Mastoparan(MAS) and α-latrotoxin(α-LTX) are two kinds of insulinotropic peptides obtained from insect toxins which can interact with islet β-cells and induce insulin secretion. The signal mechanism of these insulin...Mastoparan(MAS) and α-latrotoxin(α-LTX) are two kinds of insulinotropic peptides obtained from insect toxins which can interact with islet β-cells and induce insulin secretion. The signal mechanism of these insulinotropic peptides regulating insulin-releasing attracts notable attention and has been elucidated more and more details. MAS mainly acts on the molecular components of exocytosis at a late stage. Insulin secretion induced by MAS is obviously dependent on GTP,which subsequently activates G-protein located on insulin secretion granules(ISG),or activates the Rho subfamily of small G proteins to evoke exocytosis and sensitize fusion machinery. The MAS stimulated insulin-releasing activity can be augmented by nutrients. However,its effect is not Ca2+ dependent. There are two regulatory pathway triggered by α-LTX: one way is pore formation caused through plasma membrane,another way is the transmembrane signal transduction evoked by cytosolic second messengers. Tetrameri complexs assembled at high concentration of α-LTX toxin or in the presence of extracellular Ca2+,can insert α-LTX into plasma membrane to form Ca2+ permeable channels and trigger Ca2+-dependent secretion. By binding to transmembrane receptors and activating phospholipase C,α-LTX induces the generation of second messenger DAG and IP3. IP3 triggers Ca2+ influx and subsequently activates CaMK pathway,however,DAG also activates PKC pathway to increase insulin release.展开更多
目的总结胰高血糖素样肽-1(GLP-1)类似物的研发进展。方法检索PubMed和Web of Science数据库自建库起至2024年2月20日的GLP-1类似物相关文献,从研发概况、单分子多靶点GLP-1受体激动剂(GLP-1RA)、除治疗糖尿病外的其他适应证及其药物研...目的总结胰高血糖素样肽-1(GLP-1)类似物的研发进展。方法检索PubMed和Web of Science数据库自建库起至2024年2月20日的GLP-1类似物相关文献,从研发概况、单分子多靶点GLP-1受体激动剂(GLP-1RA)、除治疗糖尿病外的其他适应证及其药物研发新趋势方面,总结GLP-1类似物的研发进展。结果与结论GLP-1类似物的研发经历了从短效到长效,从注射剂到口服剂,并扩展到多靶点治疗的过程。目前,多靶点GLP-1RA包括GLP-1R/葡萄糖依赖性促胰岛素释放多肽受体、GLP-1R/胰高血糖素受体(GCGR)、GLP-1R/GLP-2R、GLP-1R/胰淀素3受体(AMY3R)、GLP-1R/成纤维细胞生长因子21受体(FGF-21R)等双靶点激动剂,以及GLPR/GLP-1R/GCGR、GLP-1R/GCGR/FGF-21R等三靶点激动剂。GLP-1类似物展现了在2型糖尿病、超重、肥胖症、心血管疾病、多囊卵巢综合征、非酒精性脂肪性肝炎、慢性肾脏病等疾病治疗的巨大潜力,疗效优于单靶点的双靶点和三靶点GLP-1RA是近年来研发的重点。GLP-1类似物的重组腺相关病毒载体基因治疗为研发新趋势,其现阶段存在的安全性、依从性等问题和可供参考的解决方法也一并被提出。展开更多
文摘Mastoparan(MAS) and α-latrotoxin(α-LTX) are two kinds of insulinotropic peptides obtained from insect toxins which can interact with islet β-cells and induce insulin secretion. The signal mechanism of these insulinotropic peptides regulating insulin-releasing attracts notable attention and has been elucidated more and more details. MAS mainly acts on the molecular components of exocytosis at a late stage. Insulin secretion induced by MAS is obviously dependent on GTP,which subsequently activates G-protein located on insulin secretion granules(ISG),or activates the Rho subfamily of small G proteins to evoke exocytosis and sensitize fusion machinery. The MAS stimulated insulin-releasing activity can be augmented by nutrients. However,its effect is not Ca2+ dependent. There are two regulatory pathway triggered by α-LTX: one way is pore formation caused through plasma membrane,another way is the transmembrane signal transduction evoked by cytosolic second messengers. Tetrameri complexs assembled at high concentration of α-LTX toxin or in the presence of extracellular Ca2+,can insert α-LTX into plasma membrane to form Ca2+ permeable channels and trigger Ca2+-dependent secretion. By binding to transmembrane receptors and activating phospholipase C,α-LTX induces the generation of second messenger DAG and IP3. IP3 triggers Ca2+ influx and subsequently activates CaMK pathway,however,DAG also activates PKC pathway to increase insulin release.
文摘目的总结胰高血糖素样肽-1(GLP-1)类似物的研发进展。方法检索PubMed和Web of Science数据库自建库起至2024年2月20日的GLP-1类似物相关文献,从研发概况、单分子多靶点GLP-1受体激动剂(GLP-1RA)、除治疗糖尿病外的其他适应证及其药物研发新趋势方面,总结GLP-1类似物的研发进展。结果与结论GLP-1类似物的研发经历了从短效到长效,从注射剂到口服剂,并扩展到多靶点治疗的过程。目前,多靶点GLP-1RA包括GLP-1R/葡萄糖依赖性促胰岛素释放多肽受体、GLP-1R/胰高血糖素受体(GCGR)、GLP-1R/GLP-2R、GLP-1R/胰淀素3受体(AMY3R)、GLP-1R/成纤维细胞生长因子21受体(FGF-21R)等双靶点激动剂,以及GLPR/GLP-1R/GCGR、GLP-1R/GCGR/FGF-21R等三靶点激动剂。GLP-1类似物展现了在2型糖尿病、超重、肥胖症、心血管疾病、多囊卵巢综合征、非酒精性脂肪性肝炎、慢性肾脏病等疾病治疗的巨大潜力,疗效优于单靶点的双靶点和三靶点GLP-1RA是近年来研发的重点。GLP-1类似物的重组腺相关病毒载体基因治疗为研发新趋势,其现阶段存在的安全性、依从性等问题和可供参考的解决方法也一并被提出。
