Modeling the pancreatic α-cell: dual mechanisms of glucose suppression of glucagon secretion.
Modeling the pancreatic α-cell: dual mechanisms of glucose suppression of glucagon secretion.
复制标题
胰腺α细胞建模：葡萄糖抑制胰高血糖素分泌的双重机制。
DOI：
10.1016/j.bpj.2013.11.4504
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发表时间：
2014
影响因子：
3.4
通讯作者：
Sherman,Arthur
中科院分区：
文献类型：
--
作者：
Watts,Margaret;Sherman,Arthur
葡萄糖诱导β细胞中胰岛素分泌的机制已相当清楚。然而，尽管经过多年的研究，α细胞中胰高血糖素分泌的机制仍然没有很好地建立。已经提出葡萄糖通过降低外向ATP依赖性钾通道（K（ATP））或内向储存操纵电流（SOC）的电导来调节胰高血糖素分泌。我们已经开发了一个基于小鼠数据的数学模型来测试这些假设，并发现这两种机制都是可能的。葡萄糖代谢关闭K（ATP）通道，这使细胞去极化，但矛盾的是通过失活电压依赖性钙和钠通道减少钙内流并减少分泌。葡萄糖代谢还激活SERCA泵，其填充内质网并通过减少通过SOC通道的内向电流使细胞超极化，并再次抑制胰高血糖素分泌。我们进一步发现，这两种机制可以联合收割机来解释在一些研究中观察到的分泌对葡萄糖的非单调依赖性，这是单独使用任何一种机制都无法获得的效果。
The mechanism by which glucose induces insulin secretion inβ-cells is fairly well understood. Despite years of research, however, the mechanism of glucagon secretion inα-cells is still not well established. It has been proposed that glucose regulates glucagon secretion by decreasing the conductance of either outward ATP-dependent potassium channels (K(ATP)) or an inward store-operated current (SOC). We have developed a mathematical model based on mouse data to test these hypotheses and found that both mechanisms are possible. Glucose metabolism closes K(ATP) channels, which depolarizes the cell but paradoxically reduces calcium influx by inactivating voltage-dependent calcium and sodium channels and decreases secretion. Glucose metabolism also activates SERCA pumps, which fills the endoplasmic reticulum and hyperpolarizes the cells by reducing the inward current through SOC channels and again suppresses glucagon secretion. We find further that the two mechanisms can combine to account for the nonmonotonic dependence of secretion on glucose observed in some studies, an effect that cannot be obtained with either mechanism alone.