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研究生:王雅菁
研究生(外文):Wang Yachin
論文名稱:探討氧化壓力-一氧化氮媒介發炎反應路徑在C型反應蛋白造成胰島素分泌細胞功能損傷的病理機轉中所扮演的角色
論文名稱(外文):The involvement of ROS-NO-mediated inflammatory pathway in CRP-induced detrimental effects on pancreatic insulin secretion–study in vivo and in vitro
指導教授:謝博軒
指導教授(外文):Hsieh Po-Shiuan
學位類別:碩士
校院名稱:國防醫學院
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:67
中文關鍵詞:c型反應蛋白
外文關鍵詞:CRP
相關次數:
  • 被引用被引用:0
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  • 下載下載:22
  • 收藏至我的研究室書目清單書目收藏:0
流行病學研究報告顯示C型反應蛋白的濃度升高與第二型糖尿病的發展有密切相關性。先前本實驗室利用小鼠胰島細胞及細胞株的模式發現,人類C型反應蛋白會造成細胞氧化壓力增加,進而活化下游NO的發炎訊息傳遞路徑,造成細胞存活率下降和胰島素分泌功能損害。本論文主要目標進一步探討在活體模式下,人類C型反應蛋白濃度升高時,是否也會經由影響胰島細胞之氧化壓力-NO相關發炎路徑造成胰島素分泌功能受損及細胞凋亡,其中可能直接和間接的作用機轉,以及在離體模式下,進一步探討人類C型反應蛋白造成細胞氧化壓力增加和NOS活化的可能作用機轉。
實驗結果發現,活體實驗中,給予連續靜脈注射人類C型反應蛋白40mg/kg/day 5天後,其HOMA-IR 值無顯著變化,而HOMA-細胞功能指數顯著下降。同時也造成其血漿中補體C3濃度顯著升高。從人類C型反應蛋白注射之小鼠分離出胰島細胞之胰島素分泌功能顯著降低,而當給予L-NAME、Aminoguanidine、NAC培養2小時後,可顯著逆轉胰島素分泌功能。
在離體實驗中,加入C型反應蛋白會造成小鼠胰島細胞對葡萄糖刺激胰島素分泌功能及細胞存活率顯著降低,氧化壓力的增加。在給予NADPH oxidase抑制劑Apocynin或iNOS抑制劑Aminoguanidine均能顯著改善胰島細胞中,因人類C型反應蛋白所造成葡萄糖刺激胰島素分泌功能及細胞存活率顯著降低,但後者無法改善氧化壓力的增加。給予nNOS抑制劑Nω-Propyl-L-arginine則無法影響人類C型反應蛋白所造成的損傷。
總而言之,本實驗結果顯示,在活體模式中,病理濃度下人類C型反應蛋白升高,經由直接和間接升高血中C3濃度的作用,造成胰島素分泌細胞氧化壓力的增加,進而活化下游NO媒介的發炎訊息傳遞路徑,而造成其胰島素分泌功能受損和細胞存活率降低,更進一步探討其機轉發現,人類C型反應蛋白升高,主要會透過NADPH oxidase的活化,而造成氧化壓力的增加,進而活化iNOS的發炎反應相關的訊息傳遞路徑,造成細胞分泌胰島素功能受損及細胞存活率下降。
Background:
Epidemiological studies show that chronic low-grade increase in circulating CRP levels is significantly correlated with the development of type 2 diabetes. In our previous study showed that CRP-induced oxidative stress could subsequently activate the NO-mediated inflammatory pathways to cause  cell damage in isolated mouse islets and NIT-1 insulin secreting cell line. However, the in vivo effects of CRP on  cell function remains elusive. In addition, the detailed mechanism of CRP action on insulin secretion is needed to further elucidate.
Purpose:
The aim of this study was to determine the involvement of ROS-NO-mediated inflammatory pathway in CRP-induced detrimental effects on pancreatic insulin secretion in vivo and in vitro and the possible underlying mechanism.
Materials and methods:
BALB/c mice were injected intravenously with vehicle or human CRP 40mg/kg for 5 continuous days. After the end of study, pancreatic islets were isolated from vehicle- or CRP-treated mice and then treated with or without L-NAME, a NOS inhibitor, Aminoguanidine, an iNOS inhibitor or N-acetylcysteine (NAC), an antioxidant for 2 hours. These islets were then examined with the method of glucose-stimulated insulin secretion . The blood samples were collected for measuring plasma glucose, insulin, and complement C3 levels. Pancreas were removed and fixed in 4% formalin for immunohistochemistry. On the other hand, mouse islets isolated from normal mice were treated with human CRP (50g/mL) combined with or without NADPH oxidase inhibitor, Apocynin, NOS inhibitor, L-NAME, iNOS inhibitor, Aminoguanidine and nNOS inhibitor, Nω-Propyl-L-arginine for 48 hours. Thereafter, glucose-stimulated insulin secretion was performed. Cell viability was measured by MTT assay and islets ROS production was determined by nitroblue tetrazolium (NBT) assay in 48 hour-treated islets.
