title: A selective small molecule glucagon-like peptide-1 secretagogue acting via depolarization-coupled Ca(2+) influx.
abstract: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates insulin secretion in a glucose-dependent manner. Selective GLP-1 secretagogue would be one of the potential therapeutic targets for type 2 diabetes. Here, we describe a newly identified small molecule compound (compound A) that stimulates secretion of GLP-1 in murine enteroendocrine cell lines, STC-1 and GLUTag cells, and in primary cultured fetal rat intestinal cells (FRIC). The underlying mechanism by which compound A stimulated GLP-1 secretion was also examined. Compound A stimulated GLP-1 secretion from STC-1 cells in a concentration-dependent manner, and also from GLUTag cells and FRIC. The action of compound A was selective against other tested endocrine functions such as secretion of insulin from rat islets, growth hormone from rat pituitary gland cells, and norepinephrine from rat PC-12 cells. In STC-1 cells, the compound A-stimulated GLP-1 secretion was neither due to cyclic AMP production nor to Ca(2+) release from intracellular stores, but to extracellular Ca(2+) influx. The response was inhibited by the presence of either L-type Ca(2+) channel blockers or K(+) ionophore. Perforated-patch clamp study revealed that compound A induces membrane depolarization. These results suggest that neither Galphas- nor Galphaq-coupled signaling account for the mechanism of action, but depolarization-coupled Ca(2+) influx from extracellular space is the primary cause for the GLP-1 secretion stimulated by compound A. Identifying a specific target molecule for compound A will reveal a selective regulatory pathway that leads to depolarization-mediated GLP-1 secretion.
authors.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Tsukuba, Ibaraki, Japan. junichi_eiki@merck.com
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Eiki
authors.forename: Kaori
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authors.lastname: Saeki
authors.forename: Norihiro
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authors.lastname: Nagano
authors.forename: Tomoharu
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authors.lastname: Iino
authors.forename: Mari
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authors.lastname: Yonemoto
authors.forename: Yoko
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authors.lastname: Takayenoki-Iino
authors.forename: Satoru
authors.initials: S
authors.lastname: Ito
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Nishimura
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sato
authors.forename: Makoto
authors.initials: M
authors.lastname: Bamba
authors.forename: Hitomi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Kaori
authors.initials: K
authors.lastname: Sasaki
authors.forename: Sumika
authors.initials: S
authors.lastname: Ohyama
authors.forename: Akio
authors.initials: A
authors.lastname: Kanatani
authors.forename: Toshio
authors.initials: T
authors.lastname: Nagase
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada