第 2 型糖尿病 (T2DM) 是一種以組織高血糖和胰島素抵抗 (IR) 為特徵的全球流行的代謝性疾病，通常伴有各種高風險的併發症。在藥物治療上其中一類為 Dipeptidyl peptidase 4 inhibitor，其抑製劑可以保護小腸分泌的腸泌素 (GLP-1) 不易被 DPP-IV 降解，降低血糖和改善葡萄糖耐受性受損。台灣龍膽石斑魚，其因快速生長的能力和較高的市場價格而在台灣廣泛繁殖，其魚卵富含高質量的蛋白質和脂質，然而在大規模的魚卵生產過程中，生產過剩以及孵化失敗的廢棄魚卵成為副產物，，這導致蛋白質資源大量浪費。而為了利用蛋白質副產物，並增加其附加價值，可以實施使用酵素水解以增強魚卵蛋白質水解物的生物活性。此本研究目的為探討最適水解龍膽石斑魚魚卵條件並分析水解物體外抑制 DPP-IV 能力，並進一步以動物實驗模型探討魚卵水解物對第二型糖尿病之影響。希望可以從食物蛋白質來源生產 DPP-IV 抑制胜肽來取代合成 DPP-IV 抑製劑。在體外測定使用 2 % pepsin 水解魚卵 6 小時，測定其有最高的胜肽含量、DPP-IV 抑制能力。且透過超過濾和模擬腸胃道消化可以提升其 DPP-IV 抑制能力。進一步動物實驗使用高脂飲食 (High fat diet, HFD) 及 Streptozotocin (30mg/kg) 誘導雄性小鼠成為第二型糖尿病模式，實驗組別分為控制組、糖尿病組、正控制組 (Metformin, 24.6mg/kg)、GRHs_1x(200mg/kg)、GRHs_2x (400 mg/kg) 及 GRHs_5x (1000 mg/kg)，持續餵食六周後犧牲取其海馬迴、肝臟組織及血漿進行分析。結果指出五倍劑量組能顯著降低血清中血糖、TG、TC、AST、ALT，也可降低 DPP- IV 濃度以及 DPP- IV 活性，增加葡萄糖耐受性、GLP-1 濃度、胰島素濃度並且可降低 HOMA-IR 指數改善胰島素抗性。在肝臟組織結果顯示降低發炎反應之影響，並增加組織中抗氧化酵素活性、抑制脂質過氧化。，且並也可改善其認知行為在水迷宮實驗結果顯示出學習型未的改善和逃脫時間的降低，改善其認知行為，且在肝臟組織切片脂肪油滴及脂防空泡相較於DM組顯著減少。綜合上述結果顯示，GRHs 可改善糖尿病小鼠之高血糖及胰島素阻抗，顯示了作為第 2 型糖尿病之健康食品 2 型糖尿病的潛力。

Type 2 diabetes mellitus (T2DM) is a global prevalence of metabolic diseases characterized by hyperglycemia and insulin resistance (IR) in target tissues, which is generally accompanied by a high risk of various complications. In terms of drug treatment, one of them is dipeptidyl peptidase 4 inhibitor. Its inhibitor can protect intestinal secretion of incretin (GLP-1) from being easily degraded by DPP-IV, reduce blood glucose and improve impaired glucose tolerance. Taiwan giant grouper (Epinephelus lanceolatus), which is widely bred in Taiwan due to its rapid growth ability and high market price. Its roe are rich in high-quality protein and lipids；however, during large-scale roe production, overproduction and hatching failed discarded fish roe become a by-product. It results in a massive waste of protein resources. In order to utilize protein by-products and increase their added value, an enzymatic hydrolysis can be implemented to enhance the biological activity of fish roe protein hydrolysate. The purpose of this study was to design for the DPP-IV inhibitory peptides produced from food protein sources to replace synthetic DPP-IV inhibitors. In vitro analysis, using 2% pepsin to hydrolyze fish roe for 6 hours had the highest peptide content and DPP-IV inhibitory ability. In addition its DPP-IV inhibitory ability can be enhanced by ultrafiltration and simulated gastrointestinal digestion. Therefore, this condition was chosen to prepare GRHs. The in vivo studies were carried out with three different doses of GRHs and the diabetis mice was induced by administrating with streptozotocin (30 mg/kg) and 45 % high fat diet. The groups were divided into a control group, a diabetic group (DM), a positive control group (ACTOs, 200 mg/kg), GRHs_1x(200mg/kg), GRHs_2x (400 mg/kg) and GRHs_5x (1000 mg/kg) for six weeks. The results indicated that the GRHs_5x group can significantly reduce blood glucose, TG, TC, AST, ALT in serum, as well as reducing DPP-IV concentration and DPP-IV activity, increasing glucose tolerance, GLP-1 concentration, insulin concentration and to reduce HOMA-IR, leading to the improvement of insulin resistance. Results in liver tissue showed reduced effects of inflammation, increased activity of antioxidant enzymes in tissue, and inhibited lipid peroxidation. The results observed from the water maze experiment showed that the learning ability was improved, the escape time was reduced, and the cognitive behavior was improved. In summary, GRHs shows the potential to be a functional food ingredient for treating type 2 diabetes.

