臺灣博碩士論文加值系統

第二型糖尿病發生前乃會經過糖尿病前期，判定標準為禁食血糖與葡萄糖耐受性異常，因此如何於糖尿病前期有效地控制血糖，便成為避免發展成第二型糖尿病的重點之一。早期苦瓜為學界所知之降血糖成份，乃是透過皮下或是腹腔注射投予以達到功效之植物胰島素，然而亦有許多文獻指出，以口服的方式給予苦瓜可降低血糖。本實驗室過去研究顯示：口服山苦瓜之降血糖活性存在於水萃物、且會受熱破壞；攝取山苦瓜補充飲食之動物有較高之 insulinogenic index、以及肝臟 dpp4 (dipeptidyl peptidase 4) 基因表現較低之特徵。因此，本實驗假說為：苦瓜降血糖機制之一乃是透過「腸泌素效應」－ incretin effect。
細胞實驗中，建立腸道內分泌細胞株 STC-1 之 GLP-1 (glucagon-like peptide-1) 分泌量分析作為初步篩選苦瓜降血糖物質之平台，結果發現：山苦瓜水萃物刺激 GLP-1 分泌之倍數最高；有趣的是，苦瓜苦味粗萃物亦具有活化 GLP-1 分泌之潛力。進一步評估苦瓜於動物體透過 incretin effect 降低血糖之可能，選用以 30% 高奶油飲食誘發高血糖症狀之 C57BL/6J 公鼠，結果發現：單一劑量急性投予水萃物中、3 kD 以下小分子區分物可降低血糖，並且伴隨血液胰島素與 GLP-1 濃度增加；此功效受到 GLP-1 受器之拮抗物 Exendin-9 的抑制、但卻不影響血液 DPP4 活性。推測此萃物並非透過抑制 GLP-1 之降解、而是刺激腸道內分泌 L 細胞分泌 GLP-1，進而活化胰臟 beta 細胞分泌胰島素，與細胞實驗之結果吻合。此外，刺激 GLP-1 分泌活性成份中，可能有一些是苦瓜中的苦味化合物，活化了 L 細胞上的苦味受器以刺激 GLP-1 分泌。
本研究首次發現：苦瓜水萃物中 3 kD 以下小分子區分物，透過刺激 GLP-1 分泌、而活化胰臟 beta 細胞分泌胰島素之腸泌素效應，以達到降低血糖之功效。

The health impact of type 2 diabetes and impaired glucose homeostasis has become a significant public health concern. Bitter gourd (BG) has been used to treat diabetes in Indian traditional medicine. Early research has isolated an insulin-like peptide from BG and showed its hypoglycemic effect via intraperitoneal or subcutaneous administration. Nevertheless, recent studies demonstrated that orally administered BG also lowered blood glucose. Our previous feeding studies in C57BL/6J mice showed that the water extract (WE) of BG had best hypoglycemic activity which could be destroyed by heating. Based on the facts that bitter gourd diet had higher insulinogenic index during OGTT and lower dpp4 mRNA expression in liver, we hypothesized that one of the mechanisms for the hypoglycemic effect of bitter gourd was through incretin effect.
BG WE was separated by ultra-filtration which resulted in a small molecule (< 3kD, WES) and a large molecule (>3kD, WEL) fractions. WE and WES were further hydrolyzed by beta-glucosidase and sequentially extracted with ethyl acetate and butanol. These subfractions were evaluated for their incretin potential by measuring GLP-1 secretions of treated STC-1 cells, a murine enteroendocrine cell line. It was found that WE and most of all of its subfractions dose-dependently enhanced GLP-1 secretion. Interestingly, the crude extract of BG bitter tastants also had a GLP-1 inducing effect. To assess the incretin effect and glucose homeostasis of BG in vivo, C57BL/6J male mice were fed a high fat diet to induce hyperglycemia. A single dose administration of the WES to these mice significantly lowered plasma glucose which was associated with higher levels of plasma insulin and GLP-1. This hypoglycemic effect of WES was blocked by GLP-1 receptor antagonist, Exendin-9. No association of plasma DPP4 activity was observed.
These data suggested that the small MW active fraction of BG might contain (a) GLP-1 secretagogue(s) which may induce the secretion of GLP-1 in L cells. Higher circulating GLP-1 then activates GLP-1 receptor on pancreatic cells and stimulates insulin secretion. It appears that WE subfractions did not inhibit GLP-1 degradation. It is speculated that bitter tastants in BG might contribute, at least in part, to the enhanced GLP-1 secretion in enteroendocrine cells through the bitter taste receptors. This is the first study demonstrating an incretin effect of bitter gourd water extract.

中文摘要 ……………………………………………………………………………… i
英文摘要 ……………………………………………………………………………… ii
縮寫對照表 …………………………………………………………………………… iv
組別縮寫意義 ………………………………………………………………………… v

