| AS1907417, a novel GPR119 agonist, as an insulinotropic and β-cell preservative agent for the treatment of type 2 diabetes. | |
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MedLine Citation:
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PMID: 20816753 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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G-protein-coupled receptor (GPR) 119 is involved in glucose-stimulated insulin secretion (GSIS) and represents a promising target for the treatment of type 2 diabetes as it is highly expressed in pancreatic β-cells. Although a number of oral GPR119 agonists have been developed, their inability to adequately directly preserve β-cell function limits their effectiveness. Here, we evaluated the therapeutic potential of a novel small-molecule GPR119 agonist, AS1907417, which represents a modified form of a 2,4,6-tri-substituted pyrimidine core agonist, AS1269574, we previously identified. The exposure of HEK293 cells expressing human GPR119, NIT-1 cells expressing human insulin promoter, and the pancreatic β-cell line MIN-6-B1 to AS1907417, enhanced intracellular cAMP, GSIS, and human insulin promoter activity, respectively. In in vivo experiments involving fasted normal mice, a single dose of AS1907417 improved glucose tolerance, but did not affect plasma glucose or insulin levels. Twice-daily doses of AS1907417 for 4weeks in diabetic db/db, aged db/db mice, ob/ob mice, and Zucker diabetic fatty rats reduced hemoglobin A1c levels by 1.6%, 0.8%, 1.5%, and 0.9%, respectively. In db/db mice, AS1907417 improved plasma glucose, plasma insulin, pancreatic insulin content, lipid profiles, and increased pancreatic insulin and pancreatic and duodenal homeobox 1 (PDX-1) mRNA levels. These data demonstrate that novel GPR119 agonist AS1907417 not only effectively controls glucose levels, but also preserves pancreatic β-cell function. We therefore propose that AS1907417 represents a new type of antihyperglycemic agent with promising potential for the effective treatment of type 2 diabetes. |
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Authors:
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Shigeru Yoshida; Hirotsugu Tanaka; Hiroyuki Oshima; Takao Yamazaki; Yasuhiro Yonetoku; Takahide Ohishi; Tetsuo Matsui; Masayuki Shibasaki |
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Publication Detail:
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Type: Journal Article Date: 2010-09-15 |
Journal Detail:
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Title: Biochemical and biophysical research communications Volume: 400 ISSN: 1090-2104 ISO Abbreviation: Biochem. Biophys. Res. Commun. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-04 Completed Date: 2010-11-23 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: 745-51 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 305-8585, Japan. shigeru.yoshida@jp.astellas.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cyclic S-Oxides / chemistry, pharmacology*, therapeutic use Cytoprotection* Diabetes Mellitus, Experimental / drug therapy* Diabetes Mellitus, Type 2 / drug therapy* Glucose Tolerance Test Humans Hypoglycemic Agents / chemistry, pharmacology*, therapeutic use Insulin / genetics, secretion Insulin-Secreting Cells / drug effects*, secretion Male Mice Mice, Inbred Strains Promoter Regions, Genetic / drug effects Pyrimidines / chemistry, pharmacology*, therapeutic use Rats Rats, Zucker Receptors, G-Protein-Coupled / agonists* |
| Chemical | |
Reg. No./Substance:
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0/AS 1907417; 0/Cyclic S-Oxides; 0/GPR119 protein, human; 0/Hypoglycemic Agents; 0/Pyrimidines; 0/Receptors, G-Protein-Coupled; 11061-68-0/Insulin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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