Department of Bioengineering, University of Colorado, Anschutz Medical campus, Aurora, Colorado, United States of America.
Barbara Davis center for childhood diabetes, University of Colorado, Anschutz Medical campus, Aurora, Colorado, United States of America.
PLoS Comput Biol. 2021 May 3;17(5):e1008948. doi: 10.1371/journal.pcbi.1008948. eCollection 2021 May.
The islets of Langerhans exist as multicellular networks that regulate blood glucose levels. The majority of cells in the islet are excitable, insulin-producing β-cells that are electrically coupled via gap junction channels. β-cells are known to display heterogeneous functionality. However, due to gap junction coupling, β-cells show coordinated [Ca2+] oscillations when stimulated with glucose, and global quiescence when unstimulated. Small subpopulations of highly functional β-cells have been suggested to control [Ca2+] dynamics across the islet. When these populations were targeted by optogenetic silencing or photoablation, [Ca2+] dynamics across the islet were largely disrupted. In this study, we investigated the theoretical basis of these experiments and how small populations can disproportionality control islet [Ca2+] dynamics. Using a multicellular islet model, we generated normal, skewed or bimodal distributions of β-cell heterogeneity. We examined how islet [Ca2+] dynamics were disrupted when cells were targeted via hyperpolarization or populations were removed; to mimic optogenetic silencing or photoablation, respectively. Targeted cell populations were chosen based on characteristics linked to functional subpopulation, including metabolic rate of glucose oxidation or [Ca2+] oscillation frequency. Islets were susceptible to marked suppression of [Ca2+] when ~10% of cells with high metabolic activity were hyperpolarized; where hyperpolarizing cells with normal metabolic activity had little effect. However, when highly metabolic cells were removed from the model, [Ca2+] oscillations remained. Similarly, when ~10% of cells with either the highest frequency or earliest elevations in [Ca2+] were removed from the islet, the [Ca2+] oscillation frequency remained largely unchanged. Overall, these results indicate small populations of β-cells with either increased metabolic activity or increased frequency are unable to disproportionately control islet-wide [Ca2+] via gap junction coupling. Therefore, we need to reconsider the physiological basis for such small β-cell populations or the mechanism by which they may be acting to control normal islet function.
胰岛以细胞网络的形式存在，调节血糖水平。胰岛中的大多数细胞都是可兴奋的、产生胰岛素的β细胞，它们通过缝隙连接通道电耦联。β细胞的功能存在异质性。然而，由于缝隙连接的耦联作用，当受到葡萄糖刺激时，β细胞表现出协调的[Ca2+]振荡，而在未受刺激时则表现出整体静止。已经有人提出，少量具有高功能的β细胞亚群可能控制整个胰岛的[Ca2+]动力学。当这些群体通过光遗传沉默或光消融来靶向时，胰岛的[Ca2+]动力学在很大程度上被破坏。在这项研究中，我们研究了这些实验的理论基础，以及小群体如何不成比例地控制胰岛[Ca2+]动力学。使用一个多细胞胰岛模型，我们生成了β细胞异质性的正常、偏斜或双峰分布。我们研究了当通过超极化靶向细胞或去除细胞群体时，胰岛[Ca2+]动力学是如何被破坏的；分别模拟光遗传沉默或光消融。靶向细胞群体是根据与功能亚群相关的特征选择的，包括葡萄糖氧化的代谢率或[Ca2+]振荡频率。当约 10%的代谢活性高的细胞被超极化时，胰岛对[Ca2+]的明显抑制敏感；而超极化代谢活性正常的细胞几乎没有影响。然而，当从模型中去除高代谢细胞时，[Ca2+]振荡仍然存在。同样，当从胰岛中去除具有最高频率或最早升高的[Ca2+]的约 10%的细胞时，[Ca2+]振荡频率基本保持不变。总的来说，这些结果表明，具有增加代谢活性或增加频率的β细胞小群体不能通过缝隙连接耦联不成比例地控制胰岛的[Ca2+]。因此，我们需要重新考虑这种小β细胞群体的生理基础，或者它们控制正常胰岛功能的作用机制。
