臺灣博碩士論文加值系統

隨現代人生活越來越富裕，許多的文明病像是肥胖、高血壓、糖尿病等慢性疾病的發生隨之增加。第二型糖尿病為胰島素作用缺失導致醣類、脂肪及蛋白質代謝異常之慢性疾病，佔所有相關病例九成以上，為數更多的未病群面臨逐漸惡化而仍可逆之血糖過高及胰島素阻抗，如能協助增進敏感性可避免演進至疾病狀態。蕈菇類包含黃金銀耳之多醣體已證實可能透過胰島素增敏而改善實驗動物之高血糖，而人體內脂肪組織不僅具有帶入葡萄糖能力，還可分泌多種細胞激素調節週邊組織之胰島素敏感性，本論文將黃金銀耳glucuronoxylomannan (GXM)與3T3-L1脂肪細胞共置，以作用濃度及時間等各項參數探討胰島素傳訊層面及調節分泌細胞激素的影響。
結果顯示，在高糖及高胰島素共同作用24小時後降低3T3-L1細胞Akt 磷酸化及脂聯素(Adiponectin)分泌量、增加抗素(Resistin)及IL-6分泌。於阻抗狀態下添加酸性多醣可顯著增加AMPK磷酸化和增加IL-6分泌、降低抗素含量、在200 ppm GXM作用下顯著增加脂聯素含量。在此實驗架構下即使在與胰島素共同刺激，也未觀察到酸性多醣可增強胰島素傳訊路徑。正常狀態下細胞添加酸性多醣會降低抗素及脂聯素量、增加IL-6分泌。在模擬細胞攝入葡萄糖試驗中，不管正常或阻抗態細胞，添加酸性多醣後皆可增加細胞攝入葡萄糖擬似物能力。以上結果發現，黃金銀耳酸性多醣在3T3-L1脂肪細胞中藉由改善脂泌素分泌狀況及增加AMPK活性而非經由胰島素傳訊來改善胰島素阻抗性。

Type 2 diabetes mellitus is a chronic disease associated with abnormality in carbohydrate, protein and lipid metabolism and is caused by ineffectiveness of insulin action. About 90% of the diabetic incidence belongs to type 2 diabetes. Even more are suffering from deteriorating yet reversible prediabetic hyperglycemia and insulin resistance, which could be averted by insulin-sensitizing remedies. Anti-diabetic activities of glucuronoxylomannan (GXM) from Tremella mesenterica has been demonstrated in animal model, and is linked to improved insulin sensitivity in muscle and liver cells. Recent studies suggested that adipose tissue may play active roles in glucose homeostasis not only by glucose uptake, but through the profile of secreted adipokines. In this study, differentiated 3T3-L1 murine adipocytes were rendered insulin resistant, and were coincubated with various concentrations of GXM for different durations, before targets in insulin signaling and released cytokines were investigated.
The results show that high concentrations of glucose and insulin decreased AKT phosphorylation and adiponectin secretion in 3T3-L1 cells, while elevated resistin and IL-6 levels. Addition of resistant cells with GXM significantly increased AMPK phosphorylation, adiponectin (200 ppm GXM) and IL-6 secretion but decreased resistin secretion. Enhanced insulin signaling by GXM was not observed, even when insulin was coadministrated. Uptake of 2-NBDG was greatly enhanced after adding GXM, both in normal or insulin-resistant cells. Taking together, these data suggested GXM possesses anti-hyperglycemic activity, and acting mainly through improved adipokines secreting profiles, and enhanced AMPK but not insulin signaling pathway in 3T3-L1 adipocytes.

中文摘要 I
英文摘要 II
文獻回顧
壹、糖尿病 1
一、糖尿病的分類 1
二、糖尿病的診斷 3
三、糖尿病的治療 3
四、代謝症候群與脂肪組織關係 5
貳、研究模式 6
一、脂肪組織 6
二、前驅脂肪細胞研究模式之細胞株 8
三、3T3-L1前驅脂肪細胞分化之進程 8
參、胰島素傳訊路徑與AMPK介紹 11
一、胰島素傳訊路徑 11
二、AMPK介紹 18
肆、細胞激素與胰島素阻抗關聯性 22
一、細胞激素介紹 26
伍、高糖與高胰島素誘發胰島素阻抗模式之機制 35
一、胰島素阻抗 35
二、高糖高胰島素誘發胰島素阻抗 35
陸、黃金銀耳與其生理功效 36
研究動機與實驗架構 37
材料方法
壹、實驗材料 39
一、小鼠脂肪細胞株 39
二、細胞培養基 39
三、脂肪細胞分化試劑 39
四、葡萄糖擬似物 40
五、黃金銀耳Tremella mesenterica酸性多醣 40
六、細胞培養其它藥品 40
七、 蛋白質分析試劑 41
八、ELISA Kit 42
九、油紅染色試劑 42
十、同步定量mRNA表現量分析 42
十一、主要儀器及設備 42
貳、實驗方法 44
一、黃金銀耳酸性多醣分子量測定 44
二、細胞培養、繼代與分化 44
三、油紅染色 45
四、誘導3T3-L1細胞產生胰島素抗性 45
五、細胞毒性試驗 45
六、 3T3-L1細胞葡萄糖擬似物帶入量分析 46
七、3T3-L1細胞之蛋白質萃取 46
八、蛋白質定量 46
九、 西方轉漬法 47
十、酵素連結免疫分析 49
十一、抽取3T3-L1細胞RNA 49
十二、cDNA製備 50
十三、同步定量聚合酶連鎖反應 50
十四、統計分析 51
結果
一、分化十天後成熟脂肪細胞油紅染色圖 53
二、不同濃度之glucuronoxylomannan (GXM)對3T3-L1細胞毒性測試 54
三、黃金銀耳酸性多醣分子量測定 55
四、不同濃度葡萄糖誘導3T3-L1細胞產生胰島素阻抗 58
4-1 3T3-L1細胞產生胰島素阻抗對於Akt及pAkt (Ser473)蛋白質相對含量之影響 58
4-2不同濃度葡萄糖對3T3-L1細胞分泌細胞激素之影響 61
4-3 3T3-L1細胞對葡萄糖擬似物2-NBDG攝入量 65
五、阻抗態3T3-L1細胞添加酸性多醣12小時及24小時後之影響 68
5-1胰島素傳訊路徑IR、IRS1、Akt、pAkt (Ser473)及pAMPK (Thr172)相對表現量 68
5-2阻抗態3T3-L1細胞添加酸性多醣後細胞激素分泌影響 77
六、正常態3T3-L1細胞添加酸性多醣12小時及24小時後之影響 82
6-1胰島素傳訊路徑IR、IRS1、Akt、pAkt (Ser473)及pAMPK (Thr172)相對表現量 82
6-2正常態3T3-L1細胞添加酸性多醣後細胞激素分泌影響 89
討論 94
未來展望 103
參考文獻 105

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