详细记录  
题名:Novel GPR119 agonist AS1669058 potentiates insulin secretion from rat islets and has potent anti-diabetic effects in ICR and diabetic db/db mice.
作者:OSHIMA H; YOSHIDA S; OHISHI T; MATSUI T; TANAKA H; YONETOKU Y; SHIBASAKI M; UCHIYAMA Y;
来源:Life Sci. 2013 Feb 7;92(2):167-73. doi: 10.1016/j.lfs.2012.11.015. Epub 2012 Dec [ IF= 0.00 ] ]
URL :10.1016/j.lfs.2012.11.015
日期:20130228
摘要:AIMS: G-protein-coupled receptor 119 (GPR119), mainly expressed in pancreatic
beta-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 beta-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.

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