Nonlinear Physics and Mathematical Modeling Laboratory, Campus Bio-Medico University of Rome, I-00128 Rome, Italy.
Department of Information Engineering, University of Padua, I-35131 Padua, Italy.
Phys Rev E. 2017 Sep;96(3-1):032403. doi: 10.1103/PhysRevE.96.032403. Epub 2017 Sep 6.
The importance of gap-junction coupling between β cells in pancreatic islets is well established in mouse. Such ultrastructural connections synchronize cellular activity, confine biological heterogeneity, and enhance insulin pulsatility. Dysfunction of coupling has been associated with diabetes and altered β-cell function. However, the role of gap junctions between human β cells is still largely unexplored. By using patch-clamp recordings of β cells from human donors, we previously estimated electrical properties of these channels by mathematical modeling of pairs of human β cells. In this work we revise our estimate by modeling triplet configurations and larger heterogeneous clusters. We find that a coupling conductance in the range 0.005-0.020 nS/pF can reproduce experiments in almost all the simulated arrangements. We finally explore the consequence of gap-junction coupling of this magnitude between β cells with mutant variants of the ATP-sensitive potassium channels involved in some metabolic disorders and diabetic conditions, translating studies performed on rodents to the human case. Our results are finally discussed from the perspective of therapeutic strategies. In summary, modeling of more realistic clusters with more than two β cells slightly lowers our previous estimate of gap-junction conductance and gives rise to patterns that more closely resemble experimental traces.
β 细胞之间的缝隙连接在胰岛中的耦合作用在小鼠中已经得到充分证实。这种超微结构连接使细胞活动同步，限制了生物学异质性，并增强了胰岛素的脉动性。连接功能障碍与糖尿病和β 细胞功能改变有关。然而，人β 细胞之间的缝隙连接的作用在很大程度上仍未得到探索。通过对来自人类供体的β 细胞进行膜片钳记录，我们之前通过对人β 细胞对的数学建模来估计这些通道的电学特性。在这项工作中，我们通过对三联体配置和更大的异质簇进行建模来修正我们的估计。我们发现，耦合电导在 0.005-0.020 nS/pF 范围内可以在几乎所有模拟的排列中重现实验结果。最后，我们探讨了在涉及某些代谢紊乱和糖尿病的情况下与 ATP 敏感性钾通道的突变变体的β 细胞之间这种大小的缝隙连接耦合的后果，将在啮齿动物上进行的研究转化为人类情况。最后，从治疗策略的角度讨论了我们的结果。总之，用两个以上β 细胞对更现实的簇进行建模略微降低了我们之前对缝隙连接电导的估计，并产生了更接近实验轨迹的模式。
