Identification of N-arachidonylglycine, U18666A, and 4-androstene-3,17-dione as novel insulin secretagogues
Identification of N-arachidonylglycine, U18666A, and 4-androstene-3,17-dione as novel insulin secretagogues
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DOI：
10.1016/j.bbrc.2005.06.005
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发表时间：
2005-08-05
影响因子：
3.1
通讯作者：
Sakai, J
中科院分区：
文献类型：
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作者：
Ikeda, Y;Iguchi, H;Sakai, J
葡萄糖诱导的胰岛素分泌受许多因素的微调。为了系统地鉴定促胰岛素因子，我们优化了基于原代β细胞的功能测定以监测细胞内Ca 2+通量（[Ca 2 +]，）。利用该系统，我们成功地从组织提取物中鉴定出几种促胰岛素肽，包括胆囊收缩素、胃泌素释放肽、加压素和催产素。筛选了一系列化合物，我们确定了三种新的胰岛素促分泌素：N-花生四烯酸甘氨酸（NAGly）、3 β-（2-二乙基氨基乙氧基）雄甾烯酮盐酸盐（UI 8666 A）和4-雄甾烯-3，17-二酮。NAGly通过刺激电压依赖性Ca ~（2+）通道增加[Ca ~（2+）]（i），并依赖于细胞外葡萄糖水平。另一方面，U18666 A和4-雄甾烯-3，17-二酮在K-ATP通道开放剂二氮嗪存在下增加[Ca ~（2+）]（i），而在Ca ~（2+）通道阻断剂尼群地平存在下抑制[Ca ~（2+）]（i），表明它们的作用不依赖于K-ATP通道。这些独特的功能将有助于进一步开发促胰岛素分泌因子和治疗2型糖尿病的药物。(c)2005年爱思唯尔公司All rights reserved.
The glucose-induced insulin secretion is fine-tuned by numerous factors. To systematically identify insulinotropic factors, we optimized a primary beta-cell-based functional assay to monitor intracellular Ca2+ flux ([Ca2+],). By this assay system, we successfully identified several insulinotropic peptides including cholecystokinin, gastrin releasing peptide, vasopressin, and oxytocin from tissue extracts. Screening of an assortment of chemical compounds, we determined three novel insulin secretagogues: N-arachidonylglycine (NAGly), 3 beta-(2-diethylamino-ethoxy) androstenone hydrochloride (UI8666A), and 4-androstene-3,17-dione. The NAGly increased [Ca2+](i) through stimulation of the voltage-dependent Ca2+ channels and it was dependent on extracellular glucose level. On the other hand, U18666A and 4-androstene-3,17-dione increased [Ca2+](i) in the presence of K-ATP channel opener diazoxide while it was inhibited by the presence of Ca2+ channel blocker nitrendipine, suggesting that their effects are independent of K-ATP channel. These unique features will be useful for further development of insulinotropic factors and drugs for treating type 2 diabetes. (c) 2005 Elsevier Inc. All rights reserved.