臺灣博碩士論文加值系統

糖尿病腎病變是糖尿病主要併發症之一；許多証據顯示糖尿病腎病變的機轉與持續高血糖，導致非酵素性蛋白質糖化有關。有研究指出aminoguanidine(AG)能抑制streptozotocin(STZ)誘發的糖尿病大鼠蛋白尿、腎臟基底膜間質增厚，及抑制advanced glycosylation end-products(AGEs)螢光物的發展；而精胺酸L-arginine之官能基與AG相似，另外精胺酸為NO前趨物，其可能藉由改善血管擴張，降低腎絲球血壓及其後的傷害，包括減少尿蛋白排泄，改善超過濾。本研究目的為瞭解在糖尿病(DM)時，餵食高劑量精胺酸下，對腎功能之影響及與蛋白質糖化是否有關。本實驗用STZ誘發大鼠為DM，隨後將老鼠分為三組，分別為一般飲水(DC組)，做為空白組 加2﹪甘胺酸glycine於飲水中(DG組)，做為對照組 加2﹪精胺酸於飲水中(DA組)，做為實驗組；控制組以normal saline注射，同樣分為三組一般飲水處理(CC組)加2%甘胺酸於飲水中(CG組)加2﹪精胺酸於飲水中(CA組)。讓大鼠自由進食及飲水，餵食8週及16週時收集24h尿液後犧牲，觀察餵食不同胺基酸，其腎功能的改善及營養狀態；於犧牲時搜集血漿，並稱量腎重及稱左右骨骼肌重；然後利用Nitro Blue Telrazolium (NBT Test)以分光光度計測量血漿中糖化蛋白質，並以自動分析儀測量生化值。結果顯示：STZ注射後，分別是第8週及第16週，造成餵食一般飲水組(DC組)及甘胺酸組（DG組），其尿蛋白排泄量增加，而補充精胺酸(DA組)明顯改善此現象( p<0.05)，且與CC組沒有差異；同樣的補充精胺酸 (DA組)並能改善營養狀態，如血漿albumin 值顯著提高(p<0.05)，使其與CC組沒有顯著差異，且改善部份的骨骼肌流失；又糖尿病各組持續在中、長期增加氮攝取量下，發現16週時，除精胺酸的處理組之外，其一般飲水組(DC組)及甘胺酸組（DG組）之腎絲球過濾率均與CC組有顯著差異，有超過濾情況，而DA組與CC組沒有顯著差異；精胺酸組的血糖也獲得改善。在糖化蛋白質及血脂肪方面，糖尿病三組均有較高的趨勢，且精胺酸組(DA組)並沒有改善STZ大鼠血漿糖化蛋白質之作用。由結果顯示，當糖尿病發生時，餵食高劑量精胺酸能改善腎病的進展，精胺酸有著保護腎臟功能的效果及逆轉糖尿病所造成的營養流失，此可能並非經由抑制蛋白質糖化的作用所致。甘胺酸並無如精胺酸改善糖尿病腎病的作用。

