HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0528v1 201/3/361    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Eiki, J.-i. Articles by Yada, T. Search for Related Content PubMed PubMed Citation Articles by Eiki, J.-i. Articles by Yada, T.

J Eiki, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan
K Saeki, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan
N Nagano, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan
T Iino, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan
M Yonemoto, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan
Y Takayenoki-Iino, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan
S Ito, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan
T Nishimura, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan
Y Sato, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan
M Bamba, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan
H Watanabe, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan
K Sasaki, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan
S Ohyama, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan
A Kanatani, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan
T Nagase, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan
T Yada, Department of Physiology, Division of Integrative Physiology, Jichi Medical University, School of Medicine, Shimotsuke, Japan

Correspondence: Jun-ichi Eiki, Email: junichi_eiki{at}merck.com

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 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 (FIRC). 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 FIRC. 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 Ca2+ release from intracellular stores, but to extracellular Ca2+ influx. The response was inhibited by presence of either L-type Ca2+ channel blockers or K+ ionophore. Perforated patch clamp study revealed that Compound A induces membrane depolarization. These results suggest that neither Gs- nor Gq-coupled signaling account for the mechanism of action, but depolarization-coupled Ca2+ influx from extracellular space is the primarily 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.