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研究生:簡伯修
研究生(外文):Po-HsiuChien
論文名稱:Egr-1在胰島細胞中調控胰島素製造及分泌所扮演的角色
論文名稱(外文):Role of early growth response-1 (Egr-1) in insulin production and secretion in pancreatic islets
指導教授:蔡曜聲蔡曜聲引用關係
指導教授(外文):Yau-Sheng Tsai
學位類別:碩士
校院名稱:國立成功大學
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:2012
畢業學年度:100
語文別:英文
論文頁數:52
中文關鍵詞:Egr-1胰島胰島素製造及分泌高脂肪飼料
外文關鍵詞:Egr-1pancreatic isletinsulin production and secretionhigh-fat diet
相關次數:
  • 被引用被引用:0
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Early growth response-1 (Egr-1)為一種鋅手指轉錄調控因子,其表現會受到許多刺激的影響,目前已知Egr-1能夠調控許多基因表現,包括細胞分化、生長以及細胞凋亡。Egr-1的生理功能為反應週邊環境,例如營養物質或是胰島素抗性的刺激。Egr-1在胰島中的表現量非常高,此外,在胰島素基因的啟動子上的葡萄糖反應增強序列會受到Egr-1的調控,進而影響胰島素基因的表現。因此,我們假設缺少Egr-1會導致葡萄糖耐受性的降低以及胰島功能受損。首先我們發現在餵食正常飼料的情況下,正常老鼠和Egr-1基因剔除老鼠(Egr1-/-)的血糖值是相似的,然而在餵食高脂肪飼料後,Egr-1基因剔除老鼠清除血液中葡萄糖的速度明顯較正常老鼠來得差。給予葡萄糖刺激檢視老鼠胰臟釋放胰島素的能力,我們發現高脂肪飼料餵食後,Egr-1基因剔除老鼠所釋放出的胰島素明顯比正常老鼠還要少;我們進一步利用組織形態學來觀察胰島,發現Egr-1基因剔除老鼠胰島的數量、面積以及內分泌群都明顯小於正常老鼠。此外,Egr-1基因剔除老鼠胰島中胰島素的含量明顯少於正常老鼠。這些實驗結果暗示著:在胰島中缺少Egr-1基因會影響胰島素的製造以及分泌。在體內脂肪過多的情況下,缺少Egr-1會影響感應葡萄糖、胰臟生長以及胰島分化相關的基因群表現,同時我們也發現Egr-1基因剔除老鼠的胰島中有較少的細胞增生marker:Ki67。這些實驗結果暗示著:在Egr-1基因剔除老鼠身上發現較少的胰島數量、面積以及內分泌群是因為Egr-1基因剔除老鼠的細胞較不能增生所導致。總結以上的內容,我們的研究成果顯示Egr-1會參與在葡萄糖生理平衡以及胰島功能之中,尤其是當細胞對於胰島素需求增加的情況下,Egr-1顯得更加的重要。
Early growth response-1 (Egr-1) is a zinc-finger transcription factor inducibly expressed in response to many stimuli. Egr-1 has been implicated in the regulation of cell differentiation, proliferation and apoptosis. The physiological role of Egr-1 is to response environmental challenges such as nutrient or insulin resistance. The expression of Egr-1 is highly enriched in the pancreatic islet. In addition, Egr-1 indirectly regulates the insulin promoter to converge on glucose-responsive enhancer sequences. Therefore, we hypothesized that lacking of Egr-1 results in glucose intolerance and islet dysfunction. First, we found that glucose levels were not different between regular chow (RC)-fed Egr-1 knockout (Egr1-/-) mice and wild-type (WT) mice. However, Egr1-/- mice cleared glucose less effectively than WT mice when both of them were fed a high-fat (HF) diet. Examination of the ability of pancreas to secret insulin after glucose stimulation found decreased insulin secretion in HF-Egr1-/- mice compared to HF-WT mice. Pancreatic islet morphometry showed that mean islet area, endocrine mass and number of islets were decreased in HF-Egr1-/- mice. Moreover, HF-Egr1-/- mice produced less insulin than HF-WT mice in the pancreatic islet. These data suggest that the deficiency of Egr-1 influences insulin production and secretion in pancreatic islets. The gene expression profiles involved in glucose sensing, pancreas development and islet differentiation were attenuated by Egr-1 deficiency in the condition of excess nutrient. We also detected reduced level of proliferation marker Ki67 in HF-Egr1-/- mice. These data suggest that the decreased proliferation protein level may be responsible for the reduced islet number, area and endocrine mass in HF-Egr1-/- mice. In conclusion, our data show that Egr-1 contributes to the glucose homeostasis and function of pancreatic islets especially in the condition with increased insulin demand.
INTRODUCTION 1
Pancreatic dysfunction in diabetes 1
High-fat diet and pancreas 2
Early growth response 1 2
Biological function of Egr-1 3
Egr-1 animal models 4
Egr-1 in pancreas 5
Pdx-1 and insulin synthesis 5
Insulin production 6
Insulin secretion 7
Significance 7
MATERIALS AND METHODS 9
Animals 9
Oral glucose tolerance test and acute insulin secretion test 9
Storage of tissue samples 10
Histology and Immunofluorscense 10
Morphometric analysis 11
Isolation of pancreatic islets 11
Islet RNA extraction 12
Reverse transcription and real-time PCR 13
Western blotting 13
C-peptide ELISA 14
Data analysis 14
RESULTS 15
DISCUSSION 23
REFERENCES 30
FIGURES 38
APPENDIX 48

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