臺灣博碩士論文加值系統

新的抗高血糖藥物thiazolidinediones如rosiglitazone，可增加肝臟、肌肉、及脂肪組織對胰島素的敏感性，促進胰島素之作用，用以改善第2型非胰島素依賴型糖尿病 (non-insulin-dependent diabetes mellitus, NIDDM) 病人之血糖控制。在肝臟thiazolidinediones增強胰島素抑制葡萄糖新生的作用，並增強胰島素促進葡萄糖運輸進入骨骼肌及脂肪細胞的作用，因此推測thiazolidinediones主要為增強胰島素接受器之作用。Thiazolidinediones類藥物對一核內接受器peroxisome proliferator-activated receptor γ (PPAR-γ) 具有高度特異之親和性，且thiazolidinediones結合活化PPAR-γ之能力與他們抗糖尿病的作用成正比，因此thiazolidinediones增強胰島素的作用，可能係經由PPAR-γ來調節。為瞭解rosiglitazone對胰臟胰島素分泌的影響，本研究利用活體灌流大白鼠胰臟的模式，以不同濃度的rosiglitazone (0.045-4.5 μM) 灌流大白鼠之胰臟，以競爭性放射性免疫法 (radioimmunoassay) 測定胰島素濃度。結果顯示rosiglitazone可刺激胰臟胰島素之分泌，且其刺激分泌之作用與rosiglitazone之劑量成正比。Rosiglitazone (4.5 μM) 亦明顯增強10 mM葡萄糖刺激胰島素分泌之作用，於刺激分泌的第一階段及第二階段分別增加80.7％及52.4％胰島素的分泌，但是rosiglitazone在沒有葡萄糖存在的情況下，並無增加胰島素分泌的作用。Phosphatidylinositol 3-kinase (PI-3K) 阻斷劑LY 294002 (3.9 μM) 阻斷rosiglitazone刺激大白鼠胰臟分泌胰島素之作用，但無法抑制葡萄糖刺激胰島素分泌之作用。LY 294002亦明顯阻斷rosiglitazone增強葡萄糖刺激胰島素分泌之作用，第一階段及第二階段胰島素之分泌分別降低34.3％及32.9％。另外，直接灌流利用streptozotocin破壞胰臟β細胞的功能之大白鼠，發現rosiglitazone (4.5 μM) 仍可刺激大白鼠胰臟分泌胰島素，但反應倍數不如正常大白鼠。綜合實驗結果顯示rosiglitazone可直接刺激胰臟分泌胰島素，並對葡萄糖刺激胰島素分泌之作用具有相乘效果，這些作用可能是經由細胞內PI3K的活性所調控，就LY 294002無法抑制葡萄糖刺激胰島素分泌之作用而言，rosiglitazone刺激胰島素分泌的細胞內傳遞機制，可能與葡萄糖有所不同。

中文摘要
英文摘要
目錄
圖次
表次
第一章 緒言
第二章 文獻探討
第一節 糖尿病定義及分類
第二節 第2型糖尿病治療藥物分類
第三節 Rosiglitazone
第四節 Peroxisome proliferator-activated receptor
第五節 Phosphatidylinositol 3-kinase activity
第六節 第2型糖尿病之實驗動物模式
第七節 胰島素之分泌
第三章 材料與方法
實驗動物、灌流系統、灌流方法
實驗一： Rosiglitazone對大白鼠胰臟胰島素分泌之研究
實驗二： Rosiglitazone對葡萄糖刺激胰島素分泌之影響
實驗三： Phosphatidylinositol 3-kinase阻斷劑LY 294002對
rosiglitazone刺激胰島素分泌之影響
實驗四： Phosphatidylinositol 3-kinase阻斷劑LY 294002對
rosiglitazone增強葡萄糖刺激胰島素分泌作用之研究
實驗五： Rosiglitazone灌流streptozotocin誘發糖尿病大白鼠胰臟
之研究
胰島素之測定
資料分析與統計
第四章 結果
實驗一： Rosiglitazone對大白鼠胰臟胰島素分泌之研究
實驗二： Rosiglitazone對葡萄糖刺激胰島素分泌之影響
實驗三： Phosphatidylinositol 3-kinase阻斷劑LY 294002對
rosiglitazone刺激胰島素分泌之影響
實驗四： Phosphatidylinositol 3-kinase阻斷劑LY 294002對
rosiglitazone增強葡萄糖刺激胰島素分泌作用之研究
實驗五： Rosiglitazone灌流streptozotocin誘發糖尿病大白鼠胰臟
之研究
第五章 討論
第六章 結論
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