Optical Control of Insulin Secretion Using an Incretin Switch.
Optical Control of Insulin Secretion Using an Incretin Switch.
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DOI：
10.1002/anie.201506384
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发表时间：
2015-12-14
期刊：
影响因子：
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通讯作者：
Trauner D
中科院分区：
文献类型：
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作者：
Broichhagen J;Podewin T;Meyer-Berg H;von Ohlen Y;Johnston NR;Jones BJ;Bloom SR;Rutter GA;Hoffmann-Röder A;Hodson DJ;Trauner D
肠促胰岛素模拟物将成为2型糖尿病治疗的支柱。 通过作用于胰腺和大脑，它们增强胰岛素分泌并诱导体重减轻以保持正常血糖。尽管如此，肠促胰岛素治疗仍与脱靶效应相关，包括恶心和胃肠道紊乱。设计、合成并检测了一种基于特异性胰高血糖素样肽-1受体（GLP-1 R）激动剂利拉鲁肽的新型光开关肠促胰岛素模拟物。这种肽化合物称为LirAzo，具有偶氮苯光响应元件，由于第二信使途径对光响应的差异激活，提供异构体偏向的GLP-1 R信号传导。虽然反式异构体主要参与钙内流，顺式异构体有利于cAMP的产生。因此，LirAzo允许光学控制胰岛素分泌和细胞存活。
Incretin mimetics are set to become a mainstay of type 2 diabetes treatment. By acting on the pancreas and brain, they potentiate insulin secretion and induce weight loss to preserve normoglycemia. Despite this, incretin therapy has been associated with off‐target effects, including nausea and gastrointestinal disturbance. A novel photoswitchable incretin mimetic based upon the specific glucagon‐like peptide‐1 receptor (GLP‐1R) agonist liraglutide was designed, synthesized, and tested. This peptidic compound, termed LirAzo, possesses an azobenzene photoresponsive element, affording isomer‐biased GLP‐1R signaling as a result of differential activation of second messenger pathways in response to light. While the trans isomer primarily engages calcium influx, the cis isomer favors cAMP generation. LirAzo thus allows optical control of insulin secretion and cell survival.