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博碩士論文 etd-0723107-143624 詳細資訊
Title page for etd-0723107-143624
論文名稱
Title
探討胰島素抗性在大鼠孤立束核對於中樞心血管調控所扮演的角色
Role of insulin resistance in nucleus tractus solitarii on central cardiovascular regulation in rats
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
131
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2007-07-09
繳交日期
Date of Submission
2007-07-23
關鍵字
Keywords
胰島素抗性、孤立束核、高血壓
hypertension, nucleus tractus solitarii, insulin resistance
統計
Statistics
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中文摘要
研究顯示胰島素抗性(insulin resistance)是引起代謝症候群患者高血壓的重要致病因素,目前絕大多數關於胰島素抗性導致高血壓的研究都著重於胰島素抗性在週邊組織及血管所引起的血管阻力增加進而引起高血壓;然而也有研究顯示無論在代謝症候群患者或實驗動物均可觀察到交感神經系統的過度興奮(sympathetic overactivity),但關於胰島素抗性造成中樞神經系統交感神經過度興奮的致病機轉研究寥寥無幾。我們先前的實驗證實胰島素在腦幹的心臟血管系統重要調節神經核之一的孤立束核(nucleus tractus solitarii, NTS)具有調控血壓、心跳的之功能,而且我們也證實了胰島素在孤立束核的心臟血管調節作用是透過活化磷酰肌醇-3 激酶(PI3K)-蛋白質激酶B(protein kinase B)-一氧化氮合成酶,產生一氧化氮來調控血壓心跳。此外近來報告指出氧化壓力(oxidative stress)的增加會造成糖尿病、心血管疾病發生率。而且在不同的高血壓動的物模式中都可以發現動物體內的活性氧(reactive oxygen species, ROS)會大量增加。有研究指出氧化壓力會活化多種絲胺酸激酶如絲裂原活化蛋白激酶(mitogen activated proteinkinase, MAPK)。而MAPK 會引起胰島素接受器基質1 (insulin receptor substract 1,IRS1)
位於307 位置絲胺酸(IRS1S307)的磷酸化。在先期實驗中,我們使用WKY大鼠於其飲水中加入10%果糖持續餵養8 週,另一組大鼠則在餵予10%果糖水4週後另給予促胰島素敏感藥物rosiglitazone,每週均測量其尾動脈壓及抽血觀察其血中胰島素跟血糖的變化。此後所有實驗均以餵養10%果糖水2~3 週之WKY大鼠進行實驗。結果顯示大鼠在餵養10%果糖水2 週後,其血壓較控制組已有明顯升高;但此時周邊組織的胰島素抗性尚未產生。有趣的是此時腦幹孤立束核中的胰島素含量較控制組明顯上升,而且胰島素在果糖組大鼠孤立束核的血壓心跳調節反應明顯減緩。而同時給予促胰島素敏感藥物rosiglitazone 的大鼠其血壓顯著較果糖組大鼠低,同時胰島素在大鼠孤立束核的血壓心跳調節反應明顯改善,孤立束核中的胰島素含量較控果糖明顯下降。這些結果都顯示代謝症候群大鼠的孤立束核確實會發生胰島素抗性,同時孤立束核胰島素抗性的發生與代謝症候群大鼠的高血壓有絕對的相關。在探討何訊息分子發生缺陷方面,我們發現在果糖組孤立束核中的IRS1S307 磷酸化的程度明顯較控制組高;而果糖組孤立束核中的IRS1 的下游訊息分子包括了蛋白質激酶B 及內皮性一氧化氮合成酶(endothelialnitric oxide synthase),對於胰島素刺激引起的活化程度較控制組顯著下降;而給予促胰島素敏感藥物rosiglitazone 可以明顯降低果糖組大鼠的孤立束核中的IRS1S307 磷酸化,同時改善胰島素在孤立束核中的蛋白質激酶B 及內皮性一氧化氮合成酶的活化。我們到觀察孤立束核中活性氧含量在果糖組明顯比控制組高;果糖組的p38 的磷酸化明顯的比控制組高。當給予抗氧化劑Tempol 則可以降低p38 的磷酸化,同時可以增加孤立束核中一氧化氮的含量;另在代謝症候群大鼠孤立束核中注射p38 抑制劑SB203580 則可以降低代謝症候群大鼠的血壓及心跳。綜合以上結果,我們推論代謝症候群高血壓的病因除胰島素抗性在周邊血管造成血管舒張度下降外,腦幹中調節心臟血管系統的孤立束核發生胰島素抗性亦對高血壓的發生扮演重要的角色;而孤立束核發生胰島素抗性主要機轉是孤立束核中的IRS1S307 被活化的p38MAPK 所磷酸化,進而抑制了在孤立束核具降心跳血壓作用的一氧化氮產生下降,促使血壓上升;而活化p38MAPK 的因素是孤立束核中的活化氧含量上升所致。
Abstract
Insulin resistance was thought as the major etiology of hypertension of the metabolic syndrome. Both human and animal studies revealed sympathetic overactivity were present in the metabolic syndrome. Nowadays, most of the studies that examined the etiologies of hypertension of metabolic syndrome were focused on the pathophysiologic effects of insulin resistance on the peripheral vessels. However, there was no study ever examined the insulin resistance in cardiovascular regulatory centers of central nervous system or the pathogenesis of sympathetic overactivity in metabolic syndrome. Our previous study demonstrated that insulin plays a cardiovascular regulatory role in the nucleus tractus solitarii (NTS), one of the cardiovascular regulatory centers in the brain stem. We also demonstrated that the cardiovascular regulatory effects of insulin in the NTS were accomplished through activating PI3K-PKB/Akt-NO signaling pathways. Recently, increases in oxidative stress could raise the incidence rate of diabetes mellitus and cardiovascular diseases had been reported. Besides, it has been reported that there were marked increases in reactive oxidative species (ROS) in various hypertension animal models. It was also reported that elevation of ROS in various tissues may activate the mitogen-activated protein kinase (MAPK) superfamily. Activated MAPKs may phosphorylate insulin receptor substrate 1 (IRS1) on the serine 307 residue. It has been reported that IRS1S307 phosphorylation would inhibit normal insulin signal transduction. The aims of this thesis were to investigate whether the neuronal cells in the NTS would develop insulin resistance in the metabolic syndrome rats, whether development of insulin resistance in the NTS cause hypertension in the metabolic syndrome rats, which signaling molecule in insulin signaling pathway is the key molecule that cause insulin resistance in the NTS, and what the pathogenesis of insulin resistance is in the NTS of metabolic syndrome rats. In the pioneer study, Wistar-Kyoto (WKY) rats were fed with 10% fructose water as their drinking