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研究生:阮裕程
研究生(外文):Yu Cheng Juan
論文名稱:飲食誘導產生胰島素阻抗後對腦部胰島素訊號傳遞及葡萄糖攝取能力之影響
論文名稱(外文):Effect of diet-induced insulin resistance on brain insulin signaling pathway and glucose uptake
指導教授:洪麗滿
指導教授(外文):L. M. Hung
學位類別:碩士
校院名稱:長庚大學
系所名稱:生物醫學研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
論文頁數:71
中文關鍵詞:胰島素
外文關鍵詞:insulin
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社會環境及生活型態的改變,導致許多文明病的產生。代謝症候群即現代文明病的代表,在多數國家中代謝症候群的盛行率約在20~30 % 左右。代謝症候群會併發許多慢性疾病,如:肥胖、心血管疾病、第二型糖尿病等。目前認為代謝症候群的起因是由於胰島素阻抗造成。腦部廣泛分布有胰島素受體,近年來研究指出腦部胰島素訊號的功能會影響食慾、生殖、血糖及調控學習以記憶。研究也指出,胰島素阻抗會增加發生中風、阿茲海默症、憂鬱症等疾病的風險及降低認知能力等。
本研究之目的為釐清周邊組織產生胰島素阻抗,特別在高胰島素血症的狀況下是否會影響腦部胰島素訊號傳遞及葡萄糖攝取能力。
動物實驗利用不同的飲食﹝高脂 (HFat)、高果糖 (HFru)、高膽固醇(HC)、高膽固醇與高果糖水 (HCF)﹞,餵食12週後誘導實驗大白鼠產生胰島素阻抗,並比較其差異。結果顯示,各組的血糖及血脂皆顯著高於控制組。在血糖鉗制實驗中發現HFat、HC、HCF三組之葡萄糖灌注速率顯著低於控制組。腦部CuZnSOD實驗各組皆顯著高於控制組。另外,EHC後eNOS會去磷酸化。本研究顯示,不同的飲食因子會產生周邊組織胰島素阻抗,但對於腦部胰島素訊號的影響均是輕微的。
Environmental factors and changes in lifestyle are considered the major contributors in the global epidemic of metabolic syndrome. Metabolic syndrome is characterized by a group of risk factors in a person. These include: insulin resistance or glucose intolerance, central obesity, dyslipidemia (high triglycerides and low HDL cholesterol), and hypertension. People with metabolic syndrome are at increased risk of cardiovascular diseases and type 2 diabetes. Insulin and its receptor have both recently been identified in the central nervous system (CNS); the biological function of insulin on the CNS includes maintenance of normal neuron function, regulation of food intake, inhibition of hepatic gluconeogenesis, and its influence on reproduction and cognition.
The present study aims to investigate the role of different diet components in peripheral insulin resistance and examine the effects of diet components on brain glucose uptake and insulin signaling. Male Sprague-Dawley rats were fed chow diet, high fat diet, high fructose diet, high cholesterol diet, high cholesterol diet + 10% fructose in drinking water for 12 weeks. Blood pressure and plasma lipid levels were significantly increased in the four experimental groups as compared to the control group. Under euglycermic hyperinsulinemic (EHC) condition, the glucose infusion rate (GIR) was dramatically reduced in HFat, HC, and HCF rats- suggesting development of insulin resistance in these animals. Cerebral CuZnSOD protein levels were markedly elevated in HFat、HFru groups compared to the control rats. In addition, the p-eNOS levels under EHC condition leads to dephosphorylation of eNOS .This study suggests an association between dietary factors with the development of peripheral insulin resistance. However, there seem to be less of an effect CNS.
第一章 緒論........................……………………………………………...1
一、 代謝症候群………………………………………………………………...1
二、 胰島素的生理功能………………………………………………………...4
三、 胰島素阻抗與慢性疾病之關係…………………………………………...5
四、 胰島素在大腦之功能……………………………………………………...7
五、 中樞神經系統攝取葡萄糖之機制………………………………………..11
六、 腦部胰島素訊息傳遞路徑……………………………………………….12
七、 不同飲食動物模式對腦部功能之影響………………………………….13
八、 飲食誘導胰島素阻抗的動物模式……………………………………….13
第二章 研究目的……………….………………………………………16
第三章 實驗材料與方法………………………….……………………17
一、 試劑及材料……………………………………………………………….17
二、 實驗動物………………………………………………………………….17
三、 動物分組………………………………………………………………….17
四、 實驗流程………………………………………………………………….18
五、 生化數值之檢測………………………………………………………….18
六、 血糖鉗定技術…………………………………………………………….20
七、 腦組織葡萄糖攝取之測定……………………………………………….22
八、 腦組織蛋白分析………………………………………………………….23
九、 統計分析………………………………………………………………….25
第四章 結果…………………………………………………………….26
一、 比較大白鼠餵食各種不同飼料其生化數值之變化…………………….26
二、 比較不同飲食對胰島素敏感性的影響………………………………….27
三、 比較不同飲食對大腦皮質葡萄糖攝取能力之影響…………………….27
四、 比較腦部胰島素的訊息傳遞路徑中蛋白質分子之差異……………….28
五、 比較腦部AMPK蛋白質磷酸化程度之差異……………………………28
六、 比較腦部SOD蛋白表現量之差異………………………………………28
七、 比較腦部eNOS蛋白質磷酸化程度及nNOS和iNOS蛋白表現量差異………………………………………………………………………….29
八、 比較腦部Glucose transporter 1蛋白表現量差異………………………..29
九、 比較腦部p-eNOS、p-mTOR、p-GSK-3β desensitization之差異………30
第五章 討論與結論…………………………………………………….31
圖、表……………………………………………………………………34
表一 比較大白鼠餵食各種不同飼料其生化數值之變化……………………..34
圖一 比較不同飲食對胰島素敏感性的影響…………………………………..35
圖二 比較不同飲食對肝臟糖質新生的影響…………………………………..36
圖三 比較不同飲食對大腦皮質葡萄糖攝取能力之影響……………………..37
圖四 比較腦部胰島素的訊息傳遞路徑中Akt蛋白磷酸化程度之差異……...38
圖五 比較腦部胰島素的訊息傳遞路徑中GSK-3β蛋白磷酸化程度之差異…39
圖六 比較腦部胰島素的訊息傳遞路徑中ERK、JNK蛋白磷酸化程度之差…40
圖七 比較腦部胰島素的訊息傳遞路徑中mTOR蛋白磷酸化程度之差異…..41
圖八 比較腦部AMPK蛋白質磷酸化程度之差異…………………………….42
圖九 比較腦部SOD蛋白表現量之差異……………………………………….43
圖十 比較腦部eNOS蛋白質磷酸化程度及nNOS和iNOS蛋白表現量差異..44
圖十一比較腦部Glucose transporter 1蛋白表現量差異………………………..45
圖十二比較腦部p-eNOS、p-mTOR、p-GSK-3β desensitization之差異………46
參考文獻………………………………………………………………..47
附錄……………………………………………………………………..53
附錄一 Physiology of pure brain insulin resistance and Insulin signal in neuronal function……………………………………………………..53
附錄二 Metabolic overload in the liver and skeletal muscle…………………55
附錄三 Potential mechanisms by which fructose and uric acid may induce insulin resistance………………………………………………….......56
附錄四 The ABCs of β-cell dysfunction in type 2 diabetes…………………..57
附錄五 飼料成份……………………………………………………………..58
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