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研究生:簡惠敏
研究生(外文):CHIEN HUI MIN
論文名稱:Rosiglitazone對初代培養大鼠胰島beta細胞分泌胰島素之研究
論文名稱(外文):The Studies of Rosiglitazone on Insulin Secretion in Primary Cultured Rat Islet beta Cells
指導教授:楊繼楊繼引用關係
指導教授(外文):Yang Chi
學位類別:碩士
校院名稱:國立中興大學
系所名稱:獸醫學系
學門:獸醫學門
學類:獸醫學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:66
中文關鍵詞:第2型糖尿病rosiglitazoneβ細胞
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胰島β細胞分泌胰島素的功能和胰島素在細胞接受器的作用有缺損時,是造成第2型糖尿病的兩大主因,新的抗高血糖thiazolidinediones (TZDs) 類藥物如rosiglitazone(RSG),可以增加肝臟、肌肉、及脂肪組織對胰島素的敏感性,促進胰島素之作用,從而降低血糖濃度,因此用以改善肥胖、非胰島素依賴型糖尿病(non-insulin-dependent diabetes,NIDDM)病人之血糖控制。TZDs類藥物對核內接受器peroxisome proliferator-activated receptor gamma ( PPAR)具有高度特異之親和性,藉由結合PPAR的方式,可促進脂肪細胞分化。雖然降血糖的作用被推論與PPAR有關,但實際作用機制不明;本實驗即為探討RSG之作用機制,實驗利用初代培養大白鼠胰島β細胞,測定RSG促進胰島素分泌之作用,研究首先探討不同葡萄糖濃度對β細胞胰島素分泌之反應關係,再以不同濃度的RSG (0.045-4.5 M)處理大白鼠胰島β細胞,觀察β細胞胰島素分泌之劑量反應關係,並以不同之試劑觀察對RSG 效應之阻斷作用,以判定其於細胞內主要作用機制途徑。實驗以競爭性放射性免疫法 (radio-immunoassay)測定胰島素濃度。實驗結果發現,不同濃度葡萄糖刺激初代培養胰島β細胞分泌胰島素之作用與葡萄糖濃度成正比。而RSG可刺激胰島β細胞分泌胰島素,且其刺激分泌之作用與RSG之劑量成正比。Phosphatidylinositol 3-kinase (PI3K)阻斷劑LY496002(3.9µM)以及wortmannin(1µM)對RSG所引起胰島素分泌作用,分別有34.5﹪與48.3﹪的阻斷作用。結果證明RSG刺激胰島素分泌之機制,可能部分經由PI3K調節。
Patients with type 2 diabetes mellitus have hyperglycemia as a result from both -cell dysfunction and insulin resistance. Rosiglitazone (RSG) is a new potent antidiabetic agent of thiazolidinediones (TZDs) which enhance sensitivity to insulin in liver, adipose tissue and muscle. Although the mechanism of action wasn’t understood, it was well recognized that TZDs were high-affinity ligands for the peroxisome proliferator-activated receptor  (PPAR-), a member of the nuclear receptor family. In order to elucidate the direct effect of RSG on pancreatic -cell insulin secretion, Sprague-Dowley rat pancreatic -cells were isolated and cultured. Since insulin secretion was related to -cell intracellular free calcium concentration. Primary cultured -cell intracellular free calcium was monitored by digital imaging fluorescence microscopy(DIFM). We found that 4.5 M RSG increased -cell intracellular free calcium concentration. The cultured medium was collected and assayed for insulin by using radioimmunoassay. RSG (0.045-4.5 M) also stimulated insulin release in a dose-dependent manner. A phosphatidylinositol 3-kinase (PI3K) inhibitor, LY 294002, inhibited the effect of RSG(4.5 M) on insulin secretion in a dose-dependent manner from 390 to 0.39 M LY 294002. Two different PI3K inhibitor, LY 294002 (3.9 M) and wortmannin(1 M), reduced 34.5﹪and 48﹪of RSG(4.5 M)-induced insulin secretion in cultured -cells, respectively. These results suggest that RSG has a direct effect on insulin secretion which was probably mediated through PI3K pathway.
目錄
頁碼
中文摘要 …………………………………………………………… i
英文摘要 …………………………………………………………… ii
目錄 …………………………………………………………………… iii
圖次 …………………………………………………………………… v
表次 …………………………………………………………………… vi
第一章 緒言 ……………………………………………………… 01
第二章 文獻探討 …………………………………………………… 03
第一節 糖尿病定義及分類 ………………………… 03
第二節 第2型糖尿病治療藥物分類 ………………………… 04
第三節 Rosiglitazone …………………………………… 07
第四節 Peroxisome proliferator-activated receptor …………… 14
第五節 Phosphatidylinositol 3-kinase activity ………………… 19
第六節 DIFM系統(digital imaging fluorescence microscopy) ………………………… 21
第七節 胰島細胞之分類 …………………………………… 23
第八節 胰島素之分泌 …………………………………… 24
第三章 材料與方法 ………………………………………………… 27
實驗動物、灌流系統、灌流方法 ……………………………… 27
實驗一:利用DIFM系統觀察葡萄糖刺激
初代培養胰島β-cells [Ca2+]i之變化 ……………… 30
實驗二:利用DIFM系統觀察rosiglitazone刺激
初代培養胰島β-cells [Ca2+]i之變化 …………… 30
實驗三:Rosiglitazone對大白鼠胰臟胰島素分泌之研究 …… 31
實驗四:Phosphatidylinositol 3kinase(PI3K)阻斷劑
LY 294002對rosiglitazone刺激胰島素分泌之
影響 …………………………………………………… 32
實驗五:Phosphatidylinositol 3kinase(PI3K)阻斷劑
LY 294002 及wortmannin對rosiglitazone刺激
胰島素分泌作用之研究 ………………………… 32
DIFM系統 …………………………………………………………… 33
胰島素之測定 ……………………………………………………… 34
資料分析與統計 ……………………………………………………… 35
第四章 結果 ……………………………………………………… 36
實驗一:利用DIFM系統觀察葡萄糖對初代
培養胰島β-cells[Ca2+]i影響之研究 ……………… 36
實驗二:利用DIFM系統觀察rosiglitazone刺激
初代培養胰島β-cells[Ca2+]i之變化 …………… 39
實驗三:Rosiglitazone對大白鼠胰臟
胰島素分泌之研究 ……………………… 42
實驗四:Phosphatidylinositol 3-kinase阻斷劑
LY 294002對rosiglitazone刺激胰島素分泌
之影響 ………………………………………………… 44
實驗五:Phosphatidylinositol 3-kinase阻斷劑
LY 294002及wortmannin對rosiglitazone
刺激胰島素分泌作用之研究 ……………………… 46
第五章 討論 ………………………………………………………… 48
第六章 結論 ………………………………………………………… 54
參考文獻 …………………………………………………………… 55
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