臺灣博碩士論文加值系統

背景及目的：肥胖(obesity)是潛在性的健康問題，被認為與胰島素阻抗(insulin resistance)有密切之關聯性。許多研究顯示，胰島素(insulin)及類胰島素生長因子-1(insulin-like growth factor-1, IGF-1)對於心血管功能調控扮演重要的角色，它們皆可藉由刺激一氧化氮(nitric oxide, NO)的合成，達到調控血管平滑肌而促使血管舒張的作用。此兩者可共用彼此的接受器，故訊息傳遞路徑可能是與胰島素接受器(insulin receptor, IR)或類胰島素生長因子-1接受器(insulin-like growth factor-1 receptor, IGF-1R)結合後，使insulin receptor substrate-1(IRS-1)磷酸化，再進一步活化phosphatidylinositol-3 kinase (PI3K)，增加一氧化氮合成酶(nitric oxide synthase, NOS)的活性，刺激一氧化氮的生成。本實驗室先前的實驗結果指出，經由中度運動可改善由胰島素及類胰島素生長因子-1調控之血管舒張反應，又發現肥胖鼠胰島素引起之血管舒張反應有明顯變差的情形，但經過運動訓練後對於胰島素及類胰島素生長因子-1所調控之血管舒張反應會產生什麼改變，仍是未知的。因此，本研究主要是利用肥胖鼠之實驗動物模式，去探討中度運動對於胰島素及類胰島素生長因子-1引起之血管舒張反應的影響及其背後之原理機制。方法：將肥胖鼠(obese Zucker rat)隨機分成運動組與非運動組，且選擇與其週齡相符之瘦鼠(lean Zucker rat)作為對照組，亦分成運動組與非運動組，因此共分成四組。將運動組置於跑步機上進行中度運動訓練，每週五天，持續12週；非運動組則不給予運動介入。12週後取下老鼠之胸主動脈，作為後續分析血管舒張反應及免疫組織染色之用。結果：我們發現：(1)相對於瘦鼠，肥胖鼠之胰島素引起之血管舒張反應是明顯減少的，而類胰島素生長因子-1引起之血管舒張反應則是明顯增加的；(2)中度運動會明顯增進肥胖鼠之胰島素引起之血管舒張反應，而瘦鼠在運動前後則無顯著差異；另外，中度運動會明顯增進瘦鼠之類胰島素生長因子-1引起之血管舒張反應，而肥胖鼠則無變化；(3)此運動增進血管舒張反應的作用，主要是透過改變胰島素與類胰島素生長因子-1訊息傳遞路徑中PI3K及NOS的釋放來調節；(4)對於sodium nitroprusside (SNP，一氧化氮提供者)所引起之血管舒張反應，四組間並無顯著差異；(5)免疫組織染色結果顯示，相對於瘦鼠，肥胖鼠之內皮細胞和平滑肌細胞之IR與IRS-1的蛋白質表現量顯著較少，而IGF-1R則顯著較多；但給予中度運動後，肥胖鼠之內皮細胞與平滑肌細胞之IR與IRS-1的蛋白質表現量有顯著增加的情形，此外，瘦鼠之內皮細胞與平滑肌細胞之IGF-1R亦有顯著的增加。結論：本研究結果發現，肥胖症所造成胰島素所調控之血管功能下降，可能使類胰島素生長因子-1調控之血管功能產生代償的現象，而藉由中度運動之介入，對於改善血管功能有正向的影響。

Background and purpose: Obesity is a potential medical problem that has been considered closely associated with insulin resistance. Insulin and insulin-like growth factor-1(IGF-1) play an important role in the regulation of cardiovascular function, and have vasorelaxant effects in vivo that depend on the production of nitric oxide (NO). The signaling pathways of insulin and IGF-1 are initiated through the insulin receptor (IR) and/or IGF-1 receptor (IGF-1R) to lead to phosphorylation of adaptor protein, insulin receptor substrate-1(IRS-1), and further to activate phosphatidylinositol-3 kinase (PI3K). This increases the activity of nitric oxide synthase (NOS), and then induces NO production. Moreover, it is well known that moderate exercise improves acetylcholine-induced vasorelaxation by increasing NO production. However, few studies have investigated the effects of exercise intervention on the vascular function mediated by insulin and IGF-1. Thus, the aim of this study was to investigate the effects of moderate exercise on vasorelaxant responses mediated by insulin and IGF-1 in aortas of obese rats. Methods: Obese Zucker rats and age-matched lean Zucker rats were randomly divided into sedentary and exercise groups; i.e., obese sedentary (OS), obese with exercise (OE), lean sedentary (LS), and lean with exercise (LE) groups. The exercise groups ran on a treadmill five days a week for a period of 12 weeks in total. In contrast, the sedentary groups were regularly placed on the treadmill for similar periods of time. At the end of the experiments, the thoracic aortas of rats were isolated for the analyses of vasorelaxation and immunohistochemistry. Results: We found that, (1) compared with that in aortas of lean rats, the insulin-induced vasorelaxation was significantly decreased in obese rats, whereas the IGF-1-induced vasorelaxation was significantly increased in obese rats; (2) moderate exercise significantly ameliorated insulin-induced vasorelaxation in obese rats, but did not induce significant change in lean rats. In contrast, this exercise significantly increased IGF-1-induced vasorelaxation in lean rats, but did not induce any change in obese rats.; (3) the exercise effects on vasorelaxation were mediated by the altered release of PI3K and NOS; (4) there was no significant difference in the sodium nitroprusside (SNP, a NO donor)-induced vasorelaxation among the four groups; (5) immunohistochemical analysis showed that, compared with that in lean rats, the protein expression of IR and IRS-1 significantly decreased, but IGF-1R significantly increased in the endothelium and vascular smooth muscle in aortas of obese rats. After the exercise intervention, the protein expression of IR and IRS-1 significantly increased in obese rats, and IGF-1R significantly increased in lean rats. Conclusion: Obesity would induce a significant decrease of the insulin-mediated vascular function and IGF-1 might play a compensatory role for it. Also, the intervention of moderate exercise could have positive effects on the amelioration of cardiovascular function in the obesity.

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英文摘要 ---------------------------------------------------------------- 3
緒論 -------------------------------------------------------------------- 5
材料與方法 -------------------------------------------------------------- 13
結果 -------------------------------------------------------------------- 23
討論 -------------------------------------------------------------------- 30
表 ---------------------------------------------------------------------- 39
圖 ---------------------------------------------------------------------- 42
參考文獻 ---------------------------------------------------------------- 53
附錄一 ------------------------------------------------------------------ 62
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