Life sciences · 2012
Novel GPR119 agonist AS1669058 potentiates insulin secretion from rat islets and has potent anti-diabetic effects in ICR and diabetic db/db mice.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Oshima Hiroyuki, Yoshida Shigeru, Ohishi Takahide, Matsui Tetsuo, Tanaka Hirotsugu, Yonetoku Yasuhiro, Shibasaki Masayuki, Uchiyama Yasuo
Аннотация
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.
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.