
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

39229244
10.1101/2024.08.21.608680
preprint
3
Article
Glucokinase activity controls subpopulations of β-cells that alternately lead islet Ca 2+ oscillations
Jin Erli http://orcid.org/0009-0002-9410-9738

Briggs Jennifer K. http://orcid.org/0000-0002-8737-2215

Benninger Richard K.P. http://orcid.org/0000-0002-5063-6096

Merrins Matthew J. http://orcid.org/0000-0003-1599-9227

04 9 2024
2024.08.21.608680https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.21.608680
nihpp-2024.08.21.608680.pdf
Abstract

Oscillations in insulin secretion, driven by islet Ca 2+ waves, are crucial for glycemic control. Prior studies, performed with single-plane imaging, suggest that subpopulations of electrically coupled β-cells have privileged roles in leading and coordinating the propagation of Ca 2+ waves. Here, we used 3D light-sheet imaging to analyze the location and Ca 2+ activity of single β-cells within the entire islet at >2 Hz. In contrast with single-plane studies, 3D network analysis indicates that the most highly synchronized β-cells are located at the islet center, and remain regionally but not cellularly stable between oscillations. This subpopulation, which includes ‘hub cells’, is insensitive to changes in fuel metabolism induced by glucokinase and pyruvate kinase activation. β-cells that initiate the Ca 2+ wave (‘leaders’) are located at the islet periphery, and strikingly, change their identity over time via rotations in the wave axis. Glucokinase activation, which increased oscillation period, reinforced leader cells and stabilized the wave axis. Pyruvate kinase activation, despite increasing oscillation frequency, had no effect on leader cells, indicating the wave origin is patterned by fuel input. These findings emphasize the stochastic nature of the β-cell subpopulations that control Ca 2+ oscillations and identify a role for glucokinase in spatially patterning ‘leader’ β-cells.

Highlights

Studies of islet Ca 2+ oscillations by 3D light-sheet imaging provide a more complete picture of β-cell subpopulations than prior 2D studies.

Highly synchronized β-cells (including ‘hub cells’) are a regionally-stable subpopulation located at the islet center that is insensitive to metabolic perturbation.

Glucokinase activation patterns the Ca 2+ wave axis, which originates from stochastic β-cell subpopulations on the islet periphery that change between oscillations.

The stochasticity of ‘leader’ β-cells, and the stability of ‘hubs’, is geographically consistent with the peripheral location of α/δ-cells in mouse islets.
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