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研究生:李靜宜
論文名稱:肥胖糖尿病大白鼠模式之建立
論文名稱(外文):Establishment of diabetic obese rat model
指導教授:楊繼楊繼引用關係
學位類別:碩士
校院名稱:國立中興大學
系所名稱:獸醫學系
學門:獸醫學門
學類:獸醫學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
中文關鍵詞:糖尿病肥胖
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本研究旨在建立糖尿病大白鼠之動物模式,以模擬人類糖尿病自然病程與其代謝特性。而根據目前研究指出,glucosamine(GlcN)經由hexosamine生化合成途徑代謝會造成胰島素阻抗現象,並減弱葡萄糖刺激β細胞胰島素的分泌,故實驗利用Sprague- Dawley (SD)品系之大白鼠腹腔注射GlcN(1 g/Kg)以誘發擬第2型糖尿病之動物模式,結果發現GlcN僅能短暫模擬卻無法誘發長期糖尿病大鼠模式。然而除胰島素阻抗外,脂質代謝異常與肥胖,也被視為第2型糖尿病的主要病因,故實驗使用SD大白鼠及自發性高血壓品系之大白鼠(spontaneously hypertensive rats),分別餵飼正常飼料(Basal diet)或高脂飼料(High Fat Diet 30%),數週後腹腔注射nicotinamide (NA, SD: 100 mg/Kg;SHR: 200 mg/Kg)或併用streptozotocin (STZ, 50 mg/Kg)。每週口服葡萄糖耐受性試驗(2 g/Kg)的結果顯示,餵飼高脂之大白鼠血糖濃度與對照組並無差異,但其胰島素濃度可見上升趨勢,而HF/STZ實驗組大白鼠之平均血糖濃度顯著高於其他組別,顯示其葡萄糖耐受性之不良,靜脈注射葡萄糖耐受性試驗亦可見相似之結果,且SHR與SD品系間並無明顯之差異。由胰臟灌流實驗結果則顯示,長期餵飼高脂會降低葡萄糖刺激胰臟胰島素之分泌,影響胰臟之正常功能,而經過STZ處理的HF/STZ組與HF/NA-STZ組,其胰島素分泌不因葡萄糖之刺激而上升,可見STZ對β細胞之傷害。綜合研究結果發現,高脂餵飼合併給予STZ可誘發大白鼠高血糖、葡萄糖耐受性不良和葡萄糖刺激胰島素分泌能力下降之現象,可嘗試用以建立第2型糖尿病之動物模式。
For developing an animal model to mimic the metabolic characteristics of type 2 diabetes mellitus. Glucosamine(GlcN), a product of hexosamine biosynthetic pathway, was used to increase blood glucose concentration and induce insulin resistance in Sprague-Dawley(SD) rats. The results showed that GlcN(1 g/Kg, ip) decreased insulin concentration and increased blood glucose concentration. But daily injection of GlcN for 30 days did not induce diabetic symptom. Thus, GlcN temporally induced insulin resistance and mimic type 2 diabetes mellitus in SD rats. Abnormal lipid metabolism and obesity are also considered as important factors of type 2 diabetes mellitus. Therefore, spontaneously hypertensive rats(SHR) and SD rats were fed with basal or high fat(HF) diet(30%) for 8 weeks, respectively. Rats were administered intraperitoneally with streptozotocin(STZ, 50 mg/Kg) pretreatment with or without nicotinamide(NA, SD: 100 mg/Kg; SHR: 200 mg/Kg). The results showed that the blood glucose concentration of rats fed with high fat diet was not different from control group after 2 hours of oral glucose tolerance test(2 g/Kg), but insulin concentration increased slowly. The blood glucose concentration of HF-STZ group was obviously high than the other groups after injection of STZ, the results showed that glucose tolerance was impaired. Similar results were found after treatment with intravenous glucose tolerance test. The response of blood insulin concentration in HF-STZ rats after stimulation with 10 mM glucose was also reduced. In pancreatic perfusion, the results showed that rats fed with HF diet for 8weeks decreased glucose-stimulated insulin secretion. Whereas, HF rats treated with STZ or NA-STZ was not increased insulin secretion after perfused with 10 mM glucose. The results suggested that STZ damaged β cells. Finally, all the data suggested that the diabetic obese rat model established with conjunctive treatment of HF diet and STZ was characterized by hyperglycemia, impaired glucose tolerance and decrement of glucose-stimulated insulin secretion. Such a model would help elucidation of the underlying mechanism of type 2 diabetes mellitus.
