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Exploring pancreatic beta-cell subgroups and their connectivity

Nature Metabolism volume 6, pages 2039–2053 (2024)Cite this article

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A Publisher Correction to this article was published on 23 October 2024

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Abstract

Functional pancreatic islet beta cells are essential to ensure glucose homeostasis across species from zebrafish to humans. These cells show significant heterogeneity, and emerging studies have revealed that connectivity across a hierarchical network is required for normal insulin release. Here, we discuss current thinking and areas of debate around intra-islet connectivity, cellular hierarchies and potential “controlling” beta-cell populations. We focus on methodologies, including comparisons of different cell preparations as well as in vitro and in vivo approaches to imaging and controlling the activity of human and rodent islet preparations. We also discuss the analytical approaches that can be applied to live-cell data to identify and study critical subgroups of cells with a disproportionate role in control Ca2+ dynamics and thus insulin secretion (such as “first responders”, “leaders” and “hubs”, as defined by Ca2+ responses to glucose stimulation). Possible mechanisms by which this hierarchy is achieved, its physiological relevance and how its loss may contribute to islet failure in diabetes mellitus are also considered. A glossary of terms and links to computational resources are provided.

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Fig. 1: In vitro and in vivo systems used to study beta-cell heterogeneity.
Fig. 2: Beta-cell heterogeneity revealed with cellular markers or scRNA-seq.
Fig. 3: Optical perturbation of beta-cell function.
Fig. 4: Functional examination of beta-cell subpopulations and connectivity.

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Acknowledgements

G.A.R. is supported by a Wellcome Trust Investigator award (212625/Z/18/Z); UKRI-Medical Research Council (MRC) Programme grant (MR/R022259/1), National Institutes of Health (NIH) NIH-NIDDK project grants (R01DK135268 and 1R01DK139630-01A1), a CIHR-JDRF Team grant (CIHR-IRSC TDP-186358 and JDRF 4-SRA-2023-1182-S-N), CRCHUM start-up funds and an Innovation Canada John R. Evans Leader Award (CFI 42649). L.D.S. is the recipient of a CIHR post-doctoral fellowship (#489982, CIHR-IRSC:0745000255). R.K.P.B. is supported by NIH grants R01DK102950, R01DK10641, an American Diabetes Association grant (11-22-ICTSPM-02) and JDRF grant 3-SRA-2023-1365-S-B.

We acknowledge J.K. Briggs (University of Colorado) and F. Yong (Imperial College London), who provided scripts for analysis of cell heterogeneity (Table 3). and L. Satin (University of Michigan), S. Millership (Imperial College London), A. Pospisilik (Van Andel Institute) and J. Hughes (University of Washington) for useful discussion.

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  1. CHUM Research Center and Faculty of Medicine, University of Montréal, Montréal, QC, Canada

    Guy A. Rutter & Luis Delgadillo Silva

  2. Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK

    Guy A. Rutter

  3. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

    Guy A. Rutter

  4. Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Anne Gresch & Richard K. P. Benninger

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Rutter, G.A., Gresch, A., Delgadillo Silva, L. et al. Exploring pancreatic beta-cell subgroups and their connectivity. Nat Metab 6, 2039–2053 (2024). https://doi.org/10.1038/s42255-024-01097-6

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