TY - JOUR
T1 - Identification of N-arachidonylglycine, U18666A, and 4-androstene-3,17- dione as novel insulin Secretagogues
AU - Ikeda, Yukio
AU - Iguchi, Haruhisa
AU - Nakata, Masanori
AU - Ioka, Ryoichi X.
AU - Tanaka, Toshiya
AU - Iwasaki, Satoshi
AU - Magoori, Kenta
AU - Takayasu, Shinobu
AU - Yamamoto, Tokuo T.
AU - Kodama, Tatsuhiko
AU - Yada, Toshihiko
AU - Sakurai, Takeshi
AU - Yanagisawa, Masashi
AU - Sakai, Juro
N1 - Funding Information:
We thank Dr. Robert W. Rawson and Dr. Patrick C. Reid for helpful discussions, and Yasuyo Urashima, Aoi Uchida, and Satomi Takahashi for excellent technical assistance. This work was supported through Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government and by Exploratory Research for Advanced Technology/Japan Science and Technology Agency (Yanagisawa orphan receptor project). M.Y. is an Investigator of the Howard Hughes Medical Institute.
PY - 2005/8/5
Y1 - 2005/8/5
N2 - The glucose-induced insulin secretion is fine-tuned by numerous factors. To systematically identify insulinotropic factors, we optimized a primary β-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), 3β-(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 KATP 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.
AB - The glucose-induced insulin secretion is fine-tuned by numerous factors. To systematically identify insulinotropic factors, we optimized a primary β-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), 3β-(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 KATP 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.
KW - Insulin secretion
KW - Insulinotropic peptides
KW - Intracellular calcium
KW - Islet β-cells
KW - Type 2 diabetes
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U2 - 10.1016/j.bbrc.2005.06.005
DO - 10.1016/j.bbrc.2005.06.005
M3 - Article
C2 - 15967412
AN - SCOPUS:20744452517
SN - 0006-291X
VL - 333
SP - 778
EP - 786
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -