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標題: | Vescalagin 預防 Methylglyoxal 誘發大鼠醣類代謝異常之研究 Preventive Effect of Vescalagin on Carbohydrate Metabolic Disorder in Methylglyoxal Treated Rats |
作者: | Wen-Chang Chang 張文昌 |
指導教授: | 吳瑞碧 |
關鍵字: | Vescalagin,甲基乙二醛,過度糖化終產物,發炎反應,胰臟 β 細胞,抗氧化酵素, Vescalagin,methylglyoxal,advanced glycation end products,inflammatory reaction,pantreaticβ cell,antioxidant enzymes, |
出版年 : | 2014 |
學位: | 博士 |
摘要: | 隨著人們生活水平與醫療技術的提升,慢性疾病已逐漸成為人民主要的健康威脅。根據世界衛生組織 (world health organization) 2011 年統計數據顯示,全球糖尿病罹患人數高達 3.46 億人,也推測此疾病之擴展速度二十年內應該會有雙倍之成長,故此慢性疾病預防顯得格外重要。現今社會中已有多數民眾罹患肥胖、代謝症候群及糖尿病之現況,而其主要原因則為飲食中含高量之果糖所致。已有文獻指出,甲基乙二醛 (methylglyoxal, MG) 為一種高活性的雙羰基化合物,是糖類物質代謝後之產物之一,亦為糖化終產物 (advanced glycation end products, AGEs) 主要之前驅物質,且 MG 與 AGEs 更與肥胖、代謝症候群及糖尿病之病因有極密切的關係。另外有研究指出,當 MG 與 AGEs 存在會促進體內活性氧 (reactive oxygen species)、氧化壓力 (oxidative stress) 及發炎細胞激素 (inflammatory cytokine) 之增生,導致胰臟細胞受攻擊而損傷。因此,減少體內 MG 之含量可有效抑制 AGEs 的形成進而預防糖尿病之發生。
Vescalagin (VES) 屬於鞣酸 (ellagitannin) 類化合物,是水解性單寧,屬植物多酚類物質,具抗菌、抗氧化、抗發炎及抗癌之功效。先前本實驗室研究發現 VES 具有減緩肝臟細胞胰島素阻抗之功效,且於高果糖誘發之糖尿病大鼠亦發現其具調解血糖、胰島素、減少血清中三酸甘油脂形成與降低游離脂肪酸之能力。但因目前 VES 此化合物尚未有人大量生產販售,故根據先前之研究方法從粉紅種蓮霧生果中進行萃取及純化,同時因未有利用 VES 預防 MG 誘導大鼠醣類代謝異常之相關實驗報告,故本研究先評估 VES 是否可有效預防 MG 所誘發之大鼠體內發炎與糖類代謝異常,再進一步了解 VES 是否藉由改善胰臟細胞中之抗氧化酵素活性與胰島素分泌之相關蛋白表現來預防血糖異常。 結果顯示,VES 可有效降低口服葡萄糖耐受性 (oral glucose tolerance)、動脈硬化風險指標 (cardiovascular risk index)、血脂(serum lipid)、果糖胺 (fructosamine)、糖化終產物 (AGEs)、腫瘤壞死因子 (tumor necrosis factor-α) 與介白素-6 (Interleukin 6) 之含量;同時可有效提升血液中之胰島素、C-peptide 與 D-乳酸含量,根據上述結果發現,VES 可預防 MG 所誘發之大鼠血糖代謝異常。結果亦顯示,VES 可降低胰臟細胞中糖化終產物受器 (RAGE)、細胞核因子kappa B (NF-κB) 與磷酸化 mitogen-activated protein kinases (MAPKs) 蛋白之表現,同時 VES 也促進胰島素合成蛋白正調控pancreatic-duodenal homeobox-1 (PDX-1) 蛋白表現及抑制負調控蛋白CCAAT/enhancer binding proteins-β(C/EBPβ) 之表現。另外,VES 可藉由促進抗氧化轉錄因子nuclear factor-erythroid 2-related factor 2 (Nrf2) 之蛋白表現及麩胱甘肽 (glutathione) 含量之增加來提升胰臟細胞中之抗氧化能力。故推論 VES 是藉由提升胰臟細胞中之抗氧化酵素活性來保護胰臟細胞免於遭受甲基乙二醛攻擊而降低 MG 誘發大鼠高血糖之現象。綜合上述之實驗結果,VES 應具潛力開發為食品補充劑以預防糖尿病之發生。 As advanced medical technology and improved living standard extended the expectancy of human life, chronic diseases have become a major threat to the health of people. Diabetes mellitus (DM) is a chronic disease involving inflammation in the development. The World Health Organization estimated that more than 346 million people worldwide suffered from DM in 2011. This number is likely to become more than double by 2030 in case of no intervention. The prevalence of DM, obesity, and many other metabolic syndromes has been linked to the increased consumption of fructose-containing foods. MG is a highly reactive dicarbonyl metabolite produced during glucose metabolism, and it is a major precursor of advanced glycation end products (AGEs) that are involved in the pathogenesis of inflammation, metabolic syndromes and diabetes. MG and AGEs also promote the production of reactive oxygen species and inflammatory cytokines that cause the damage of pancreatic β-cells. Therefore, to reduce the MG content can be effective in the retard of AGEs formation and the prevention of DM. Ellagitannins are bioactive polyphenols with antioxidant and anti-inflammatory activities. Pink wax apple fruit contain the ellagitannin vescalagin (VES). VES has been reported to be antibacterial, antitumor, insulin-resistance alleviative and dyslipidemia mediative. Our laboratory previously reported that VES may reduce serum glucose content with a simultaneous increase in the serum insulin and C-peptide levels. No commercial VES is available on the market. Therefore, we extracted and purified VES from young pink wax apple. No literatures with regard to the protective effect of VES on pancreatic β-cells against MG induced inflammation and hyperglycemia has been reported yet. The aims of this study were to investigate the preventive effect of VES against MG-induced inflammation and carbohydrate metabolic disorder in rats and to elucidate its mechanism by assessing on the activities of oxidation enzymes and the expressions of insulin secretion-related protein in pancreatic β-cells in rats orally administered with MG and VES. Results showed that VES reduced the value of oral glucose tolerance test, serum lipid, cardiovascular risk index, fructosamine, AGEs, tumor necrosis factor-α and Interleukin 6 (IL-6) contents while increased insulin, C-peptide and D-lactate contents significantly in the rats orally administered with MG and VES together. Further, we want to elucidate the mechanism by assessing the effect of VES on inflammation and insulin secretion of pancreatic β-cells in MG-induced diabetic rats. The results revealed that VES down-regulated the expressions of advanced glycation end products receptor (RAGE), the nuclear factor kappa B (NF-κB) and the phosphorylation of mitogen-activated protein kinases (MAPKs) in the β-cells, and that VES promoted insulin synthesis via the up-regulation of pancreatic-duodenal homeobox-1 (PDX-1) and the down-regulation of MG-mediated CCAAT/enhancer binding proteins-β(C/EBPβ) expression. VES was also found to promote the translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and glutathione (GSH) to increase antioxidant enzymes activity in MG-induced diabetic rats. We propose that the mechanism for VES to protect pancreatic β-cells of rats against methylglyoxal-induced inflammation and hyperglycemia involves the promotion of antioxidative ability in these cells. These findings suggest the potential for VES to become an ingredient of food supplement in the prevention of diabetes and its complications. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58754 |
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顯示於系所單位: | 食品科技研究所 |
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