Biomathematics Laboratory, Department of Applied Mathematics, School of Mathematical Sciences, Tarbiat Modares University, Tehran, Iran.
Sci Rep. 2021 May 13;11(1):10268. doi: 10.1038/s41598-021-89333-x.
Type 2 diabetes (T2D) is a challenging metabolic disorder characterized by a substantial loss of [Formula: see text]-cell mass and alteration of [Formula: see text]-cell function in the islets of Langerhans, disrupting insulin secretion and glucose homeostasis. The mechanisms for deficiency in [Formula: see text]-cell mass and function during the hyperglycemia development and T2D pathogenesis are complex. To study the relative contribution of [Formula: see text]-cell mass to [Formula: see text]-cell function in T2D, we make use of a comprehensive electrophysiological model of human [Formula: see text]-cell clusters. We find that defect in [Formula: see text]-cell mass causes a functional decline in single [Formula: see text]-cell, impairment in intra-islet synchrony, and changes in the form of oscillatory patterns of membrane potential and intracellular [Formula: see text] concentration, which can lead to changes in insulin secretion dynamics and in insulin levels. The model demonstrates a good correspondence between suppression of synchronizing electrical activity and published experimental measurements. We then compare the role of gap junction-mediated electrical coupling with both [Formula: see text]-cell synchronization and metabolic coupling in the behavior of [Formula: see text] concentration dynamics within human islets. Our results indicate that inter-[Formula: see text]-cellular electrical coupling depicts a more important factor in shaping the physiological regulation of islet function and in human T2D. We further predict that varying the whole-cell conductance of delayed rectifier [Formula: see text] channels modifies oscillatory activity patterns of [Formula: see text]-cell population lacking intercellular coupling, which significantly affect [Formula: see text] concentration and insulin secretion.
2 型糖尿病（T2D）是一种具有挑战性的代谢紊乱，其特征是胰岛中β细胞数量大量减少和β细胞功能改变，破坏胰岛素分泌和葡萄糖稳态。在高血糖发展和 T2D 发病机制中，β细胞数量和功能不足的机制很复杂。为了研究β细胞数量对 T2D 中β细胞功能的相对贡献，我们利用了人类β细胞簇的综合电生理模型。我们发现，β细胞数量的缺陷导致单个β细胞功能下降，胰岛内同步性受损，以及膜电位和细胞内[Formula: see text]浓度的振荡模式形式发生变化，这可能导致胰岛素分泌动力学和胰岛素水平发生变化。该模型在抑制同步电活动方面与已发表的实验测量结果具有良好的一致性。然后，我们比较了间隙连接介导的电耦合与β细胞同步和代谢耦联在人胰岛内[Formula: see text]浓度动力学行为中的作用。我们的结果表明，细胞间电耦合在塑造胰岛功能的生理调节和人类 T2D 方面是一个更重要的因素。我们进一步预测，改变延迟整流[Formula: see text]通道的全细胞电导会改变缺乏细胞间耦合的β细胞群体的振荡活动模式，这会显著影响[Formula: see text]浓度和胰岛素分泌。
