2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/649248摘要：因為糖尿病與心血管疾病近幾年來在台灣一直居於十大死因的第四位與第五位，所以我們計畫研究治療糖尿病藥物GLP-1 改善β細胞功能與保護心臟及神經細胞的分子機轉。另一方面，我們也將探討hypoxia preconditioning 可保護心臟及神經細胞減少因細胞缺氧所造成的細胞凋亡之分子機轉。GLP-1 可經由cAMP dependent 及cAMPindependent pathway 抑制KATP channel 的活性，進而刺激胰島素分泌。另一方面，已有研究指出hypoxia preconditioning 可經由活化AMPK 及打開KATP channel 達到保護心臟的效果。根據本研究團隊先前發表的結果，我們發現一種治療糖尿病藥物rosiglitazone可透過活化AMPK 與磷酸化KATP channel 上的Kir6.2 subunit 第385 個氨基酸serine 而刺激怡島速的分泌。根據此一新發現的藥物作用分子機轉，我們將進一步探討AMPK與Kir6.2 subunit 第385 個氨基酸serine 在GLP-1 改善β細胞功能與GLP-1 及hypoxiapreconditioning 保護心臟及神經細胞的角色。透過了解這些分子機轉，希望可以發現治療糖尿病、心血管與腦血管疾病的新標的。<br> Abstract: Because diabetes and cardiovascular disease have been the 4th and 5th of leading mortalitycauses in Taiwan for several years, we plan to investigate the molecular mechanism toimprove pancreatic βcell function by GLP-1 and the cardioprotective and neuroprotectiveeffect of GLP-1 and hypoxia preconditioning on cardiomyocytes and neurons. GLP-1stimulates insulin secretion by reducing KATP activity through both cAMP-dependent andindependent pathway. It has been reported that hypoxia preconditioning protectscardiomyocytes from ischemic injury via activation AMPK and opening of KATP channel.According to our previous research, we found a novel pathway that serine-385phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependentprotein kinase (AMPK) plays a key role in rosiglitazone-induced closure of the KATP channeland insulin secretion in rats. Based on this novel finding, we will further investigate the roleof AMPK and phosphorylation of Ser385 in Kir6.2 on the effect of GLP-1 on the beta cellfunction and cardioprotective & neuroprotective effect of hypoxia-preconditioning and GLP-1.Through understanding of these molecular mechanism, we may find novel targets to treatdiabetes, cardio- and cerebrovascular disease.