Results:
The HOMA-beta cell function in CRP-treated mice were significantly suppressed in absence of the change in HOMA-IR as compared with those in control. Immunohistichemical staining showed significantly deposition of complement protein C3 within pancreatic islets of CRP-treated mice. The glucose-stimulated insulin secretion in islets isolated from CRP-treated mice were significantly suppressed as compared with those in control and markedly reversed in those treated with L-NAME, Aminoguanidine, and NAC. Plasma complement C3 concentration was significantly higher in CRP-treated mice than in control. While treated with human CRP, islets isolated from normal mice were exhibited significant suppression in glucose-stimulated insulin secretion, decrease in cell survival and increase in ROS production. Co-treatment with Apocynin and Aminoguanidine could significantly reverse the detrimental effects of CRP on insulin secretion and cell survival. Notedly, only the administration of Aminoguanidine failed to change CRP-stimulated ROS production. Nevertheless, co-treatment with Nω-Propyl-L-arginine failed to alter CRP-induced decrease in glucose-stimulated insulin secretion and cell survival, and increase in CRP-induced ROS production.
Conclusion:
The elevation of human CRP could cause the detrimental effect on pancreatic insulin secretion and  cell survival directly and indirectly by increasing plasma complement C3 levels in mouse model. In addition, the activation of NADPH oxidase and iNOS-mediated inflammatory pathway plays a crucial role in the action of CRP on pancreatic  cell function.
目 錄 ………………………………………………………………………….Ⅰ
圖 次 ………………………………………………………………………….Ⅳ
縮寫表 …………………………………………………………...……………Ⅵ
中文摘要 ………………………………………………………………...……Ⅶ
英文摘要 …………………………………………………………………...…Ⅸ
第一章 前言…………………………………………………………………… 1
第一節 第二型糖尿病與發炎之關係的研究 …………………………….. 1
第二節 C型反應蛋白 ………………………………………………...….... 2
第三節 C型反應蛋白與心血管疾病之關係的研究 ……………………... 3
第四節 補體與C型反應蛋白及糖尿病的關係 ………………….………. 4
第五節 C型反應蛋白與第二型糖尿病之關係研究 ……………….…….. 5
第六節 本實驗室先前的研究結果 ……………………………………….. 6
第七節 C型反應蛋白造成細胞氧化壓力及NO增加的可能病理機轉 ... 7
第八節 假說 ……………………………………………………………….. 9
第二章 目的 …………………………………………...……………………. 10
第三章 材料與方法 …………………………………………...……………. 11
第一節 實驗動物 …………………………………………………...……. 11
第二節 C型反應蛋白 ……………………………………………………. 11
第三節 NIT-1細胞株 …………………………………………………….. 12
第四節 儀器設備 …………………………………...……………………. 13
第五節 化學製劑 ……………………………………...…………………. 14
第六節 實驗設計與測定方法 …………………………...………………. 16
第七節 統計方法 …………………………………...……………………. 28
第四章 結果 …………………………………………...……………………. 29
第一節 活體模式下人類C型反應蛋白對胰臟胰島素分泌功能的影響 .29
第二節 活體模式下人類C型反應蛋白對血漿中補體C3濃度之影響 ... 30
第三節 離體模式下給予NAC、Apocynin、L-NAME、Aminoguanidine、N-Propyl-L-arginine對人類C型反應蛋白損傷葡萄糖刺激胰島素分泌之影響 ……………………………………………….... 31
第四節 離體模式下給予NAC、Apocynin、L-NAME、Aminoguanidine、N-Propyl-L-arginine對人類C型反應蛋白損傷細胞存活率之影響 … …………………………………………..………………. 32
第五節 離體模式下給予NAC、Apocynin、L-NAME、Aminoguanidine、N-Propyl-L-arginine對人類C型反應蛋白損傷氧化壓力程度之影響 ………………………………………………...…………. 33

第五章 結論 ………………………...………………………………………. 36
第六章 討論 ………………………………...………………………………. 37
參考文獻 ……………………………………………...……………………... 45
附 錄 …………..…………………………………...………………………... 50
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