title: Identification of N-arachidonylglycine, U18666A, and 4-androstene-3,17-dione as novel insulin Secretagogues.
abstract: 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+]i). 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), 3beta-(2-diethylamino-ethoxy) androstenone hydrochloride (U18666A), 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.
authors.affiliation: Yanagisawa Orphan Receptor Project, Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Tokyo 135-0064, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Iguchi
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakata
authors.forename: Ryoichi X
authors.initials: RX
authors.lastname: Ioka
authors.forename: Toshiya
authors.initials: T
authors.lastname: Tanaka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iwasaki
authors.forename: Kenta
authors.initials: K
authors.lastname: Magoori
authors.forename: Shinobu
authors.initials: S
authors.lastname: Takayasu
authors.forename: Tokuo T
authors.initials: TT
authors.lastname: Yamamoto
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Juro
authors.initials: J
authors.lastname: Sakai
mesh_terms: D000735:Androstenedione / Q000494:pharmacology*; D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000736:Androstenes; D001095:Arachidonic Acids; D007328:Insulin; C465623:N-arachidonylglycine; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D000735:Androstenedione; D002118:Calcium; D005998:Glycine