Department of Information Engineering, University of Padova , Padova , Italy.
Department of Mathematics "Tullio Levi-Civita, " University of Padova , Padova , Italy.
Am J Physiol Endocrinol Metab. 2019 Mar 1;316(3):E475-E486. doi: 10.1152/ajpendo.00380.2018. Epub 2019 Jan 8.
Glucose-stimulated insulin secretion from pancreatic β-cells is controlled by a triggering pathway that culminates in calcium influx and regulated exocytosis of secretory granules, and by a less understood amplifying pathway that augments calcium-induced exocytosis. In response to an abrupt increase in glucose concentration, insulin secretion exhibits a first peak followed by a lower sustained second phase. This biphasic secretion pattern is disturbed in diabetes. It has been attributed to depletion and subsequent refilling of a readily releasable pool of granules or to the phasic cytosolic calcium dynamics induced by glucose. Here, we apply mathematical modeling to experimental data from mouse islets to investigate how calcium and granule pool dynamics interact to control dynamic insulin secretion. Experimental calcium traces are used as inputs in three increasingly complex models of pool dynamics, which are fitted to insulin secretory patterns obtained using a set of protocols of glucose and tolbutamide stimulation. New calcium and secretion data for so-called staircase protocols, in which the glucose concentration is progressively increased, are presented. These data can be reproduced without assuming any heterogeneity in the model, in contrast to previous modeling, because of nontrivial calcium dynamics. We find that amplification by glucose can be explained by increased mobilization and priming of granules. Overall, our results indicate that calcium dynamics contribute substantially to shaping insulin secretion kinetics, which implies that better insight into the events creating phasic calcium changes in human β-cells is needed to understand the cellular mechanisms that disturb biphasic insulin secretion in diabetes.
胰岛β细胞的葡萄糖刺激胰岛素分泌受触发途径控制，该途径最终导致钙离子内流和分泌颗粒的受调控胞吐作用，以及了解较少的放大途径，该途径增强了钙离子诱导的胞吐作用。在葡萄糖浓度突然增加的情况下，胰岛素分泌表现出第一峰，随后是较低的持续第二相。这种双峰分泌模式在糖尿病中受到干扰。它归因于颗粒的易释放池的耗尽和随后的再填充，或者归因于葡萄糖诱导的相细胞质钙离子动力学。在这里，我们应用数学模型来研究从胰岛获得的实验数据，以研究钙和颗粒池动力学如何相互作用以控制动态胰岛素分泌。将实验钙轨迹用作三种池动力学模型的输入，这三种模型是根据使用一组葡萄糖和甲苯磺丁脲刺激方案获得的胰岛素分泌模式拟合的。提出了新的关于所谓的“阶梯”方案（其中葡萄糖浓度逐渐增加）的钙和分泌数据。与以前的建模不同，由于非平凡的钙动力学，这些数据可以在不假设模型中存在任何异质性的情况下进行复制。我们发现，葡萄糖的放大作用可以通过增加颗粒的动员和引发来解释。总的来说，我们的结果表明，钙动力学对塑造胰岛素分泌动力学具有重要贡献，这意味着需要更好地了解在人类β细胞中产生相钙变化的事件，以了解扰乱糖尿病中双峰胰岛素分泌的细胞机制。