壹、前言 1
貳、文獻回顧 2
一、台灣龍膽石斑魚 2
1.1 簡介 2
1.2 養殖現況 2
1.3 種魚培育 3
二、龍膽石斑魚卵 3
2.1 培育 3
2.2 副產物 4
2.3 生理活性 4
三、糖尿病 9
3.1近年趨勢 9
3.2 糖尿病定義與種類 9
3.3 胰島素阻抗 10
3.4併發症 11
3.5 糖尿病患者治療方式 12
3.6糖尿病患者醫療成本 13
四、Dipeptidyl peptidase- IV 14
4.1 簡介 14
4.2 降血糖機制 14
4.3 Dipeptidyl peptidase- IV抑制劑 16
五、糖尿病動物模式 17
5.1 STZ誘導 17
5.2 db/db 小鼠 17
參、實驗架構 18
肆、實驗材料 20
一、實驗材料 20
1.1 龍膽石斑魚卵 20
1.2 實驗動物 20
1.3 實驗動物飼料 20
1.4 藥品 20
1.5 儀器設備 23
伍、實驗方法 24
一、樣品製備及體外測定 24
1.1 魚卵前處理 24
1.2 魚卵成分分析 24
1.3十二烷基硫酸鈉聚丙烯醯胺膠體電泳 (SDS-PAGE) 25
1.4 酵素水解 25
1.5 酵素水解物特性分析 26
1.6 DPP-IV抑制能力測定 27
1.7 超過濾 27
1.8 模擬腸胃道消化 (SGID) 28
二、第二型糖尿病小鼠之動物實驗 28
2.1 第二型糖尿病誘導 28
2.2 實驗設計 28
2.3 實驗動物飼養 29
2.4 血液生化分析 29
2.5 動物認知行為能力試驗 34
2.6 小鼠器官採集及均質液體製備 35
2.7肝臟組織中蛋白含量分析 36
2.8組織中氧化與抗氧化成分析 36
2.9肝臟組織發炎細胞激素濃度分析 39
2.10組織病理分析 41
2.11 統計分析 42
陸、結果與討論 43
一、龍膽石斑魚卵成分分析 43
二、龍膽石斑魚卵水解物分析 43
三、糖尿病小鼠之誘導 45
四、GRHs對糖尿病小鼠生長表現和臟器重量之影響 45
五、GRHs對糖尿病小鼠血脂及肝指數之影響 46
六、GRHs 對糖尿病小鼠血清抗氧能力、血糖及胰島素及相關生化指數之影響 47
七、GRHs 對糖尿病小鼠肝臟組織氧化壓力及抗氧化與抗發炎能力之影響 49
八、GRHs 對糖尿病小鼠肝臟組織切片影響 50
九、GRHs 對糖尿病小鼠認知行為改善之影響 51
十、GRHs對糖尿病小鼠海馬迴切片之影響 52
柒、結論 54
捌、未來研究方向 55
玖、參考文獻 56
拾、附錄 92

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