臺灣博碩士論文加值系統

目前糖尿病在台灣地區保守估計總數約在30萬~40萬人之間，且佔台灣十大死因之第五位。糖尿病致病機轉是因葡萄糖的代謝及吸收不當所致。在糖尿病的治療方面，目前降血糖藥物被認為對病情並無建設性及保護性，且易出現低血糖症狀之副作用。所以目前糖尿病藥物對血糖的控制仍有待改進或開發。
香椿(Toona sinensis Roem.)為楝科(Meliaceae)原產於中國之落葉喬木，目前已在全世界均有種植。在著名的「中藥辭典」，「台灣藥用植物誌」及文獻報導可知全植物各部分均有保健或治療之功能。在美國及台灣於民間飲用椿葉水萃取液後發現可改善高血壓及糖尿病症狀。而且於民間飲用椿葉水萃取液後，發現有些糖尿病人除了能降低一般降血糖藥物所不能改善之高血糖症狀，且不會產生低血糖之情形。所以令我們有興趣的是，香椿是透過什麼機轉來降低血糖？
我們用Alloxan及Streptozotocin誘發糖尿病及Epinephrine誘發
高血糖的動物模式，來觀察香椿之降血糖能力。由實驗結果顯示，
Alloxan所誘發的糖尿病鼠投予椿葉粗萃取粉劑後有明顯降血糖的功
能，而Streptozotocin及Epinephrine所誘發的糖尿病和高血糖鼠卻無
降血糖的效果。所以我們以Alloxan所誘發糖尿病鼠的動物模式來探
討香椿降血糖之機轉。我們發現椿葉粗萃取粉劑不但能降低糖尿病鼠
的血糖值、增加葡萄糖的耐受性，亦無急性及慢性的毒性，而且也不
會影響正常老鼠的血糖值。但是臨床常見的糖尿病用藥，例如：
Glibenclamid雖然也能降低血糖值，增加葡萄糖的耐受性，但卻會使
正常老鼠產生低血糖的情形。
Alloxan誘導產生糖尿病的原理為選擇性的破壞胰臟中分泌胰島素的b細胞，而導致胰島素含量減少，因而可能影響白脂、褐脂、心肌、白肌和紅肌等組織之細胞膜上的胰島素所依賴的葡萄糖轉運蛋白(GLUT4)及GLUT4 mRNA的表現量有關係。由實驗結果得知椿葉粗萃取粉劑可改善Alloxan所誘發的糖尿病鼠中的血中胰島素分泌量。而在GLUT4蛋白質表現方面結果顯示，糖尿病鼠的白脂、褐脂及白肌之GLUT4蛋白質表現量減少了，投予椿葉粗萃取粉劑與Glibenclamide後，白脂及褐脂的GLUT4蛋白質表現量增加，但白肌卻減少了。在紅肌及心肌方面，不論在糖尿病的狀態或投予椿葉粗萃取粉劑或Glibenclamide的GLUT4表現量皆無明顯變化。而在GLUT4 mRNA表現方面結果顯示，糖尿病鼠的白脂及褐脂的GLUT4 mRNA表現量減少了，投予椿葉粗萃取粉劑及Glibenclamide後GLUT4 mRNA表現量增加了。在心肌、紅肌及白肌方面，不論在糖尿病的狀態或投予椿葉粗萃取粉劑或Glibenclamide的GLUT4 mRNA表現量皆無明顯變化。
肝臟是影響葡萄糖的調控中一重要器官，GLUT2與肝臟的葡萄糖轉運蛋白有密切關係。但由實驗結果得知，Alloxan所誘發的糖尿病鼠的肝臟之GLUT2蛋白質表現量並無明顯的變化，而投予椿葉粗萃取粉劑與Glibenclamide後亦不改變GLUT2之蛋白質表現量。
綜合以上的結果我們認為，椿葉粗萃取粉劑的降血糖作用機轉中，脂肪組織上的GLUT4 mRNA及蛋白質表現應扮演一重要的角色。