第一章 緒論…………………………………………………………………………… 1
第一節 研究動機與目的………………………………………………………… 1
第二節 文獻回顧………………………………………………………………… 2
一、代謝症候群與第二型糖尿病 ………………………………………… 2
二、Incretin effect…………………………………………………………… 4
(一) 定義……………………………………………………………… 4
(二) GLP-1 之合成…………………………………………………… 5
(三) GLP-1 之分泌…………………………………………………… 5
(四) GLP-1 之作用…………………………………………………… 6
(五) GLP-1 之降解與清除…………………………………………… 7
三、Incretin effect 相關指標異常與第二型糖尿病……………………… 8
四、GLP-1 治療糖尿病…………………………………………………… 9
五、腸道內分泌細胞與 incretin effect 降血糖之動物生理研究………… 10
六、苦瓜 …………………………………………………………………… 19
第三節 研究假說與架構………………………………………………………… 24
一、研究假說 ……………………………………………………………… 24
二、實驗架構 ……………………………………………………………… 24
第二章 山苦瓜水萃物暨其區分物對 STC-1 腸道內分泌細胞株分泌 GLP-1 之影響…………………………………………………………………………… 25
第一節 前言……………………………………………………………………… 25
第二節 材料與方法……………………………………………………………… 26
一、細胞株 ………………………………………………………………… 26
二、試劑 …………………………………………………………………… 26
(一) 細胞培養………………………………………………………… 26
(二) Real-time PCR 法分析基因表現………………………………… 27
(三) 處理樣品………………………………………………………… 28
三、儀器設備 ……………………………………………………………… 28
四、山苦瓜萃取物暨其區分物之製備 …………………………………… 29
五、實驗方法 ……………………………………………………………… 33
(一) 細胞培養………………………………………………………… 33
(二) 細胞處理及處理後培養液之 GLP-1 含量測定 ……………… 34
(三) GLP-1 基因 proglucagon mRNA 表現量分析………………… 35
六、數據整理與統計分析 ………………………………………………… 36
第三節 結果……………………………………………………………………… 37
一、山苦瓜各種萃物或化合物對 STC-1 細胞 GLP-1 分泌量之影響… 37
(一) 山苦瓜水萃物暨其區分物對 STC-1 細胞分泌 GLP-1 之影響 37
(二) 山苦瓜水萃物及小分子區分物經 beta-glucosidase 酵素水解後之產物對 STC-1 細胞分泌 GLP-1 之影響…………………… 38
(三) 山苦瓜苦味物質粗萃物與苦味化合物 denatonium benzoate 對 STC-1 細胞分泌 GLP-1 之影響…………………………… 40
(四) 山苦瓜酒精萃物暨其區分物對 STC-1 細胞分泌 GLP-1 之影響………………………………………………………………… 41
(五) 山苦瓜乙酸乙酯萃物暨其區分物對 STC-1 細胞分泌 GLP-1 之影響 …………………………………………………………… 41
(六) 其他成分對 STC-1 細胞分泌 GLP-1 之影響………………… 41
二、山苦瓜水萃物及其區分物對 STC-1 細胞 proglucagon mRNA 表現量之影響……………………………………………………………… 42
第四節 討論……………………………………………………………………… 52
一、山苦瓜刺激腸道內分泌細胞分泌 GLP-1 之可能成份 …………… 52
二、苦味物質調控葡萄糖恆定之可能機制 ……………………………… 54
三、山苦瓜刺激腸道內分泌細胞分泌 GLP-1 之可能機制 …………… 55
第五節 結論……………………………………………………………………… 56
第三章 長期餵食山苦瓜水萃物於鼠體所產生之 incretin effect ………………… 57
第一節 前言……………………………………………………………………… 57
第二節 材料與方法……………………………………………………………… 58
一、實驗大綱 ……………………………………………………………… 58
二、動物飼養 ……………………………………………………………… 59
三、飼料 …………………………………………………………………… 59
四、口服葡萄糖耐受性測試 ……………………………………………… 60
五、血漿 GLP-1 濃度分析 ……………………………………………… 61
六、胰島素耐受性測試 …………………………………………………… 62
七、動物犧牲 ……………………………………………………………… 62
八、血脂分析 ……………………………………………………………… 62
九、血漿 DPP4 酵素活性分析…………………………………………… 64
十、組織 DPP4 酵素活性分析…………………………………………… 64
十一、胰臟胰島素分析 …………………………………………………… 65
十二、肝脂分析 …………………………………………………………… 65
十三、Real-time PCR 法分析肝臟與副睪脂中 dpp4 之基因表現量…… 66
十四、數據整理與統計分析 ……………………………………………… 66
第三節 結果……………………………………………………………………… 67
一、體重變化、攝食量、飼料利用率與能量攝取………………………… 67
二、組織器官絕對與相對重量 …………………………………………… 67
三、血脂與肝脂分析 ……………………………………………………… 67
四、葡萄糖恆定與 incretin effect 指標分析 …………………………… 68
第四節 討論……………………………………………………………………… 91
第五節 結論……………………………………………………………………… 97
第四章 單一劑量投予山苦瓜水萃物於鼠體所產生之 incretin effect …………… 98
第一節 前言……………………………………………………………………… 98
第二節 材料與方法……………………………………………………………… 99
一、動物飼養 ……………………………………………………………… 99
二、Exendin-9 (GLP-1receptor 拮抗物) 投予試驗 ……………………… 99
三、山苦瓜水萃物小分子區分物投予試驗及Exendin-9 介入對於血糖變化之影響……………………………………………………………… 100
四、山苦瓜水萃物小分子區分物投予對於血糖、GLP-1 與胰島素分泌之影響………………………………………………………………… 100
五、山苦瓜水萃物小分子區分物經 beta-glucosidase 酵素水解後之乙酸乙酯萃物 (Se-E) 投予對於血糖與 GLP-1 分泌之影響……………… 100
六、山苦瓜水萃物投予對於血糖與 GLP-1 分泌之影響………………… 100
七、山苦瓜水萃物小分子區分物投予對於 ipGTT 試驗中、血糖與血液 DPP4 活性之影響 …………………………………………………… 101
八、數據整理與統計分析 ………………………………………………… 101
第三節 結果……………………………………………………………………… 102
第四節 討論……………………………………………………………………… 111
第五節 結論……………………………………………………………………… 114
第五章 綜合討論與總結論…………………………………………………………… 115
第一節 綜合討論………………………………………………………………… 115
第二節 總結論…………………………………………………………………… 117
第六章 參考文獻…………………………………………………………………… 118

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