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The physiological role of β-cell heterogeneity in pancreatic islet function

Abstract

Endocrine cells within the pancreatic islets of Langerhans are heterogeneous in terms of transcriptional profile, protein expression and the regulation of hormone release. Even though this heterogeneity has long been appreciated, only within the past 5 years have detailed molecular analyses led to an improved understanding of its basis. Although we are beginning to recognize why some subpopulations of endocrine cells are phenotypically different to others, arguably the most important consideration is how this heterogeneity affects the regulation of hormone release to control the homeostasis of glucose and other energy-rich nutrients. The focus of this Review is the description of how endocrine cell heterogeneity (and principally that of insulin-secreting β-cells) affects the regulation of hormone secretion within the islets of Langerhans. This discussion includes an overview of the functional characteristics of the different islet cell subpopulations and describes how they can communicate to influence islet function under basal and glucose-stimulated conditions. We further discuss how changes to the specific islet cell subpopulations or their numbers might underlie islet dysfunction in type 2 diabetes mellitus. We conclude with a discussion of several key open questions regarding the physiological role of islet cell heterogeneity.

Key points

  • Pancreatic β-cells are heterogeneous in terms of function (the regulation of insulin secretion) and their transcriptional profile.

  • Functionally distinct subpopulations of β-cells can be identified by genetic and cell surface markers or based upon functional analyses by optogenetics and Ca2+ dynamics.

  • Cell–cell communication allows functional subpopulations of β-cells to influence the regulation of insulin secretion across the rest of the islet.

  • Under basal conditions, both excitable insulin secretory β-cells and suppressive inexcitable β-cells can be observed.

  • Under glucose-stimulated conditions, a number of highly functional subpopulations of β-cells can be observed that influence the coordinated dynamics of islet [Ca2+] and insulin secretion.

  • Changes in islet cell heterogeneity, loss of functional subpopulations or disruption to the communication between functional subpopulations may all underlie islet dysfunction in diabetes mellitus.

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Fig. 1: Heterogeneity in insulin secretion by β-cells.
Fig. 2: β-Cell intrinsic and extrinsic mechanisms affecting glucose-stimulated insulin release.
Fig. 3: β-Cell subpopulations suppress electrical activity and basal insulin release in other β-cells across the islet.
Fig. 4: Dynamics underlying different β-cell subpopulations within the islet.

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Acknowledgements

The authors would like to thank Lori Sussel (University of Colorado Anschutz Medical campus) for providing constructive feedback in preparing this Review. R.K.P.B. acknowledges funding from National Institute of Health (NIH) grants R01 DK102950, R01 DK106412 and JDRF grant 1-INO-2019-783-S-B. V.K. acknowledges funding from JDRF grant 3-PDF-2019-741-A-N, a Human islet research network emerging leader award and a Burroughs Wellcome Fund Career Award at the Scientific Interface.

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Benninger, R.K.P., Kravets, V. The physiological role of β-cell heterogeneity in pancreatic islet function. Nat Rev Endocrinol 18, 9–22 (2022). https://doi.org/10.1038/s41574-021-00568-0

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