臺灣博碩士論文加值系統

糖尿病的病患比率在我國日漸增高，因此，研究開發糖尿病的治療藥乃為當日之主要課題。民間常用的「補中益氣湯」具有改善糖尿病的效果，「升麻」 (Cimicifuga rhizoma)即是組成「補中益氣湯」的中藥材之一。本實驗針對升麻根莖的抽取物「升麻酸」(isoferulic acid)進行降血糖機轉的探討，期望助益於降血糖新藥之研發。
首先，將升麻酸自股靜脈注射不同劑量到遺傳性胰島素依賴型糖尿病大白鼠(Bio—Breeding/Worcester rats; BB/W rats)或用streptozotocin (STZ)誘導的胰島素依賴型糖尿病(insulin dependent diabetic mellitus; IDDM)大白鼠。升麻酸隨著劑量的增加，使兩種胰島素依賴型糖尿病大白鼠的血糖值下降得更強。可是，在胰島素非依賴型(non-insulin dependent diabetic mellitus; NIDDM)大白鼠，升麻酸則需在較大的劑量及較長的作用時間，才會出現顯著的降血糖作用。另外，使用外來葡萄糖所進行的刺激試驗(glucose challenge test)，升麻酸確可增加大白鼠對葡萄糖的利用率。
接下來以C2C12 小鼠肌母細胞(mouse myoblast cell line)進行體外實驗以確定升麻酸的作用受體。發現，升麻酸能以劑量相關的方式來增強C2C12 肌母細胞對葡萄糖的吸回；這項作用可被a1A-adrenoceptor (a1A-AR) 的阻斷劑所解消。同時，升麻酸隨著濃度的增高可漸進地取代a1-AR 的ligand，[3H]YM617，於C2C12 肌母細胞的結合。另一方面，以phospholipase C (PLC)及protein kinase C (PKC)的阻斷劑將a1A-AR活化後有關的訊息傳遞路徑阻斷後，亦可解消升麻酸增強C2C12肌母細胞對葡萄糖吸回的作用。進一步以STZ糖尿病大白鼠進行體內實驗，發現，a1A-AR 的阻斷劑亦會依劑量相關的型式阻斷升麻酸在胰島素依賴型糖尿病老鼠所產生的降血糖效果。因此，在沒有胰島素存在的情況下，a1A-AR的活化與升麻酸產生降血糖作用有重要的相互關係。
在胰島素依賴型糖尿病大白鼠引致降血糖效果的有效劑量下，升麻酸亦能同時增加STZ糖尿病大白鼠血中b-endorphin的含量；這項作用可被a1A-AR阻斷劑所拮抗。另一方面，外加的b-endorphin確能增強STZ糖尿病大白鼠離體的骨骼肌及肝細胞(hepatocytes)對葡萄糖的吸回作用。而且，嗎啡m型受體阻斷劑亦會以劑量相關的型式阻斷升麻酸在STZ糖尿病大白鼠的降血糖效果。同時，在嗎啡m型受體剔除(opioid m-receptors knockout)的胰島素依賴型糖尿病小鼠，升麻酸也無法出現降血糖的作用。因此，升麻酸在胰島素依賴型糖尿病老鼠所產生的降血糖作用，嗎啡m型受體的活化應扮演著重要的角色。
在STZ糖尿病大白鼠離體的腎上腺髓質(adrenal medulla)，升麻酸會隨著劑量的增加來促進b-endorphin的釋放；這項作用可被a1A-AR或 PLC、PKC的阻斷劑所抑制。相對於控制組(sham-operation)，靜脈注射給予升麻酸至兩側腎上腺已摘除(bilateral adrenalectomy)的糖尿病大白鼠身上，血中b-endorphin的含量並無改變，且仍維持在高血糖的狀態。由此可知，升麻酸乃藉由活化腎上腺的a1A-AR來促使b-endorphin釋放才得到降血糖效果。
為了進一步瞭解升麻酸降血糖的分子作用機轉，使用升麻酸在胰島素依賴型糖尿病老鼠能產生降血糖作用的有效劑量，以尾靜脈注射給藥的方式，每日注射三次到STZ誘導的糖尿病大白鼠。連續一日注射後，升麻酸可明顯地降低大白鼠的血糖值之外，亦可增強STZ糖尿病大白鼠骨骼肌之葡萄糖第四型轉移蛋白(glucose transporter subtype 4 form; GLUT4) mRNA及蛋白的表現。同時，升麻酸可降低STZ糖尿病大白鼠肝臟之解糖酵素(phosphoenolpyruvate carboxykinase; PEPCK) mRNA及蛋白的表現量。若先處理a1A-AR 或嗎啡m型受體的阻斷劑，升麻酸則無法再出現上述的作用。
綜合以上的結果可知，在胰島素依賴型糖尿病大白鼠，升麻酸的降血糖作用主要是藉由活化位於腎上腺髓質的a1A-AR，啟動PLC-PKC這條訊息傳遞路徑來加強腎上腺髓質釋放b-endorphin的能力。釋出的b-endorphin會作用於周邊組織的嗎啡m型受體，藉以增強糖尿病大白鼠骨骼肌對葡萄糖的吸回，配合肝臟的糖新生能力減弱，因而降低了糖尿病大白鼠的高血糖現象。

Diabetes mellitus (DM) is one of the serious disorders around the world. Cimicifuga rhizoma is contained in the prescription of “Bu-Zhong-I-Chi-Tang”, a medication to be effective for the handling of DM in traditional Chinese medicine. Isoferulic acid is one of the active prinicles in Cimicifuga rhizoma. The present study is performed to investigate the antihyperglycemic action of isoferulic acid.
A dose-dependent lowering of plasma glucose was obtained in the fasting rats with insulin dependent DM, both Bio—Breeding/Worcester rats and steptozotocin-induced diabetic rats (STZ-diabetic rats). However, plasma glucose levels in normal and non-insulin dependent DM rats can be lowered by isoferulic acid at a higher dose. Isoferulic acid at the effective dose significantly attenuated the increase of plasma glucose induced by intravenous glucose challenge test in Wistar rats.
