Novel GPR119 agonist AS1669058 potentiates insulin secretion from rat islets and has potent anti-diabetic effects in ICR and diabetic db/db mice.

Abstract

AIMS:

G-protein-coupled receptor 119 (GPR119), mainly expressed in pancreatic β-cells, represents a new target for treating type 2 diabetes. GPR119 agonist is known to induce insulin secretion in a glucose-dependent manner by elevating intracellular cAMP concentrations. This study mainly examined the anti-hyperglycemic effect of a novel candidate small-molecule GPR119 agonist AS1669058 2-(4-bromo-2,5-difluorophenyl)-6-methyl-N-[2-(1-oxidopyridin-3-yl)ethyl]pyrimidin-4-amine ethanedioate on ICR mice and diabetic db/db mice.

MAIN METHODS:

We measured blood glucose, plasma insulin, and insulin content in the pancreas after repeated administration of AS1669058 to db/db mice twice daily for one week.

KEY FINDINGS:

Under high-concentration glucose conditions, AS1669058 induced insulin secretion in a dose-dependent manner in the hamster pancreatic β-cell line HIT-T15 and in rat pancreatic islets. In addition, AS1669058 increased human insulin promoter activity in NIT-1 cells. In in vivo studies, a single administration of AS1669058 (1 mg/kg) in ICR mice improved oral glucose tolerance based on insulin secretion. Further, 1-week repeated treatment (3 mg/kg, twice daily) in diabetic db/db mice significantly reduced blood glucose levels and tended to increase insulin content in the pancreas.

SIGNIFICANCE:

These results suggest that AS1669058 has promising potential as an extremely more effective anti-hyperglycemic agent than other compounds we previously reported as GPR119 agonists.

• Authors: Hiroyuki Oshima, Shigeru Yoshida, Takahide Ohishi, Tetsuo Matsui, Hirotsugu Tanaka, Yasuhiro Yonetoku, Masayuki Shibasaki, Yasuo Uchiyama
• Journal: Life sciences (Life Sci) Vol. 92 Issue 2 Pg. 167-73 (Feb 07 2013) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 23246743 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• AS1669058
• Blood Glucose
• GPR119 protein, rat
• Gpr119 protein, mouse
• Hypoglycemic Agents
• Insulin
• Pyridines
• Pyrimidines
• Receptors, G-Protein-Coupled

Topics

• Animals
• Blood Glucose (analysis)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Hypoglycemic Agents (blood, therapeutic use)
• Insulin (analysis, blood, metabolism)
• Insulin Secretion
• Insulin-Secreting Cells (chemistry, drug effects, metabolism)
• Male
• Mice
• Mice, Inbred ICR
• Pyridines (blood, therapeutic use)
• Pyrimidines (blood, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptors, G-Protein-Coupled (antagonists & inhibitors)