Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/13552
標題: Demethylasterriquinone B-1對大白鼠胰臟分泌胰島素之影響
The Studies of Demethylasterriquinone B-1 on Insulin Secretion in Perfused Rat Pancreas
作者: 羅玉珊
Lo, Yu-Shan
關鍵字: DMAQ-B1
胰島素分泌
L783,281
insulin secretion
糖尿病
胰臟灌流
出版社: 獸醫學系暨研究所
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摘要: 從1921年發現胰島素以來,由於第1型和第2型糖尿病病患的增加,發展岀一種可以口服的活性胰島素樣的藥物一直是大家所致力的藥物研究方向。最近幾年,在糖尿病的治療藥物發展中,Zhang等人使用大規模、適量的細胞水平分析系統,篩選一系列合成的化學物質及天然產品的萃取物,最後發現一種菌類(Pseudomassarias sp.)萃取物可以活化胰島素接受器 (insulin receptor, IR)。萃取物為一種小分子、非胜肽類的化合物,經過一連串的高效液相層析儀 (high-performance liquid chromatrography, HPLC)和核磁共振 (nuclear magnetic resonance, NMR)分析後,得知此小分子為demethylasterriquinone B-l,簡稱為DMAQ-Bl,又稱為L-783,281。目前證實DMAQ-Bl在體外有類似賀爾蒙的作用,可以活化胰島素接受器上的酪胺酸激酶 (insulin receptor tyrosine kinase),以及刺激細胞內所儲存的鈣離子的釋放,接著引起胰臟內的β細胞分泌胰島素,並由體外試驗結果推測DMAQ-B1所刺激的胰島素分泌可能為活化胰島素接受器基質-1 (insulin receptor substrate-1, IRS-1)和Phosphatidylinositol-3-kinase (PI3 kinase)所造成。本實驗則是使用活體灌流大白鼠胰臟的模式術來探討DMAQ-B1對大白鼠胰臟胰島素分泌之影響,發現10 μM DMAQ-B1在正常大白鼠的胰臟具有直接刺激胰島素分泌的作用,其分泌呈緩慢上升的形態,10 μM的DMAQ-B1可刺激胰島素分泌達到240%,且其作用與DMAQ-B1之劑量(1-20 μM) 呈現劑量效應上的關係。此外,DMAQ-B1具有增強葡萄糖刺激胰島素分泌達18.9%。使用PI3 kinase抑制劑LY 294002 (3.9 μM)或wortmannin (100 nM)合併DMAQ-B1灌流,分別抑制胰島素之分泌達到46.3%和57.4%,接著使用LY 294002 (3.9 μM)或wortmannin (100 nM)合併DMAQ-B1與葡萄糖灌流,分別抑制胰島素之分泌達到70.3%和79.0%。實驗結果顯示DMAQ-B1直接刺激胰島素之分泌,且具有增強葡萄糖刺激胰島素之分泌的能力,其分泌作用主要是藉由活化PI3 kinase的路徑來達成。
The development of an orally insulin mimetic drug has been the way for the treatment of diabetes mellitus. In order to discover a compound that could activate the human insulin receptor tyrosine kinase (IRTK), Zhang et al established a cell-based assay to screen a collection of synthetic chemicals and natural product extracts from fungus. The fungal extract isolated from Pseudomassarias sp. was characterized as a small and nonpeptidyl compound. Following analysis of high-performance liquid chromatography and nuclear magnetic resonance, the compound was identified as demethylasterriquinone B-1 (DMAQ-B1) and named as L-783, 281. It was recognized that DMAQ-B1 had hormone-like action in vitro and induced the activity of human insulin receptor tyrosine kinase. DMAQ-B1 also induced an increase in [Ca2+]i and insulin secretion in mice pancreatic β-cells at nonstimulatory glucose (3 mM) concentrations via insulin receptor substrate-1 /phosphatidylinositol-3-kinase (PI3 kinase) pathway. By using rat pancreatic perfusion technique, we found that 10 μM DMAQ-B1 directly stimulated insulin secretion with a slow release pattern in normal rat pancreas. DMAQ-B1 (10 μM) stimulated insulin secretion up to 240%. In the dosage range from 1 to 20 μM, DMAQ-B1 stimulated insulin secretion in a dose dependent manner. Furthermore, glucose-induced insulin secretion was enhanced by DMAQ-B1 by 18.9%, respectively. The results also shown that PI3 kinase inhibitor LY 294002 (3.9 μM) and wortmannin (100 nM) inhibited DMAQ-B1-induced insulin secretion by 46.3% and 57.4%, respectively. LY 294002 and wortmannin also inhibited glucose mixed with DMAQ-B1-induced insulin secretion by 70.3% and 79.0%, respectively. The results suggested that DMAQ-B1 dose-dependently stimulated insulin secretion and enhanced glucose-induced insulin secretion. DMAQ-B1 may activate PI3 kinase pathway to stimulate insulin secretion.
URI: http://hdl.handle.net/11455/13552
其他識別: U0005-1306200815221800
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