Toona sinensis (TS) is a broadleaf tree, which grows all around the world, which is composed of only four or five ‘good’ species. TS are the only Toona species in which the leaflet margins can be serrate to serrulate. The trees provide very high quality timber and are widely used medicinally, the bark being used as an astringent and depurative, the root as a refreshment and a diuretic, the tender leaves as a carminative and a corrective, and the fruits as an astringent and for treatment of eye infections. The leaves and young shoots have been used as a vegetable in China for thousands of years. The leaves and stems of this plant have been used for the treatment of enteritis, dysentery and itch in oriental medicine. Recently, Aqueous leaf extracts of TS was used as a folk medicine for lowering blood pressure and blood sugar in the U.S.A. and Taiwan. It is said that TS leaf aqueous extracts can reduce the fasting blood glucose (FBG) level of ill-controlled NIDDM patients who were treated with conventional medicines, but don’t affect the FBG level of a healthy person. However, the mechanism of hypoglycemic effect of TS on diabetes is still obscure.
Alloxan causes severe damage in pancreatic b cells damage in rats. STZ cytotoxyicity is highly specific to the b cell, it also causes functional abnormalities in the islet a and d cells. Epinephrine increases the hepatic output of glucose and glycogenolysis. Testing with these three different diabetic or hyperglycemic animal models may provide us with the different possible mechanisms involved in hypoglycemic effect of TS. We found that aqueous leaf extracts of TS can lower the FBG level in alloxan-induced diabetic rats, while in STZ-induced and Epinephrine- induced diabetic rats the lowering effect was not shown.
Glucose transporter 4 (GLUT4), an insulin-dependent glucose transporter, is wide spread in adipose tissue and muscle. It translocates to the membrane when activated by insulin. Thus, the present study was designed to compare the effects of TS and Glibenclamide (GC) and find out if TS affects the secretion of insulin. Moreover, the possible role of membrane-associated GLUT4 in participating the hypoglycemic effect of TS on diabetes was investigated. Animal model of Alloxan-induced diabetes was used. The incidence of Alloxan-induced diabetes was more than 75%. We found that TS lowered the blood sugar level only in diabetic rats in a time-dependent manner, but GC lowered fasting blood glucose levels in both diabetic and normal rats. In addition, TS improved the glucose intolerance of diabetic rats the same as GC. In our preliminary results, the serum level of insulin was increased by TS treatment. The protein and mRNA expression of GLUT4 glucose transporter in adipose tissues, but not in skeletal muscle and heart, were significantly decreased in diabetic rats. TS or GC treatment caused a significant increase of GLUT4 protein and mRNA content in white and brown adipose tissues.
The liver plays an especially important role in regulating glucose by taking up incoming glucose from the small intestine and by releasing glucose into the circulation. Both uptake and release of glucose require transport of glucose across the plasma membrane. In general, specific carriers termed glucose transporters mediate glucose transport across the plasma membrane, and the presence of a facilitative glucose transporter, GLUT2, was suggested in the liver. In our preliminary results, the expression of GLUT2 glucose transporter was unchanged.
These results show that TS might enhance the secretion of insulin by an unknown mechanism and GLUT4 protein and mRNA of adipose tissues might participate in the hypoglycemic effect of TS on diabetic rats.
II英文摘要………………………………………………… 4-6
III緒論
香椿 …………………………………………………. 7-8
糖尿病………………………………………………… 9-12
葡萄糖轉運裝置(GLUT)……………………………… 13-14
GLUT4及GLUT2與糖尿病的關係……… 15-16
研究動機 .. …………………………………………. 17
IV實驗方法
實驗動物………………………………………………. 18
誘發糖尿病及高血糖之動物模式…………………….. 19-21
香椿葉萃取法…………………………………………. 22
最大耐受量測定(安全限度試驗)……………………… 23
血液中葡萄糖的濃度…………………………………. . 24
血中胰島素測定……………………………………….. 24-25
口服葡萄糖耐量試驗…………………………………… 26
細胞膜表面葡萄糖轉運裝置表現的測定…………….. 26-32
資料分析…………………………………………………… 33
V實驗結果
壹. 基本表現
1. 誘發糖尿病及高血糖動物模式
(A) 配製藥物注意事項………………………………. 35-36
(B) 治療前後之空腹血糖變化………………………. 36-37
(C) 動物評估………………………………………… 37-38
2. 外在因素對糖尿病鼠血糖值的影響……………… 38-39
3. 椿葉粗萃取粉劑的最大耐受量測定(安全限度試驗)… 39-40
4. 椿葉粗萃取粉劑與Glibenclamide對正常鼠及Alloxan誘
發的糖尿病鼠各項實驗結果
(A) 體重、飲水量、飲食量、排便量的變化…………. 40
(B) 空腹血糖
(1) 治療前血糖之穩定度……………………………. 41
(2) 治療後血糖的變化………………………………. 41-45
(C) 血中胰島素濃度……………………………………. 45-46
(D) 口服葡萄糖耐受性…………………………………… 46-47
貳.機轉探討
細胞膜表面葡萄糖轉運裝置的表現
(A) GLUT4蛋白質的表現………………………………… 48-49
(B) GLUT2蛋白質的表現………………………………… 49
(C) GLUT4 mRNA的表現………………………………… 50-51
參.附圖……………………………………………………… 52-79
VI討論……………………………………………………….. 80-89
VII參考文獻………………………………………………… 90-98

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