中文摘要……………………………………………………… 01
英文摘要 …………………………………………………… 02
目錄……………………………………………………………….. 04
圖次……………………………………………………………..… 07
表次…………………………………………………..……… 09
第一章、 緒言 …………………………………………… 10
第二章、 文獻探討 ………………………………………..…… 12
第一節、糖尿病簡介 ………………………..……… 12
一、 糖尿病的定義 ………………………………… 12
二、 糖尿病的分類 ………………….……………… 12
三、 糖尿病的病因 ………………………….…… 13
四、 糖尿病診斷 …….………………………… 15
五、 糖尿病流行病學 ………….…………………… 16
第二節、胰島素訊息傳遞與作用(Insulin signal transduction and action) ….......................... 17
一、 胰島素受體(Insulin receptor)…………...… 17
二、 胰島素受體基質(Insulin receptor substrate, IRS) ..............................................18
三、 磷酸肌醇3’激酶(Phosphatidylinositol-3-OH-kinase, PI(3)K) …........................................ 19
四、 Akt (Protein kinase B) ……….…………… 19
五、 葡萄糖轉運蛋白(Glucose transporter, GLUT) ………….……….......................................... 20
第三節、糖尿病實驗動物模式之建立 ………...… 21
一、 基因誘導模式 ………………………. 21
二、 藥物誘導模式 ………………………. 22
第四節、Glucosamine和hexosamine生化合成途徑 ………… 24
第五節、肥胖與糖尿病胰島素之測定 ………………… 28
一、 游離脂肪酸(free fatty acid, FFA) ………… 29
二、 Adiponectin …………………………… 31
第六節、Streptozotocin作用機制 ……………………. 32
一、 DNA alkylation …….…………………………. 32
二、 一氧化氮(nitric oxide, NO) …………………… 33
三、 自由基(Free radical) ……………………… 34
第七節、Nicotinamide(NA) ………………….. 34
第八節、胰島素與升糖素 ……………………….……… 36
一、 影響胰島素分泌之因子 …………………….. 36
二、 胰島素分泌的分期 ………………...……………… 38
三、 升糖素之分泌..................................38
第3章 材料與方法……………………………………....…… 41
實驗動物、頸動脈埋管系統、血管插管系統 ……………………………..........…... 41
灌流系統、灌流方法 ………………………………………..… 42
實驗一:Glucosamine及口服葡萄糖對SD品系大白鼠血醣及胰島素分泌之
研究 …………………………………………………….. 44
實驗二:併用streptozotocin及nicotinamide對餵食高脂飼料之SHR品系大
白鼠血醣及胰島素分泌之研究 ………………………………. 45
實驗三:餵食高脂飼料及併用streptozotocin對SD品系大白鼠血醣及胰島素分泌之研究 ………………………………………….. 46
實驗四:餵食高脂飼料及併用streptozotocin對SD品系大白鼠血醣、胰島素及升糖素分泌之研究 ………………………………… 47
胰島素之測定 …………………………………………….. 48
升糖素之測定 …………………………………………….. 48
資料分析與統計 ……………………………………………… 49
第四章、 結果 ……………………………………………… 50
實驗一:Glucosamine及口服葡萄糖對SD品系大白鼠血醣及胰島素分泌之研究 ..............................................50
實驗二:併用streptozotocin及nicotinamide對餵食高脂飼料之SHR品系大白鼠血醣及胰島素分泌之研究………………… 56
實驗三:餵食高脂飼料及併用streptozotocin對SD品系大白鼠血醣及胰島素分泌之研究 ………………………………………………60
實驗四:餵食高脂飼料及併用streptozotocin對SD品系大白鼠血醣、胰島素及升糖素分泌之研究 ………………………………… 64
第五章、 討論 ………………………………………………67
第六章、 結論 …………………………………………… 75
參考文獻 ……….……………………..……………………… 77
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