臺灣博碩士論文加值系統

第2型糖尿病的新穎療法是利用腸泌素 (incretin) 來治療，腸泌素為腸道所分泌的荷爾蒙，主要有glucagon like peptide-1 (GLP-1)，可促進餐後胰島素分泌、維持血糖恆定；GLP-1屬於多肽，易被體內雙胜肽水解酶 (dipeptidyl peptidase IV；DPP-IV) 水解而失去活性，DPP-IV主要作用為移去胜肽中N-端之雙肽，且N-端第二個位置為Pro或Ala之胜肽具有較佳抑制DPP-IV活性，因此若能製備出Pro或Ala含量較高之胜肽，可能具有降低DPP-IV對GLP-1的作用，進而改善甚至於治療第2型糖尿病的功效。研究發現明膠 (gelatin) 含有豐富的胺基酸，其中Pro、Ala、Hyp的含量豐富，且魚皮明膠的胺基酸分析發現溫水魚 (warm-water fish) 之imino acids含量較冷水魚 (cold-water fish) 為高。
本實驗以冷水魚：比目魚；溫水魚：吳郭魚、虱目魚魚皮明膠為原料，使用商業蛋白酶flavourzyme (Fla) 進行水解，製備具抑制DPP-IV活性之蛋白質水解物，以動物實驗鑑定其抗糖尿病的功效，期望能開發成保健食品並提升加工副產物之經濟價值。其實驗結果如下：
1. 總胺基酸分析：比目魚、吳郭魚、虱目魚魚皮明膠中Pro、Ala、Hyp之胺基酸的總量為32.18、37.6、38.55 mole/100 mole amino acid residues，以上結果可得知吳郭魚、虱目魚魚皮明膠中Pro、Ala、Hyp之胺基酸的總量比比目魚高。
2. 比目魚、吳郭魚、虱目魚魚皮明膠以Fla酵素基質比 (enzyme/substrate ratio, E/S ratio) 1、3、5%水解4 h，結果發現隨著酵素基質比濃度提高，水解度和DPP-IV抑制活性也有上升的趨勢，水解物濃度調整為5 mg/mL，Fla 5%水解4 h其抑制DPP-IV的能力分別為36.30%，43.17%，42.45%，而當延長水解時間為6, 8 h，結果發現吳郭魚、虱目魚魚皮明膠水解6 h具有最佳抑制DPP-IV的能力，其抑制活性分別達48.08%，45.63%，且吳郭魚、虱目魚其DPP-IV抑制活性在魚種間無顯著差異。
3. 根據此結果，將吳郭魚、虱目魚魚皮明膠以Fla 5%水解6 h經由超過濾的劃分後發現＜1 kDa的吳郭魚魚皮明膠水解物抑制DPP-IV的效果最好，當濃度為5 mg/mL，其抑制率高達51.91%，並選用此＜1 kDa的吳郭魚魚皮明膠水解物進行動物實驗，而由總胺基酸分析發現其Pro、Ala之胺基酸含量分別為11.22、16.39 mole/100 mole amino acid residues。
4. 動物實驗以管餵中劑量：750 mg/kg BW以上的吳郭魚魚皮明膠水解物即可達到良好的效果，有效降低糖尿病鼠的血漿中DPP-IV活性達31.74%
(p＜0.05)，並且增加35.4% GLP-1濃度的趨勢，此外實驗結果也觀察到管餵吳郭魚魚皮明膠水解物能增加血漿中胰島素濃度達121% (p＜0.05)，在口服葡萄糖耐受試驗中可以證實吳郭魚魚皮明膠水解物有效改善血糖的調控( p＜0.05 )。
綜合上述結果，可以發現魚皮明膠中Pro、Ala、Hyp之胺基酸的總量會影響DPP-IV抑制活性，而<1 kDa的吳郭魚魚皮明膠水解物具有最佳DPP-IV抑制能力。由動物實驗證實吳郭魚魚皮明膠水解物具有抗糖尿病功效並與開發成為降血糖保健食品的潛力，可望提升加工副產物之經濟價值。

