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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 莊立民 | |
dc.contributor.author | Hsing-Chi Tseng | en |
dc.contributor.author | 曾幸祺 | zh_TW |
dc.date.accessioned | 2021-06-17T00:38:36Z | - |
dc.date.available | 2014-03-02 | |
dc.date.copyright | 2012-03-02 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-01-30 | |
dc.identifier.citation | Ashcroft, F. M. (2005). ATP-sensitive potassium channelopathies: focus on insulin secretion. J Clin Invest, 115(8), 2047-2058.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/66487 | - |
dc.description.abstract | 胰臟β細胞(pancreatic β cells)發生自體凋亡(apoptosis)是糖尿病的指標。眾多引起β細胞apoptosis的因子中,體內累積大量糖解作用之中間產物2含氧丙醛(methylglyoxal; MG)會對細胞形成慢性的葡萄糖毒性(glucotoxicity),最後導致apoptosis。類升糖素胜肽1 (glucagon-like peptide-1; GLP-1)是由人體腸道中所分泌,具有保護β細胞免於apoptosis。然而,GLP-1影響MG的分子機制尚未完全明瞭。尤其在GLP-1促進胰島素分泌機制扮演重要角色之胰臟的ATP敏感性鉀離子通道 (ATP-sensitive potassium; KATP channel), Kir6.2是否也參與在GLP-1對MG影響β細胞凋亡的分子機制是本研究致力於探討的。
本研究利用大鼠胰島細胞瘤細胞RIN-m5做為材料,以1 mM MG處理經過隔夜靜置培養後,我們發現MG會降低細胞的存活率,且增加apoptosis的現象,包括細胞膜外翻,DNA斷裂,活化的胱天蛋白酶-3(caspase-3),以及磷酸化的c-jun 胺基端蛋白激酶(c-jun N-terminal kinase, JNK)。此外,我們發現JNK和eIF2的磷酸化增加,顯示MG會引起細胞的內質網壓力( ER stress); 我們也發現β細胞氧耗率和ATP含量降低,顯示MG也造成細胞粒線體 (mitochondria)的功能受創。但是,若以GLP-1前處理,則β細胞仍可維持高的存活率,抑制上述與apoptosis和ER stress相關的現象,可以保護mitochondria的功能。而當細胞的Kir6.2受到shRNA抑制表現後,GLP-1卻仍可對抗apoptosis,ER stress,及保護mitochondria的能力。由於MG可以長期活化AMP-活化蛋白激酶 (AMP-activated protein kinase; AMPK),但AMPK的活化會被GLP-1所抑制。因此,我們總結GLP-1可能是透過降低AMPK的長期活化而來調節MG引起的β細胞apoptosis,且此路徑不需要Kir6.2的參與。 | zh_TW |
dc.description.abstract | Pancreatic β-cell apoptosis is the hall marker of diabetes. Among various potential factors involved, the accumulation of methylglyoxal (MG), an intermediate of glycolysis which contributes to glucotoxicity, is a promising factor leading to β-cell apoptosis. Glucagon-like peptide-1 (GLP-1), secreted from small intestine, possesses the protective ability against β-cell apoptosis. However, the molecular mechanism by which GLP-1 prevents MG-induced β-cell apoptosis remains unclear. ATP-sensitive potassium channels (KATP channels) has a tissue-specific expression, similar to GLP-1 receptor, plays a crucial role on GLP-1’s insulinotropic function. We aim to study molecular mechanisms of protective effect of GLP-1 on β-cell apoptosis and examine whether KATP channels is involved in the effects of GLP-1 on MG-induced β-cell apoptosis.
In the present study, we use rat insulinoma cell line, RIN-m5f cells as a model. We found that MG-treated cells showing decreased cell viability and increased apoptotic markers, including externalization of phosphatidylserine (PS), DNA fragmentation, activation of caspase 3 and increased phosphorylation of JNK. Besides, MG-treated cells showed a higher ER stress as phosphorylation of JNK and eIF2α was enhanced. We also found mitochondria dysfunction in the MG-treated cells, as was documented decline in oxygen consumption rate and ATP production. Importantly, we found GLP-1 pretreatment can protect β cells from MG-induced apoptosis. This effect is independent of Kir6.2 as shown by the shRNA experiments. Finally, GLP-1 prevented the MG-induced prolonged activation of AMPK and mitochondria dysfunction. Taken together, we conclude that GLP-1 can protect β cells from MG-induced apoptosis via ameliorating ER stress and mitochondrial dysfunction. This effect is independent of Kir6.2. The role of prolonged AMPK activation on β-cell apoptosis deserves further studies. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T00:38:36Z (GMT). No. of bitstreams: 1 ntu-101-R98448017-1.pdf: 1853223 bytes, checksum: 9b0cc379065965aae5aeceb67d74d49b (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | 謝 誌 I
摘要 III Abstract V Table of Contents VII List of Figures IX Introduction 1 Public health impact of diabetes mellitus (DM) 1 β-cell apoptosis 1 Dual roles of GLP-1 in β-cell 3 ATP-sensitive potassium channel in pancreatic β-cell 4 Methylglyoxal and diabetes 5 Materials and Methods 8 Materials 8 Cell culture 8 Cell treatment 8 MTT assay 9 Staining for DAPI and annexin V 10 Extracellular flux (XF) analysis 10 ATP assay 11 Western Blot 12 Statistical analyses 13 Results 14 GLP-1 protects insulin-secreting cells (RIN-m5f) from MG-induced cytotoxicity 14 GLP-1 inhibits external phosphatidylserine (PS) and nuclear condensation of elicited by MG 14 GLP-1 suppressed the activation of caspase-3 and JNK 15 GLP-1 protects RIN-m5f cells from ER-stress as well as apoptosis induced by MG 16 GLP-1 protects MG-induced mitochondrial dysfunction 17 Protective effect of GLP-1 on MG-induced β-cell apoptosis is independent of Kir6.2 18 AMPK activation in MG-induced β-cell apoptosis 19 Discussion 20 Figures 24 References 39 | |
dc.language.iso | en | |
dc.title | GLP-1抵抗胰臟β細胞凋亡的分子機制 | zh_TW |
dc.title | Molecular mechanism on anti-apoptotic effect of
GLP-1 in pancreatic beta cell | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 呂勝春,蘇銘嘉 | |
dc.subject.keyword | β細胞,自體凋亡,類升糖胜肽,1,ATP敏感性鉀離子通道,AMP激活的蛋白激酵素, | zh_TW |
dc.subject.keyword | pancreatic β-cell apoptosis,GLP-1,methylglyoxal,Kir6.2,AMPK, | en |
dc.relation.page | 50 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2012-01-31 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
顯示於系所單位: | 分子醫學研究所 |
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