Computational modelling of natural cell-to-cell heterogeneity reveals key parameters that control the diversity of human pancreatic islet β-cell excitability in response to glucose
Year: 2026
Type: preprint
Abstract: ABSTRACT Insulin-producing β-cells demonstrate remarkable heterogeneity in their individual responsiveness to glucose, and that cellular heterogeneity contributes to coordinating islet activity and glucose homeostasis. Our current understanding of how variation in cell-intrinsic factors control cellular excitability and insulin secretion is informed by foundational experiments conducted on dispersed single β-cells. Such studies are limited in their ability to link multiple electrical or metabolic properties within a single cell and preclude the ability to relate, post hoc , each parameter’s contribution to glucose responsiveness. Computational modelling represents a unique and underutilized tool to integrate and investigate the role of natural β-cell heterogeneity in physiologic glucose responses. Herein, we utilize a high-volume single-cell electrophysiology “patch-seq” dataset to define the physiologically relevant sources of variability in human β-cell electrophysiology and model their influence on single-cell glucose responses. Three thousand in silico human β-cells were fitted to physiologically relevant variations in glucokinase activity, K + current, Na + current, Ca 2+ current, and exocytotic function. Four dominant electrical phenotypes arose at low (2 mM) and high (20 mM) glucose: silent, bursting, spiking, and depolarized. Approximately 50% of uncoupled β-cells remained electrically silent at high glucose. Furthermore, Na + channel half-inactivation voltage was a major predictor of the silent and spiking phenotypes at each glucose concentration, and of cells that transition from silent to spiking when glucose increased. Indeed, experimentally observed variation in Na + channel voltage dependence was second only to variation in ATP-sensitive potassium channel conductance in determining β-cell excitability. Our data-driven computational modelling highlights the functional importance of electrical heterogeneity in human β-cell glucose responses, and provides a useful tool for generating testable hypotheses.
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7133184265