Gresch Anne, Osthues Jana, Hüwel Jan D, Briggs Jennifer K, Berger Tim, Koch Ruben, Deickert Thomas, Beecks Christian, Benninger Richard K P, Düfer Martina
Pharmaceutical and Medicinal Chemistry, Department of Pharmacology, University of Münster Pharma Campus, Münster, Germany.
Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO.
Diabetes. 2025 Mar 1;74(3):343-354. doi: 10.2337/db23-0870.
Glucose-stimulated β-cells exhibit synchronized calcium dynamics across the islet that recruit β-cells to enhance insulin secretion. Compared with calcium dynamics, the formation and cell-to-cell propagation of electrical signals within the islet are poorly characterized. To determine factors that influence the propagation of electrical activity across the islet underlying calcium oscillations and β-cell synchronization, we used high-resolution complementary metal-oxide-semiconductor multielectrode arrays (CMOS-MEA) to measure voltage changes associated with the membrane potential of individual cells within intact C57BL6 mouse islets. We measured fast (milliseconds, spikes) and slow (seconds, waves) voltage dynamics. Single spike activity and wave signal velocity were both glucose-dependent, but only spike activity was influenced by N-methyl-d-aspartate receptor activation or inhibition. A repeated glucose stimulus revealed a highly responsive subset of cells in spike activity. When islets were pretreated for 72 h with glucolipotoxic medium, the wave velocity was significantly reduced. Network analysis confirmed that in response to glucolipotoxicity the synchrony of islet cells was affected due to slower propagating electrical waves and not due to altered spike activity. In summary, this approach provided novel insight regarding the propagation of electrical activity and the disruption of cell-to-cell communication due to excessive stimulation.
The high-resolution complementary metal-oxide-semiconductor multielectrode array is suited to track the spatiotemporal propagation of electrical activity through the islet on a cellular scale. A highly responsive subpopulation of islet cells was identified by action potential-like spike activity and proved to be robust to glucolipotoxicity. Electrical waves revealed synchronized electrical activity and their propagation through the islet was slowed down by glucolipotoxicity. The N-methyl-d-aspartate receptor did not influence islet synchronization since modulation of the receptor only affected electrical spikes. The technique is a useful tool for exploring the pancreatic islet network in health and disease.
葡萄糖刺激的β细胞在整个胰岛中表现出同步的钙动力学，从而促使β细胞增强胰岛素分泌。与钙动力学相比，胰岛内电信号的形成和细胞间传播的特征尚不明确。为了确定影响钙振荡和β细胞同步化背后的电活动在胰岛中传播的因素，我们使用高分辨率互补金属氧化物半导体多电极阵列（CMOS-MEA）来测量完整C57BL6小鼠胰岛内单个细胞膜电位相关的电压变化。我们测量了快速（毫秒级，尖峰）和慢速（秒级，波）电压动力学。单个尖峰活动和波信号速度均依赖于葡萄糖，但只有尖峰活动受N-甲基-D-天冬氨酸受体激活或抑制的影响。重复的葡萄糖刺激揭示了尖峰活动中一组高反应性细胞亚群。当胰岛用糖脂毒性培养基预处理72小时后，波速显著降低。网络分析证实，响应糖脂毒性时，胰岛细胞的同步性受到影响是由于电波传播较慢，而非尖峰活动改变。总之，这种方法为电活动传播以及过度刺激导致的细胞间通讯中断提供了新的见解。
高分辨率互补金属氧化物半导体多电极阵列适合在细胞水平追踪电活动在胰岛中的时空传播。通过类似动作电位的尖峰活动鉴定出一组高反应性胰岛细胞亚群，且该亚群对糖脂毒性具有抗性。电波揭示了同步电活动，且糖脂毒性使其在胰岛中的传播减慢。N-甲基-D-天冬氨酸受体不影响胰岛同步化，因为该受体的调节仅影响电尖峰。该技术是探索健康和疾病状态下胰岛网络的有用工具。
