Regulation of glucagon secretion at low glucose concentrations: Evidence for adenosine triphosphate sensitive potassium channel involvement
Regulation of glucagon secretion at low glucose concentrations: Evidence for adenosine triphosphate sensitive potassium channel involvement
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DOI：
10.1210/en.2005-0637
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发表时间：
2005-12-01
期刊：
影响因子：
4.8
通讯作者：
Rajan, AS
中科院分区：
文献类型：
--
作者：
Muñoz, A;Hu, M;Rajan, AS
胰高血糖素是一种有效的反调节激素，它对抗胰岛素控制血糖的作用。胰腺α细胞胰升糖素分泌对低血糖反应的细胞机制知之甚少。SUR1/K(IR)6.2型ATP敏感性K+(KATP)通道参与了中枢和外周水平的胰高血糖素反调节反应，但其作用尚不清楚。在这项研究中，我们使用缺乏神经内分泌型KATP通道的Sur1KO小鼠和配对的野生型(WT)对照，在体外和体内检测了低血糖诱导的胰岛胰高血糖素分泌。随意喂养的Sur1KO小鼠具有正常的胰高血糖素水平，并动员肝糖原对外源胰高血糖素做出反应，但对胰岛素诱导的低血糖表现出迟钝的胰高血糖素反应。当葡萄糖浓度为2.8 mmol/L时，Sur1KO和WT胰岛的胰高血糖素释放增加，而增加葡萄糖浓度则抑制其释放。与Sur1KO胰岛相比，WT胰岛在0.1mmoL/L葡萄糖刺激下可使胰岛分泌的胰升糖素增加约20倍。胰升糖素的释放需要钙离子，并被硝苯地平抑制。与K-ATP通道和胰岛内锌胰岛素之间的调节相互作用相一致，WT胰岛表现出β细胞分泌和胰升糖素释放之间的负相关。格列本脲刺激WT胰岛胰岛素分泌，减少胰岛高血糖素释放，但对Sur1KO胰岛分泌无影响。结果表明，α细胞K-ATP通道的缺失使胰升血糖素的释放从β细胞的抑制中解脱出来，揭示了KATP通道在低糖调节胰升糖素释放中的作用。
Glucagon is a potent counterregulatory hormone that opposes the action of insulin in controlling glycemia. The cellular mechanisms by which pancreatic alpha-cell glucagon secretion occurs in response to hypoglycemia are poorly known. SUR1/ K(IR)6.2-type ATP-sensitive K+ (KATP) channels have been implicated in the glucagon counterregulatory response at central and peripheral levels, but their role is not well understood. In this study, we examined hypoglycemia-induced glucagon secretion in vitro in isolated islets and in vivo using Sur1KO mice lacking neuroendocrine-type KATP channels and paired wild-type (WT) controls. Sur1KO mice fed ad libitum have normal glucagon levels and mobilize hepatic glycogen in response to exogenous glucagon but exhibit a blunted glucagon response to insulin-induced hypoglycemia. Glucagon release from Sur1KO and WT islets is increased at 2.8 mmol/liter glucose and suppressed by increasing glucose concentrations. WT islets increase glucagon secretion approximately 20-fold when challenged with 0.1 mmol/liter glucose vs. approximately 2.7-fold for Sur1KO islets. Glucagon release requires Ca2+ and is inhibited by nifedipine. Consistent with a regulatory interaction between K-ATP channels and intraislet zinc-insulin, WT islets exhibit an inverse correlation between beta-cell secretion and glucagon release. Glibenclamide stimulated insulin secretion and reduced glucagon release in WT islets but was without effect on secretion from Sur1KO islets. The results indicate that loss of alpha-cell K-ATP channels uncouples glucagon release from inhibition by beta-cells and reveals a role for KATP channels in the regulation of glucagon release by low glucose.