Antidiabetic sulfonylurea stimulates insulin secretion independently of plasma membrane KATP channels.
Antidiabetic sulfonylurea stimulates insulin secretion independently of plasma membrane KATP channels.
复制标题
抗糖尿病磺酰脲类药物可独立于质膜 KATP 通道刺激胰岛素分泌。
DOI：
10.1152/ajpendo.00016.2007
复制
发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Drain,Peter
中科院分区：
文献类型：
--
作者：
Geng,Xuehui;Li,Lehong;Bottino,Rita;Balamurugan,AN;Bertera,Suzanne;Densmore,Erik;Su,Anjey;Chang,Yigang;Trucco,Massimo;Drain,Peter
了解格列本脲刺激胰岛素释放的机制很重要，特别是考虑到最近格列本脲对永久性新生儿糖尿病患者有希望的治疗。抗糖尿病磺脲类药物被认为仅通过抑制β细胞质膜上的高亲和力三磷酸腺苷敏感钾通道受体来刺激胰岛素的分泌。这通常发生在葡萄糖刺激期间，质膜KATP通道的三磷酸腺苷抑制导致L类钙通道的电压激活，从而快速开启和关闭钙内流，控制胰岛素分泌的持续时间。然而，越来越多的证据表明，磺脲类药物，包括格列本脲，在胰岛素颗粒的β细胞内有额外的KATP通道受体。我们测试了小鼠胰岛中非通透性β细胞对格列本脲刺激的胰岛素分泌的影响，这种分泌是由颗粒定位的KATP通道介导的，条件是绕过格列本脲对质膜KATP通道的作用。高钾刺激引起β细胞钙水平持续升高，但胰岛素分泌短暂增加。在持续高钾去极化的情况下，加入格列本脲显著增加胰岛素的分泌，而不影响钙。这些发现支持这样的假设，即格列本脲，或增加的ATP/ADP比率，部分通过结合颗粒定位的KATP通道来刺激胰岛素的分泌，而颗粒定位的KATP通道在功能上有助于持续的第二时相胰岛素分泌。
Understanding mechanisms by which glibenclamide stimulates insulin release is important, particularly given recent promising treatment by glibenclamide of permanent neonatal diabetic subjects. Antidiabetic sulfonylureas are thought to stimulate insulin secretion solely by inhibiting their high-affinity ATP-sensitive potassium (KATP) channel receptors at the plasma membrane of β-cells. This normally occurs during glucose stimulation, where ATP inhibition of plasmalemmal KATPchannels leads to voltage activation of L-type calcium channels for rapidly switching on and off calcium influx, governing the duration of insulin secretion. However, growing evidence indicates that sulfonylureas, including glibenclamide, have additional KATPchannel receptors within β-cells at insulin granules. We tested nonpermeabilized β-cells in mouse islets for glibenclamide-stimulated insulin secretion mediated by granule-localized KATPchannels by using conditions that bypass glibenclamide action on plasmalemmal KATPchannels. High-potassium stimulation evoked a sustained rise in β-cell calcium level but a transient rise in insulin secretion. With continued high-potassium depolarization, addition of glibenclamide dramatically enhanced insulin secretion without affecting calcium. These findings support the hypothesis that glibenclamide, or an increased ATP/ADP ratio, stimulates insulin secretion in part by binding at granule-localized KATPchannels that functionally contribute to sustained second-phase insulin secretion.