Resolving Spatiotemporal Electrical Signaling Within the Islet via CMOS Microelectrode Arrays

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.