Isoferulic acid enhanced the uptake of radioactive glucose into mouse myoblast cells, C2C12 cells, in a concentration-dependent manner. Effect of isoferulic acid on a1-adrenoceptors was supported by the displacement of [3H]YM617 binding in C2C12 cells. The action of isoferulic acid to enhance the uptake of radioactive glucose was abolished in C2C12 cells pre-incubated with the antagonist at concentrations sufficient to block a1A-adrenoceptor (a1A-AR). The plasma glucose lowering effect of isoferulic acid in the STZ-diabetic rats was also abolished by pretreatment with a1A-AR antagonists. Pharmacological inhibition of phospholipase C (PLC) resulted in a concentration-dependent reduction of the isoferulic acid-stimulated uptake of radioactive glucose into C2C12 cells. Moreover, chelerythrine and GF 109203X diminished the action of isoferulic acid at concentration sufficient to inhibit protein kinase C (PKC).The obtained data suggest that activation of a1A-AR may play an important role in the plasma glucose lowering activity of isoferulic acid in the absence of insulin.
Injection of isoferulic acid at the effective dose increased the plasma b-endorphin-like immunoreactivity (BER) in STZ-diabetic rats that can be abolished by a1A-AR. Treatment with b-endorphin enhanced the uptake of radioactive glucose in a concentration-dependent manner in skeletal muscle and hepatocytes isolated from STZ-diabetic rats. The plasma glucose lowering effect of isoferulic acid was also abolished by pretreatment with naloxone or naloxonazine at doses sufficient to block opioid m-receptors. Plasma glucose lowering action of isoferulic acid disappeared in opioid m-receptors knockout mice, while the plasma glucose lowering response to isoferulic acid was still observed in wild-type mice. Mediation of opioid m-receptors in the plasma glucose lowering action of isoferulic acid can thus be considered.
In addition, isoferulic acid enhanced the BER secretion from isolated adrenal medulla of STZ-diabetic rats in a concentration-dependent manner and the antagonists of a1A-AR abolished this action. In the presence of PLC inhibitor, isoferulic acid-induced change of BER was reduced in a concentration-dependent manner. Moreover, pharmacological inhibition of PKC diminished this action of isoferulic acid. Bilateral adrenalectomy made the loss of the plasma glucose lowering action of isoferulic acid and no increase of plasma BER was obtained in isoferulic acid treated STZ-diabetic rats.
