A K ATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of Langerhans.
A K ATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of Langerhans.
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DOI：
10.1371/journal.pbio.0050143
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发表时间：
2007-06
期刊：
影响因子：
9.8
通讯作者：
Rorsman P
中科院分区：
文献类型：
--
作者：
MacDonald PE;De Marinis YZ;Ramracheya R;Salehi A;Ma X;Johnson PR;Cox R;Eliasson L;Rorsman P
胰高血糖素由胰岛α细胞分泌，刺激胰岛细胞生成和肝糖原分解。调节胰高血糖素释放的机制存在争议，并不同地归因于神经元控制、邻近β细胞的旁分泌控制或α细胞自身的内在葡萄糖感知。我们检测了完整啮齿动物和人类胰岛内α和β细胞的激素分泌和Ca 2+反应。当旁分泌GABA或Zn 2+信号传导被阻断时，胰高血糖素释放的葡萄糖依赖性抑制持续存在，但可被低浓度（1-20 μM）ATP敏感性K+（KATP）通道开放剂二氮嗪逆转，该药物对胰岛素释放或β细胞反应无影响。KATP通道阻滞剂甲苯磺丁脲（100 μM）可阻止该效应。较高的二氮嗪浓度（≥30 μM）可平行降低胰高血糖素和胰岛素分泌以及α和β细胞Ca 2+反应。在没有葡萄糖的情况下，低浓度（<1 μM）的甲苯磺丁脲刺激胰高血糖素分泌，而高浓度（>10 μM）则抑制胰高血糖素分泌。在最大抑制浓度的甲苯磺丁脲（0.5 mM）的存在下，葡萄糖没有额外的抑制作用。在KATP通道下游，抑制电压门控Na+（TTX）和N型Ca 2+通道（ω-芋螺毒素），但不抑制L型Ca 2+通道（硝苯地平），可阻止胰高血糖素分泌。在去极化膜电位下，N型Ca ~（2+）通道和α细胞胞吐作用均失活。啮齿动物和人胰高血糖素分泌受α细胞KATP通道依赖性机制调节。我们认为，葡萄糖升高通过去极化诱导的参与动作电位放电和分泌的离子通道失活来降低电活动和胞吐作用。胰高血糖素是葡萄糖稳态的关键调节剂。它的主要作用是从肝脏动员葡萄糖。胰岛α细胞的胰高血糖素分泌受到血糖升高的抑制，这是糖尿病中经常出现的一种反应。许多工作集中在神经元因子和邻近细胞的旁分泌因子（包括重要的胰岛激素胰岛素）对α细胞胰高血糖素分泌的调节上。相反，我们提供的证据支持葡萄糖对完整啮齿动物和人类胰岛内α细胞的直接影响。值得注意的是，我们的工作暗示了一种与胰岛素分泌β细胞中发现的类似的α细胞葡萄糖敏感途径，涉及在葡萄糖存在下ATP依赖性K+通道的关闭。此外，我们发现膜去极化导致Na+和Ca ~（2+）通道活性和α细胞胞吐的抑制。因此，我们认为血糖升高通过使参与动作电位放电和分泌的离子通道失活而降低α细胞电活动和胰高血糖素分泌。升高的葡萄糖水平通过胰岛细胞中离子通道的失活降低电活动和胰高血糖素的释放。
Glucagon, secreted from pancreatic islet α cells, stimulates gluconeogenesis and liver glycogen breakdown. The mechanism regulating glucagon release is debated, and variously attributed to neuronal control, paracrine control by neighbouring β cells, or to an intrinsic glucose sensing by the α cells themselves. We examined hormone secretion and Ca2+ responses of α and β cells within intact rodent and human islets. Glucose-dependent suppression of glucagon release persisted when paracrine GABA or Zn2+ signalling was blocked, but was reversed by low concentrations (1–20 μM) of the ATP-sensitive K+ (KATP) channel opener diazoxide, which had no effect on insulin release or β cell responses. This effect was prevented by the KATP channel blocker tolbutamide (100 μM). Higher diazoxide concentrations (≥30 μM) decreased glucagon and insulin secretion, and α- and β-cell Ca2+ responses, in parallel. In the absence of glucose, tolbutamide at low concentrations (<1 μM) stimulated glucagon secretion, whereas high concentrations (>10 μM) were inhibitory. In the presence of a maximally inhibitory concentration of tolbutamide (0.5 mM), glucose had no additional suppressive effect. Downstream of the KATP channel, inhibition of voltage-gated Na+ (TTX) and N-type Ca2+ channels (ω-conotoxin), but not L-type Ca2+ channels (nifedipine), prevented glucagon secretion. Both the N-type Ca2+ channels and α-cell exocytosis were inactivated at depolarised membrane potentials. Rodent and human glucagon secretion is regulated by an α-cell KATP channel-dependent mechanism. We propose that elevated glucose reduces electrical activity and exocytosis via depolarisation-induced inactivation of ion channels involved in action potential firing and secretion. Glucagon is a critical regulator of glucose homeostasis. Its major action is to mobilize glucose from the liver. Glucagon secretion from α cells of the pancreatic islets of Langerhans is suppressed by elevated blood sugar, a response that is often perturbed in diabetes. Much work has focused on the regulation of α-cell glucagon secretion by neuronal factors and by paracrine factors from neighbouring cells, including the important islet hormone insulin. In contrast, we provide evidence in support of a direct effect of glucose on α cells within intact rodent and human islets. Notably, our work implicates an α-cell glucose-sensing pathway similar to that found in insulin-secreting β cells, involving closure of ATP-dependent K+ channels in the presence of glucose. Furthermore, we find that membrane depolarisation results in inhibition of Na+ and Ca2+ channel activity and α-cell exocytosis. Thus, we propose that elevated blood glucose reduces α-cell electrical activity and glucagon secretion by inactivating the ion channels involved in action potential firing and secretion. Elevated glucose levels reduce electrical activity and the release of glucagon via inactivation of ion channels in pancreatic islet cells.
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肾上腺素通过增加 Ca2+ 电流和靠近 L 型 Ca2+ 通道的颗粒数量来刺激胰腺 A 细胞的胰高血糖素分泌。
影响因子：
3.8
作者：
Gromada, J;Bokvist, K;Ding, WG;Barg, S;Buschard, K;Renstrom, E;Rorsman, P
通讯作者：
Rorsman, P
影响因子：
7.7
作者：
Hope, KM;Tran, POT;Robertson, RP
通讯作者：
Robertson, RP
影响因子：
--
作者：
LECLERCQMEYER, V;MARCHAND, J;MALAISSE, WJ
通讯作者：
MALAISSE, WJ
影响因子：
4
作者：
Liu, YJ;Vieira, E;Gylfe, E
通讯作者：
Gylfe, E
影响因子：
4.8
作者：
Fox, Jocelyn E. Manning;Gyulkhandanyan, Armen V.;Wheeler, Michael B.
通讯作者：
Wheeler, Michael B.