| Novel GPR119 agonist AS1535907 contributes to first-phase insulin secretion in rat perfused pancreas and diabetic db/db mice. | |
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MedLine Citation:
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PMID: 20937249 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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G protein-coupled receptor (GPR) 119 is highly expressed in pancreatic β-cells and enhances the effect of glucose-stimulated insulin secretion (GSIS) on activation. The development of an oral GPR119 agonist that specifically targets the first phase of GSIS represents a promising strategy for the treatment of type 2 diabetes. In the present study, we evaluated the therapeutic potential of a novel small molecule GPR119 agonist, AS1535907, which was modified from the previously identified 2,4,6-tri-substituted pyrimidine core agonist AS1269574. AS1535907 displayed an EC50 value of 4.8 μM in HEK293 cells stably expressing human GPR119 and stimulated insulin secretion in rat islets only under high-glucose (16.8 mM) conditions. In isolated perfused pancreata from normal rats, AS1535907 enhanced the first phase of insulin secretion at 16.8 mM glucose, but had no effect at 2.8mM glucose. In contrast, the sulfonylurea glibenclamide predominantly induced insulin release in the second phase at 16.8 mM glucose and also markedly stimulated insulin secretion at 2.8 mM glucose. In in vivo studies, a single 10 μM administration of AS1535907 to diabetic db/db mice reduced blood glucose levels due to the rapid secretion of insulin secretion following oral glucose loading. These results demonstrate that GPR119 agonist AS1535907 has the ability to stimulate the first phase of GSIS, which is important for preventing the development of postprandial hypoglycemia. In conclusion, the GPR119 agonist AS1535907 induces a more rapid and physiological pattern of insulin release than glibenclamide, and represents a novel strategy for the treatment of type 2 diabetes. |
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Authors:
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Shigeru Yoshida; Takahide Ohishi; Tetsuo Matsui; Hirotsugu Tanaka; Hiroyuki Oshima; Yasuhiro Yonetoku; Masayuki Shibasaki |
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Publication Detail:
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Type: In Vitro; Journal Article Date: 2010-10-16 |
Journal Detail:
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Title: Biochemical and biophysical research communications Volume: 402 ISSN: 1090-2104 ISO Abbreviation: Biochem. Biophys. Res. Commun. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-15 Completed Date: 2010-12-28 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0372516 Medline TA: Biochem Biophys Res Commun Country: United States |
Other Details:
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Languages: eng Pagination: 280-5 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. shigeru.yoshida@jp.astellas.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Cyclic N-Oxides / chemistry, pharmacology*, therapeutic use Diabetes Mellitus, Type 2 / drug therapy Glucose / metabolism, pharmacology Glucose Tolerance Test Humans Hypoglycemic Agents / chemistry, pharmacology*, therapeutic use Insulin / secretion* Islets of Langerhans / drug effects, secretion Male Mice Pancreas / drug effects*, secretion Perfusion Pyridines / chemistry, pharmacology*, therapeutic use Rats Rats, Sprague-Dawley Receptors, G-Protein-Coupled / agonists* |
| Chemical | |
Reg. No./Substance:
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0/2-(4-bromophenyl)-6-methyl-N-(2-(1-oxidopyridin-3-yl)ethyl)pyrimidin-4-amine; 0/Cyclic N-Oxides; 0/GPR119 protein, human; 0/Hypoglycemic Agents; 0/Pyridines; 0/Receptors, G-Protein-Coupled; 11061-68-0/Insulin; 50-99-7/Glucose |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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