School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
J Mol Endocrinol. 2013 Jun 1;51(1):69-77. doi: 10.1530/JME-13-0019. Print 2013.
GW9508 is an agonist of G protein-coupled receptor 40 (GPR40) that is expressed in pancreatic β-cells and is reported to regulate insulin secretion. However, the effects of GW9508 on pancreatic β-cells in primary culture have not been well investigated. This study measured the acute effects of GW9508 on insulin secretion from rat pancreatic islets in primary culture, and the insulin secretion-related events such as the changes in membrane potential, ATP-sensitive potassium currents (KATP currents), and intracellular Ca(2+) concentrations ([Ca(2+)]i) of rat islet β-cells were also recorded. GW9508 (10-40 μM) did not influence basal insulin levels at 2 mM glucose, but it (above 20 μM) significantly inhibited 5 and 15 mM glucose-stimulated insulin secretion (GSIS). GW9508 did not inhibit insulin secretion stimulated by tolbutamide, the closer of KATP channels. GW9508 activated KATP channels and blocked the membrane depolarization and the increase in [Ca(2+)]i that were stimulated by glucose. GW9508 itself stimulated a transient increase in [Ca(2+)]i, which was fully blocked by depletion of intracellular Ca(2+) stores with thapsigargin or by inhibition of phospholipase C (PLC) activity with U73122. GW9508-induced activation of KATP channels was only partly inhibited by U73122 treatment. In conclusion, although it stimulates a transient release of Ca(2+) from intracellular Ca(2+) stores via activation of PLC, GW9508 inhibits GSIS by activating KATP channels probably in a distal step to GPR40 activation in rat β-cells.
GW9508 是一种 G 蛋白偶联受体 40（GPR40）激动剂，在胰腺β细胞中表达，据报道可调节胰岛素分泌。然而，GW9508 对原代培养的胰腺β细胞的影响尚未得到很好的研究。本研究测定了 GW9508 对原代培养的大鼠胰岛胰岛素分泌的急性作用，以及与胰岛素分泌相关的事件，如大鼠胰岛β细胞的膜电位变化、ATP 敏感性钾电流（KATP 电流）和细胞内 Ca(2+)浓度([Ca(2+)]i)。GW9508（10-40 μM）在 2 mM 葡萄糖时不影响基础胰岛素水平，但在 20 μM 以上时显著抑制 5 和 15 mM 葡萄糖刺激的胰岛素分泌（GSIS）。GW9508 不抑制 KATP 通道更接近的甲苯磺丁脲刺激的胰岛素分泌。GW9508 激活 KATP 通道并阻断葡萄糖刺激的膜去极化和 [Ca(2+)]i 增加。GW9508 本身刺激 Ca(2+)的短暂增加[i]，用 thapsigargin 耗尽细胞内 Ca(2+)储存或用 U73122 抑制磷脂酶 C (PLC)活性可完全阻断。GW9508 诱导的 KATP 通道激活仅部分被 U73122 处理抑制。总之，尽管 GW9508 通过激活 PLC 从细胞内 Ca(2+)储存中刺激 Ca(2+)的短暂释放，但通过激活 KATP 通道，GW9508 抑制 GSIS，可能在 GPR40 在大鼠β细胞中激活的远步骤中。