Diabetic nephropathy is a major complication in diabetes mellitus (DM). There are a lot of evidences showe that the hyperglycemia induced non-enzymatic glycated proteins are related to the diabetic nephropathy. Recent studies pointed out that aminoguanidine (AG) can inhibit the occurrence of proteinuria, the thickening of the glomerular basement membrane, and the synthesis of the advanced glycosylation end products (AGEs) in streptozotocin (STZ)-induced DM rats. The functional group of L-arginine is similar to that of AG. In addition, being the known precursor of nitric oxide，L-arginine may alleviate the damages of glomerular via the production of NO. The aims of the present study are to investigate the relationship between high levels of arginine intake on renal function and glycated proteins in DM. After administered with STZ, rats were divided into three groups, that is, rats provided with distilled water (DC group), water containing 2% glycine (DG group), or water containing 2% L-arginine (DA group) as their drinking water. Three control groups administered with saline injection were also included, that is, rats provided with distilled water (CC group), water containing 2% glycine (CG group), or water containing 2% L- arginine (CA group) as their drinking water. Rats were free access to diet and water for 8 or 16 weeks and then sacrificed after 24h urine collection. Renal function and nutritional status were observed. Plasma was collected and the weights of kidney and skeletal muscle were obtained. The levels of glycated proteins in plasma were measured by NitroBlueTelrazolium (NBT test) using spectrophotometer. The levels of plasma substrates were measured by automatic analyzer. The results of the present study showed that STZ injection increased the excretion of protein in the urine in rats fed with distilled water (DC group) and glycine contained water (DG group) for 8 or 16 weeks, whereas L-arginine supplementation (DA group) improved the STZ-induced proteinuria (p<0.05). Arginine supplementation also improved the nutritional status, for example, the levels of plasma albumin was significantly greater in DA group (p<0.05) compared with that of in DC and DG groups, but not significantly different from that of in CC group. The loss of skeletal muscle was also improved by arginine. After 16 weeks, the glomerular filtration rate (GRF) was significantly increased in DC and DG groups, even to the conditions with hyperfiltration. There was no significant difference in GRF between DA and CC groups. The levels of plasma glucose were also improved in DA group. However, all of the three STZ injected groups were tended to have greater levels of glycated proteins and lipid in the plasma. Supplemental L-arginine (DA group) did not improve the STZ induced protein glycosylation in rats. The results of the present study suggested that high levels of L-arginine intake might improve the process of the diabetic nephropathy, protect the renal function, and reverse the DM caused nutritional loss. These functions of supplemental L-arginine might not due to the inhibition of the protein glycosylation. Supplemental glycine did not improve the diabetic nephropathy as what arginine did.

目錄
頁次
中文摘要…………………………………………………………III
英文摘要…………………………………………………………V中英專有名詞及縮寫對照表………………………………..…VII
第壹章、前言……………………………………………………1
第貳章、文獻探討……………………………………………..2
一、糖尿病與糖尿病腎病變的關係………………………………….2
(一)流行病學……………………………………………………….2
(二)糖尿病腎病的特質…………………………………………….3
(三)病理學………………………………………………………….4
(四)病因學………………………………………………………….7
二、蛋白質與腎病的關係……………………………………………11
(一)攝取蛋白質的量與腎病的關係………………………………11
(二)不同胺基酸與腎病之間的探討………………………………11
(三）在腎疾病上精胺酸L-arginine與腎臟關係的探討………14
(四) 在腎疾病上飲食限制或補充L-arginine的影響………..…17
三、高血糖與非酵素性蛋白質糖化對腎臟的影響…………………19
四、L-arginine對蛋白質糖化之抑制作用及對糖尿病腎病之
可能作用…………………………………………………………22
五、以streptozotocin誘發的糖尿病的實驗動物模型………….23
第參章、實驗材料與方法…………………………………….25
一、 實驗材料…………………………………………………………25
(一)化學材料……………………………………………………….25
(二)儀器設備……………………………………………………….26
(三)實驗動物………………………………………………………..26
二、實驗方法………………………………………………………….26
(一)糖尿病動物模型之建立…………………………………… …26
(二)血清及血漿製備………………………………………………..27
(三)小腿三條骨骼肌及腎臟製備…………………………………..27
(四)測量方法………………………………………………………..27
(五)代謝受質分析…………………………………………………..28
三、腎功能試驗及計算公式………………………………………….36
四、統計方法………………………………………………………….38
第肆章、實驗結果……………………………………………..39
一、以STZ誘發大白鼠為糖尿病及其死亡率………………………39
二、胺基酸強化的飲食對腎臟大小的影響………………………….40
三、攝取胺基酸強化的飲食對腎功能之影響……………………….41
四、攝取胺基酸強化的飲食對血液生化值及小腿骨骼肌的影響….42
五、攝取胺基酸強化的飲食對尿蛋白尿量及24小時尿生化物質
的影響…………………………………………………………….44
六、攝取胺基酸強化的飲食對糖化蛋白質的影響………………….46
第伍章、結果表格……………………………………………..47
第陸章、討論………………………………………………….57
一、L-arginine對糖尿病腎病變大鼠營養狀態之影響……………57
二、L-arginine對糖尿病腎病變大鼠之尿蛋白排泄、腎功能、腎
臟大小之影響…………………………………………………….59
三、L-arginine對糖尿病腎病變大鼠血糖改善之影響…………….61
四、L-arginine對糖尿病腎病變大鼠血脂肪改善之影響………….62
五、L-arginine對糖尿病腎病變大鼠糖化蛋白質的影響………….63
結論………………………………………………………………65
參考文獻…………………………………………………………66

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