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  • 學位論文

桑葉萃取物於streptozotocin誘發之糖尿病大鼠之抗糖尿病作用

Anti-diabetic effects of mulberry leaf extract on STZ-induced diabetic rats

指導教授 : 劉承慈

摘要


糖尿病( DM )是全球盛行的慢性疾病之一,血糖控制不良是導致此症併發症的重要因素,且與體內氧化壓力增加有關。過去研究指出白桑(Morus alba) 的葉及其萃取物 ( ME ) 具有降血糖功效,且與其中1-Deoxynojirimycin (1-DNJ)之作用有關,但ME或1-DNJ降血糖之胰內及胰外機制所知均有限,且也不清楚其對DM腎病發展之影響。本研究目的是探討ME與1-DNJ抗糖尿病作用之機制,及其是否可延緩DM腎病變發展。雄性Wistar大鼠注射streptozotocin ( 65 mg/kg BW,i.v. ) 誘發DM,而control組大鼠則注射檸檬酸緩衝溶液。誘發第7天將DM大鼠隨機分為6組,每日分別灌食1、3、10、30 mg / kg BW之ME以及30 mg/ kg BW之1-DNJ或載劑二次水 ( 2 ml/ kg BW ),連續灌食一週,且control組與亦灌食載劑。於誘發後第7天及第11天進行口服葡萄糖耐受測試 (OGTT),或於第11天進行胰島素耐受測試 (ITT),並於誘發後第14天犧牲,收集尿液、血液與臟器進行生化、氧化壓力指數分析以及腎功能指標測定。結果顯示,所有劑量ME皆具有急性、慢性降低空腹血糖及OGTT期間血糖上升面積之作用 ( p<0.05 ),而1-DNJ具有改善空腹血糖及OGTT期間血糖上升曲線下面積之慢性作用 ( p<0.05 )。且所有劑量ME及1-DNJ皆提升血漿及胰臟之胰島素含量及HOMA-IR ( p<0.05 ),且ME在劑量10及30 mg/ kg可增加DM大鼠在胰島素刺激下之降血糖速率 ( p<0.05 )。在抗氧化作用方面,所有劑量ME及1-DNJ皆逆轉DM所致之胰臟、腎臟、肝臟、骨骼肌及周邊血TBARS上升,並改善DM所致之腎臟GPx及胰臟GRd活性降低 ( p<0.05 ),此外,1-DNJ改善DM所致之肝臟及骨骼肌GPx及GRd活性降低 ( p<0.05 )。 在DM大鼠,ME在劑量30 mg/kg改善骨骼肌GPx活性,在劑量10至30 mg/kg改善腎臟GRd活性,在劑量1 mg/kg改善肝臟GRd活性,且在劑量3至30 mg/kg改善骨骼肌GRd活性 ( p<0.05 )。所有劑量ME及1-DNJ皆顯著降低胰臟、腎臟、肝臟及骨骼肌之發炎產物NO含量 ( p<0.05 )。在腎功能指標方面,所有劑量ME及1-DNJ皆改善糖尿病引之腎絲球高過濾作用,顯著逆轉BUN、CCR、GFR1及GFR2上升 ( p<0.05 ),且ME在劑量30 mg/ kg及1-DNJ改善DM腎病變導致之血壓上升 ( p<0.05 )。腎絲球組織型態學觀察則呈現,ME在劑量30 mg / kg之ME及1-DNJ改善DM腎絲球間質增厚的情形。由本研究結果得知,ME及1-DNJ具有促進胰島素分泌及改善胰島素阻抗之胰內及胰外作用,並能延緩糖尿病腎病變發展,此作用至少有部分與改善氧化壓力有關。

並列摘要


Diabetes Melitus (DM) is one of the most popular chronic diseases in the world. Poor glycemic control is a known major factor that leads to diabetic complications and is attributed to increased oxidative stress. According to previous studies, Morus alba leaves and its extract (ME) possesses hypoglycemic effect with 1-deoxynojirimycin (1-DNJ) as a functional compound. However, the mechanisms underlying which ME and 1-DNJ lowering blood glucose level remain to be clarified. It is also not known how ME and 1-DNJ affect the development of DM nephropathy. The aim of this study is to investigate the antidiabetic effect of ME and 1-DNJ including their effect on the development of diabetic nephropathy and the related mechanisms. Male Wistar rats were injected with streptozotocin (65 mg/kg BW, i.v.) to induce DM. Control rats were injected with citrate buffer solution. 7 days after induction, the DM rats were assigned randomly to six groups and were treated with 1, 3, 10, 30 mg/kg BW of ME, 30 mg/kg BW of DNJ or vehicle (d.d. H2O; 2 ml/kg BW) for a week. Normal control rats also received vehicle. OGTT was carried out at 7 or 11 days and ITT was carried out at 11 days after induction. At 14 days after induction, rats were killed with CO2 and organ/tissue samples collected for various biochemical analyses and the determination of oxidative stress and renal function. On the DM rats all doses of ME and 1-DNJ significantly ameliorated fasting blood glucose and AUC of glucose during OGTT period chronically and ME also showed such effect acutely. All doses of ME and 1-DNJ significantly increased peripheral and pancreatic levels of insulin and improved HOMA-IR in DM rats. Ten and 30 mg/kg of ME improved insulin-induced lowering of blood glucose level in DM rats. In the other hand, all doses of ME and 1-DNJ significantly reversed increased TBARS of the pancreas, kidneys, livers, muscles and peripheral blood in DM as well as decreased GRd activity of the pancreas and kidneys in DM. In addition, 1-DNJ significantly reversed lowered GPx and GRd activity of the livers and muscles in DM. ME at 30 mg/kg significantly reversed lowered GPx activity of the muscle, at 10 to 30 mg/kg significantly reversed lowered GRd activity of the kidneys, at 1 mg/kg significantly reversed lowered GRd activity of of the livers, at 3 to 30 mg/kg significantly reversed lowered GRd activity of the muscles. All ME doses and 1-DNJ significantly decreased NO content of the pancreas, kidneys, livers,and muscles in DM. The indices of renal function, including BUN, CCR, and GFR were all ameliorated by all doses of ME and 1-DNJ. In addition, 30 mg/kg of ME and 1-DNJ improved glomerular morphology of the kidneys and lowered blood pressure in DM. In conclusion, ME and 1-DNJ improved insulin secretion and insulin sensitivity and attenuated the development of diabetic nephropathy. The antidiabetic effects of ME and 1-DNJ is at least partly due to the amelioration of the increased oxidative stress in DM.

參考文獻


糖尿病腎臟病變的形成和機轉
張鳴宏(2005) 認識糖尿病神經病變
陳俞琦(2008)桑葉降血糖之研究
徐愛良(2005)桑葉的現代研究進展
張嘉哲(2006)台灣桑樹之分類及品種改良.

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