water for 8 weeks. Another group of fructose-fed WKY rats were fed with insulin sensitizer, rosiglitazone, since the 5th week. Blood pressure was measured by tail vein sphygmomanometer every week and venous blood were draw to measure blood sugar and insulin level every other week. Thereafter, all the rats enrolled in this study were fed with 10% fructose water with/without rosiglitazone for 2-3 weeks. My results demonstrated the blood pressure of fructose-fed WKY rats was significantly elevated after 2-week fructose feeding. But at the same time, HOMA-IR did not elevated, which indicated the insulin resistance in the peripheral did not develop yet. Interestingly, at the same time, endogenous insulin in the NTS was significantly elevated in the fructose-fed group. The cardiovascular responses of insulin in the NTS were diminished in the fructose-fed group. While in the rosiglitazone-treated group, the blood pressure and endogenous insulin in the NTS were decreased the baseline level. The cardiovascular responses of insulin in the NTS were restored in the rosiglitazone-treated group. These results indicated insulin resistance do develop in the NTS of fructose-fed rats, and the neuronal insulin resistance in the NTS can induce hypertension. The immunoblotting results demonstrated the phosphorylation of IRS1S307 was significantly elevated in the fructose-fed rats. While the phosphorylation of its downstream molecules, such as AktS473 and eNOSS1177, were significantly decreased as compared with the control group. In the NTS of rosiglitazone-treated group, the phosphorylation of IRS1S307 was decreased, and the phosphorylation of AktS473 and eNOSS1177 were restored. These results indicated that the underline pathogenesis of insulin resistance in the NTS was phosphorylation on the inhibitory serine residue of IRS1, which interfered with the normal insulin signal transduction in the NTS. Increases in ROS in the NTS of fructose-fed rats were demonstrated in the DHE histostaining. Phosphorylation of p38MAPK in the NTS of fructose-fed rats was also detected by immunoblotting. In the NTS of Tempol-treated fructose-fed rats, the phosphorylation of p38MAPK reduced and the nitric oxide production elevated to the basal level. Blood pressure decreased significantly when p38MAPK inhibitor, SB203680, was microinjected into the NTS of fructose-fed rats. These results indicated the pathogenesis of insulin resistance in the NTS is increases in ROS in the NTS, which activate p38MAPK and then phosphorylate IRS1S307. In conclusion, the neuronal cells in the NTS may develop insulin resistance in fructose-fed rats, and the neuronal insulin resistance in the NTS contributes to the hypertension of metabolic syndrome. The mechanism of insulin resistance in the NTS is phosphorylation on the serine 307 residue of IRS1, which interfere with insulin signaling and subsequent NO production in the NTS. The pathogenesis of IRS1S307 phosphorylation is activated p38MAPK which in turn is activated by ROS in the NTS.
目次 Table of Contents
Chinese Abstract……………………………………………………………………i
English Abstract…………………………………………………………………….iv
Contents……………………………………………………………………………..viii
Abbreviation………………………………………………………………………...x

Chapter 1
The Cardiovascular Effects and insulin signaling pathway defect of Insulin
Resistance in the Nucleus Tractus Solitarii Of Fructose Fed Rats
1.1 Introduction………………………………………………………………………..2
1.2 Specific Aims……………………………………………………………….……13
1.3 Materials and Methods……………………………………………………...…....14
1.4 Results……………………………………………………………………………25
1.5 Discussion………………………………………………………………………..32
1.6 Conclusion…………………………………………………………………...…...37
1.7 References………………………………………………………………………..38



Chapter 2
The Molecular Mechanisms of Insulin Resistance in the Nucleus Tractus Solitarii of Fructose Fed Rats
2.1 Introduction………………………………………………………………………64
2.2 Specific Aims…………………………………………………………………….71
2.3 Materials and Methods………………….………………………………………..72
2.4 Results……………………………………………………………...…………….78
2.5 Discussion………………………………………………………………………..84
2.6 Conclusion……………………………………………………………………….88
2.7 References……………………………………………………………………….89


Chapter 3

3.1 Future Perspectives……………………………………………………………..112
3.2 Appendix………………………………………………………………………..114
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