The mRNA and protein levels of glucose transporter subtype 4 form (GLUT4) in skeletal muscle was increased by isoferulic acid after repeated treatment for 1 day in STZ-diabetic rats. Otherwise, similar repeated treatment with isoferulic acid reversed the elevated mRNA level of phosphoenolpyruvate carboxykinase (PEPCK) in liver of STZ-diabetic rats to the normal level. Pharmacological inhibition of a1A-AR or opioid m-receptors resulted in the loss of isoferulic acid-induced action.
These results suggest that release of b-endorphin from the adrenal gland seems responsible for the lowering of plasma glucose in STZ-diabetic rats by isoferulic acid through an activation of a1A-AR. Activation of opioid m-receptors by the released b-endorphin can increase the utilization of glucose and/or decrease hepatic gluconeogenesis to lower plasma glucose in diabetic rats lacking insulin.

封面
中文摘要
英文摘要
縮寫指引
第一章　緒論
1. 引言
2. 本論文研究目的
3. 升麻酸的特性
第二章　實驗材料與方法
一、實驗動物及細胞
（一）實驗動物
（二）實驗用細胞株
二、實驗材料
（一）實驗試劑
（二）實驗器材
（三）實驗方法
第三章　升麻酸對胰島素依賴型糖尿病大白鼠的降血糖作用
1. 升麻酸在糖尿病大白鼠的降血糖作用
2. 連續投與升麻酸對胰島素依賴型糖尿病大白鼠血糖的影響
3. 升麻酸與葡萄糖挑戰試驗
4. 升麻酸在糖尿病大白鼠骨骼肌對葡萄糖轉移蛋白基因的影響
5. 升麻酸在糖尿病大白鼠肝臟對葡萄糖新生限制效酵素PEPCK基因的影響
討論
第四章　升麻酸藉由沽化A1a-adrenocepor增強C2c12肌母細胞對葡萄糖吸回的作用
1. 升麻酸在C2C12肌母細胞對葡萄糖吸回作用之影響
2. 升麻酸取代[3H]YM617結合於C2C12肌母細胞的能力
3. a1-AR阻斷劑對升麻酸在C2C12肌母細胞葡萄糖吸回作用之影響
4. Phospholipase C(PLC)或protein kinase C(PKC)的阻斷劑對升麻酸在C2C12肌母細胞葡萄糖吸回作用之影響
討論
第五章　升麻酸藉由活化a1A-adrenoceptor對胰島素依賴型糖尿病大白鼠產生降血糖作用
1. a1A-AR阻斷劑對升麻酸在胰島素依賴型糖尿病大白鼠所產生降血糖作用之影響
2. a1A-AR阻斷劑對升麻酸在糖尿病大白鼠骨骼肌之葡萄糖轉移蛋白基因的影響
3. a1S-AR阻斷劑對升麻酸在胰島素依賴型糖尿病大白鼠肝臟基因的影響
討論
第六章　升麻酸會增強糖尿病大白鼠體內B-endorphin的釋放來產生降血糖作用
1. 升麻酸對糖尿病大白鼠血中B-endorphin濃度之影響
2. a1A-AR阻斷劑對升麻酸在胰島素依賴型糖尿病大白鼠血中B-endorphin濃度之影響
3. 嗎啡ｕ型受體阻斷劑對升麻畯在胰島素依賴型糖尿病大白鼠所產生降血作用之影響
4. 升麻酸在嗎啡ｕ型受體剔除的胰島素依賴型糖尿病小鼠的作用
5. B-endophin在胰島素依賴型糖尿病大白鼠對朋骼肌及肝細胞葡萄糖吸回作用之影響
6. 嗎啡ｕ型受體阻斷劑對升麻酸在糖尿病大白鼠骨骼肌之葡萄糖轉杼蛋白基因的影響
7. 嗎啡ｕ型受體阻斷劑對升麻酸在胰島素依賴型糖尿病大白鼠肝臟PEPCK基因的影響
討論
第七章　升麻酸藉由活化腎上腺髓質的a1A-adrenoceptor來促進B-endophin釋放的作用
1. 升麻酸在離骿腎上腺髓質對釋放B-endorphin之影響
2. a1A-AR阻斷劑對升麻酸在離體腎上腺髓質釋放B-endorphin之影響
3. PCL或PKC阻斷劑對於升麻酸在腎上腺髓質釋放B-endorphin之影響
4. 升麻酸在腎上腺去除的糖尿病大白鼠對血糖及血中B-endorphin之影響
討論
總結
引用文獻
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引用文獻
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