A novel approach for treatment of type 2 diabetes is the use of gut hormone glucagon-like peptide-1 (GLP-1), which possesses multi-functions such as the stimulation of insulin secretin and the blood glucose homeostasis. GLP-1 is a polypeptide that is rapidly inactivated by dipeptidyl peptidase IV (DPP-IV). DPP-IV is a postproline-cleaving enzyme with the specificity for removing X-proline or X-alanine dipeptides from the N-terminus of polypeptides. Therefore, the peptides with Pro or Ala as the penultimate amino acid residue of N-terminus would be efficient DPP-IV inhibitors to elongate the half life of endogenous GLP-1. It is well-known that gelatin is rich in Pro, Ala, Hyp, while that of warm-water fish skin has higher contents of the three amino acid residues than cold-water fish.
The objective of this study is to utilize commercial proteases flavourzyme to hydrolyze gelatin extracted from halibut, tilapia and milkfish skin, and to produce the DPP-IV inhibitory peptides and determine their antidiabetic activity in animal in vivo experiments. The results were shown as follows:
1. The contents of Pro, Ala, Hyp from halibut, tilapia, milkfish skin gelatin were 32.18, 37.6, 38.55 mole/100 mole amino acid residues. The warm-water fish (tilapia and milkfish) skin gelatin showed higher contents of the three amino acid residues than the cold-water fish (halibut).
2. Halibut, tilapia and milkfish skin gelatins were hydrolyzed with Fla at various enzyme/substrate (E/S) ratio (1, 3, 5%) for 4 h. The DHs and DPP-IV inhibitory activity of the gelatin hydrolysates obtained by Fla hydrolysis increased with the increment of E/S ratio. When the hydrolysis process was done with the E/S ratio of 5% for 6 and 8 h, the both warm-water fish skin gelatin hydrolysates showed the greater DPP-IV inhibition rates of 45-48% as compared to the cold-water fish. The hydrolysates from both warm-water fish skin gelatin with E/S of 5% and 6-h hydrolysis were used for ultrafiltration.
3. The peptides within <1 kDa fraction from tilapia skin gelatin hydrolysates had the greatest DPP-IV inhibition rate of 51.91% as compared to those within the other two high-molecular-weight fractions (1-2.5 kDa and >2.5 kDa). The <1 kDa fraction was then used to evaluate its in vivo antidiabetic effect by the animal experiment, and the peptides in this fraction were comprised of Pro and Ala of 11.22, 16.39 mole/100 mole amino acid residues, respectively.
4. The oral administration with medial dose (750 mg/kg BW) of tilapia fish skin gelatin hydrolysate could significantly (p<0.05) decrease the plasma DPP-IV activity for 31.74%, and slightly but insignificantly (p>0.05) increase plasma GLP-1 for 35.4% in diabetic (DM) rats. Also, the hydrolysate effectively increased the plasma insulin concentration for 121% (p<0.05) as compared to DM rats and improve the blood glucose control.
The tilapia fish skin gelatin hydrolysate is useful for the therapy or prevention of type 2 diabetes. Tilapia fish skin gelatin hydrolysate can be develop a new functional food and to increase the economic values of fish processing byproducts.

目錄 i
圖目錄 v
表目錄 vi
中文摘要 I
Abstract III
第一章 前言 1
第二章 文獻探討 2
一、 糖尿病 (Diabetes mellitus) 2
(一) 糖尿病之定義及分類 2
(二) 糖尿病診斷標準 5
(三) 第2型糖尿病的治療 7
(四) 腸泌素對於第2型糖尿病之作用 9
二、 漁業資源 16
(一) 重要水產原料與利用 16
(二) 魚的種類及簡介 17
三、 蛋白質水解物及其生物活性 19
(一) 水解目的 19
(二) 明膠水解物及其生物活性 20
四、 抗糖尿病生物活性胜肽 22
1. 乳製品中抑制DPP-IV的活性胜肽 22
2. 雞蛋水解物抑制DPP-IV的活性胜肽 23
3. 玉米醇溶蛋白水解物抑制DPP-IV的活性胜肽 23
4. 藍鱈魚肌肉蛋白水解液抑制DPP-IV的活性胜肽 23
5. 豬皮明膠水解物抑制DPP-IV的活性胜肽 24
6. 其他活性胜肽與DPP-IV活性之探討 24
五、 藥物誘發高血糖動物實驗模式 27
1. 遺傳性自發高血糖動物： 27
2. 以高劑量nicotinamide (NA)＋streptozotocin (STZ) 誘發動物高血糖 27
3. 以低劑量NA＋STZ誘發胰島素阻抗型之高血糖 27
4. 以高果糖誘發胰島素阻抗與高血糖之動物實驗模式 27
5. 以高油飼料誘發胰島素阻抗與高血糖動物之實驗模式 27
六、 研究目的 30
第三章 材料與方法 31
一、 實驗材料 31
(一) 實驗動物 31
(二) 魚皮 31
(三) 商業蛋白酶 32
二、 實驗藥品 33
三、 分析實驗套組 34
四、 實驗儀器與設備 34
五、 實驗方法 36
(一) In vitro實驗 36
1. 明膠之萃取 37
2. 總胺基酸測定 37
3. 酵素水解魚皮明膠之製備 38
4. 水解度測定 38
5. 抑制DPP-IV活性in vitro測定 41
6. 超過濾劃分 41
(二) In vivo實驗 42
1. 實驗分組 43
2. NA+STZ誘發糖尿病 44
3. 口服葡萄糖耐受試驗 44
4. 血液、臟器之收集 44
5. 胰島素 (insulin) 濃度測定 44
6. GLP-1濃度測定 45
7. DPP-IV活性測定 46
(三) 統計分析 46
第四章 結果與討論 47
一、 魚皮明膠水解物製備 47
(一) 總胺基酸測定 47
(二) 不同酵素基質比之水解度及抑制DPP-IV活性測定 51
(三) 超過濾劃分物之抑制DPP-IV活性測定及總胺基酸測定 56
二、 五週動物實驗分析 61
(一) 體重變化 61
(二) 攝食量 64
(三) 飲水量 66
(四) 口服葡萄糖耐受試驗 68
(五) 臟器重量 72
(六) 血漿中胰島素濃度 75
(七) 血漿中DPP-Ⅳ活性 78
(八) 血漿中GLP-1濃度 80
第五章 結論 82
第六章 參考文獻 83
第七章 附錄 93

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