臺灣博碩士論文加值系統

研究發現肥胖、高血糖及高胰島素血症等會影響腫瘤的發生、進展和預後。腫瘤藉由改變代謝策略以滿足其快速生長的需求，例如增加葡萄糖的攝取、醣酵解及胺基酸代謝，尤其是麩醯胺酸(glutamine)的代謝。臨床前試驗及人類醫療流行病學的資料顯示使用metformin的第二型糖尿病患者具有較低的癌症罹患風險。然而，肥胖及相關代謝異常增加癌症罹患風險及惡性程度的作用機制複雜，目前仍須進一步的研究。因此，本研究的目的是探討二甲雙胍對皮下植入肺腺癌的正常體態小鼠與肥胖小鼠的腫瘤生長情況及對腫瘤代謝的影響。本實驗將五十九隻雄性C57BL/6NCrlBltw小鼠隨機分成八組：control diet + non-tumor + saline 組(CNS)、control diet + non-tumor + metformin 組(CNM)、control diet + tumor + saline 組(CTS)、control diet + tumor + metformin 組(CTM)、high-fat diet + non- tumor +saline 組(HNS)、high-fat diet + non- tumor + metformin組(HNM)、high-fat diet + tumor +saline組(HTS)及high-fat diet + tumor + metformin組(HTM)。依照組別之不同，分別餵予標準飼料及高脂飼料十週，之後標準飼料及高脂飼料各一半數的小鼠進行皮下腫瘤接種(5 X 104 LLC1 cells)。腫瘤移植後，連續三週、每日一次管餵投予metformin (300 mg/kg BW)。結果顯示十週的高脂飲食成功誘導肥胖及高血糖，而經過三週投藥期後，metformin能顯著改善此高血糖、高胰島素血症及胰島素阻抗的現象。肥胖小鼠的腫瘤生長明顯大於正常體態的小鼠，且有趣的是，metformin減輕了肥胖小鼠的腫瘤生長，而這種效應卻未見於正常體態的小鼠。西方墨點法的結果顯示肥胖腫瘤小鼠的胰島素傳訊路徑受到損害，而metformin能改善此損害。腫瘤移植後，正常體 態小鼠的血漿麩醯胺酸濃度顯著增加，但肥胖小鼠則未見相似變化。西方墨點法的結果顯示metformin調控肥胖腫瘤小鼠的肝臟麩醯胺酸代謝，增加其麩醯胺酸轉運蛋白(ASCT2)及麩醯胺酸酶(glutaminenase, GA)的蛋白質表現量，但減少麩醯胺酸合成酶(glutamine synthetase, GS)的蛋白質表現量。基於上述結果，我們證實metformin的抗癌作用可能涉及麩醯胺酸代謝的改變。

Previous studies reveal that obesity, hyperglycemia and hyperinsulinemia have an impact on tumorigenesis, progression and prognosis. Tumor cells alter metabolic strategies, such as enhancing glucose uptake, glycolysis and amino acid metabolism, especially for glutamine metabolism. Epidemiological and preclinical studies have shown that diabetic patients treating by metformin had lower cancer burden. However, the role of metformin on tumor metabolism is still unclear. Therefore, the aim of this study is to investigate the effects of metformin on isograft tumor growth and tumor metabolism produced by subcutaneously implantation of Lewis lung adenocarcinoma (LLC1) to lean and obese C57BL/6NCrlBltw mice. Fifty-nine male mice were randomly divided into eight groups: control diet + non-tumor + saline (CNS); control diet + non-tumor + metformin (CNM); control diet + tumor + saline (CTS); control diet + tumor + metformin (CTM); high-fat diet + non- tumor +saline (HNS); high-fat diet + non- tumor + metformin (HNM); high-fat diet + tumor +saline (HTS) and high-fat diet + tumor + metformin (HTM). Mice were fed with control diet or high-fat diet for 10 weeks. Half lean and obese mice were subcutaneously inoculated with 5 X 104 LLC1 cells. After implantation, daily administration of metformin (300 mg/kg BW) was delivered by oral gavage for 3 weeks. Results revealed that high-fat diet-fed for 10 weeks successfully induced obesity and hyperglycemia and metformin treatment effectively improved hyperglycemia, hyperinsulinemia and insulin resistance. There was an increased tumor growth in obese mice than in lean mice. Intriguingly, metformin attenuated tumor growth in obese mice and that effect was minor in lean mice. Results of Western blotting showed that tumor-bearing obese mice impaired hepatic insulin actions and the impairment was improved by metformin. Isograft tumor implantation increased plasma glutamine level in lean mice but not in obese mice. Results of Western blotting showed that metformin modulated hepatic glutamine metabolism in tumor-bearing obese mice by further increasing ASCT2 transporter and glutaminase expression but decreasing glutamine synthetase expression. Based on these results, we concluded that metformin have an anti-neoplastic effect which maybe involve alteration of glutamine metabolism.

摘要 i
Abstract ii
目次 iii
圖次 v
表次 vi
第一章 前言 - 1 -
第二章 文獻探討 - 2 -
第一節 肥胖與代謝異常 - 2 -
1.1 代謝症候群 - 2 -
1.2 胰島素阻抗 - 2 -
1.3 胺基酸代謝異常 - 3 -
第二節 肥胖/第二型糖尿病與腫瘤之關聯 - 3 -
2.1 流行病學上的證據 - 3 -
2.2 可能之作用機制 - 4 -
第三節 腫瘤的代謝重新規劃 - 4 -
3.1 基本介紹 - 4 -
3.2 腫瘤好比是葡萄糖及麩醯胺酸的代謝陷阱 - 5 -
3.3 腫瘤由宿主組織中提取麩醯胺酸及其他必須胺基酸 - 5 -
3.4 宿主組織之麩醯胺酸代謝酵素異常 - 6 -
3.5 腫瘤之麩醯胺酸降解作用 - 6 -
3.6 腫瘤之代謝多功能性：葡萄糖代謝與麩醯胺酸降解之相互作用 - 7 -
3.7 麩醯胺酸酶同工酶：於腫瘤發生時扮演相反的角色 - 8 -
第四節 二甲雙胍Metformin - 8 -
4.1 發展簡史 - 8 -
4.2 臨床應用 - 9 -
4.3 抗癌作用：流行病學調查 - 9 -
4.4 抗癌作用：可能之作用機制 - 9 -
第五節 研究目的與實驗設計 - 10 -
第三章 材料與方法 - 16 -
第一節 實驗動物與試驗規劃 - 16 -
第二節 禁食血糖與血漿胰島素濃度 - 16 -
第三節 恆定模式評估指數HOMA-IR - 16 -
第四節 血漿麩醯胺酸濃度 - 17 -
第五節 臟器萃取與西方墨點法 - 17 -
第六節 統計分析 - 17 -
第四章 結果 - 18 -
第一節 體重變化 - 18 -
第二節 攝食量 - 18 -
第三節 攝食熱量 - 18 -
第四節 腫瘤重量 - 18 -
第五節 禁食血糖 - 18 -
第六節 血漿胰島素濃度 - 19 -
第七節 恆定模式評估指數(Homeostasis Model Assessment Index) - 19 -
第八節 血漿麩醯胺酸濃度 - 20 -
第九節 肝臟胰島素傳訊路徑及麩醯胺酸代謝之相關蛋白質表現量 - 20 -
第五章 討論 - 33 -
第六章 結論 - 37 -
參考文獻 - 38

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