δ-cells and β-cells are electrically coupled and regulate α-cell activity via somatostatin.
δ-cells and β-cells are electrically coupled and regulate α-cell activity via somatostatin.
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DOI：
10.1113/jp274581
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发表时间：
2018-01-15
期刊：
影响因子：
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通讯作者：
Rorsman P
中科院分区：
文献类型：
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作者：
Briant LJB;Reinbothe TM;Spiliotis I;Miranda C;Rodriguez B;Rorsman P
我们用一只在β细胞中表达光敏离子通道的小鼠来了解α细胞如何调节β细胞的活动。β细胞的光激活通过缝隙连接依赖的α细胞激活触发了δ细胞活性的抑制。对人胰岛的数学模拟表明，葡萄糖对胰升糖素分泌的抑制作用中有23%是由β细胞通过缝隙连接依赖的δ细胞/生长抑素分泌的激活而介导的。胰升糖素是人体主要的高血糖激素，由胰岛的α细胞释放。这种激素的分泌在2型糖尿病中是失调的，但控制分泌的机制还不是很清楚。由邻近的β和δ细胞分泌的因子调节胰升糖素的分泌(旁分泌调节)被认为是重要的。在这项研究中，我们利用光遗传策略来探索旁分泌调节的重要性。表达光门通道视紫红质-2的小鼠胰岛中的β细胞在光诱导下被特异性激活，导致δ细胞的电活动被刺激，而α细胞的活动被抑制。缝隙连接抑制剂Carbenoxolone对δ细胞的激活迅速而敏感，而生长抑素-2受体拮抗剂Cyn 154806可阻断其对α细胞电活动的影响。这些观察表明，β细胞的光遗传激活通过缝隙连接传播到δ细胞，随后对生长抑素分泌的刺激通过旁分泌机制抑制α细胞的电活动。为了探索这一途径是否对调节人胰岛的α细胞活性和胰升糖素分泌起重要作用，我们构建了人胰岛的计算模型。这些模型有基于人类胰岛的详细架构，并由一组>；500α-，β-和δ-细胞组成。对这些模型的模拟表明，这种缝隙连接/旁分泌机制可以解释高糖抑制胰高血糖素分泌的高达23%。我们用一只在β细胞中表达光敏离子通道的小鼠来了解α细胞如何调节β细胞的活动。β细胞的光激活通过缝隙连接依赖的α细胞激活触发了δ细胞活性的抑制。对人胰岛的数学模拟表明，葡萄糖对胰升糖素分泌的抑制作用中有23%是由β细胞通过缝隙连接依赖的δ细胞/生长抑素分泌的激活而介导的。
We used a mouse expressing a light‐sensitive ion channel in β‐cells to understand how α‐cell activity is regulated by β‐cells. Light activation of β‐cells triggered a suppression of α‐cell activity via gap junction‐dependent activation of δ‐cells. Mathematical modelling of human islets suggests that 23% of the inhibitory effect of glucose on glucagon secretion is mediated by β‐cells via gap junction‐dependent activation of δ‐cells/somatostatin secretion. Glucagon, the body's principal hyperglycaemic hormone, is released from α‐cells of the pancreatic islet. Secretion of this hormone is dysregulated in type 2 diabetes mellitus but the mechanisms controlling secretion are not well understood. Regulation of glucagon secretion by factors secreted by neighbouring β‐ and δ‐cells (paracrine regulation) have been proposed to be important. In this study, we explored the importance of paracrine regulation by using an optogenetic strategy. Specific light‐induced activation of β‐cells in mouse islets expressing the light‐gated channelrhodopsin‐2 resulted in stimulation of electrical activity in δ‐cells but suppression of α‐cell activity. Activation of the δ‐cells was rapid and sensitive to the gap junction inhibitor carbenoxolone, whereas the effect on electrical activity in α‐cells was blocked by CYN 154806, an antagonist of the somatostatin‐2 receptor. These observations indicate that optogenetic activation of the β‐cells propagates to the δ‐cells via gap junctions, and the consequential stimulation of somatostatin secretion inhibits α‐cell electrical activity by a paracrine mechanism. To explore whether this pathway is important for regulating α‐cell activity and glucagon secretion in human islets, we constructed computational models of human islets. These models had detailed architectures based on human islets and consisted of a collection of >500 α‐, β‐ and δ‐cells. Simulations of these models revealed that this gap junctional/paracrine mechanism accounts for up to 23% of the suppression of glucagon secretion by high glucose. We used a mouse expressing a light‐sensitive ion channel in β‐cells to understand how α‐cell activity is regulated by β‐cells. Light activation of β‐cells triggered a suppression of α‐cell activity via gap junction‐dependent activation of δ‐cells. Mathematical modelling of human islets suggests that 23% of the inhibitory effect of glucose on glucagon secretion is mediated by β‐cells via gap junction‐dependent activation of δ‐cells/somatostatin secretion.