胰島素蛋白量的含量 60
Fig.10.β細胞處理CML後胰島素的變化 61
Fig.11.β細胞處理CML後細胞內胰島素的變化 62
Fig.12.β細胞處理CML後胰島素分泌的能力 63
Fig.13.β細胞處理CML後細胞內mtDNA copy numbers的變化 64
Fig.14.β細胞處理CML後造成細胞內mtDNA有刪除(deletion)的現象 65
Fig.15.β細胞處理CML後細胞內UCP2含量的變化 66

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