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  • Review Article
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Impact of islet architecture on β-cell heterogeneity, plasticity and function

Key Points

  • Phenotypic and functional β-cell heterogeneity arise during β-cell development in utero; however, such heterogeneity is also acquired during the postnatal period owing to cell maturation, ageing and plasticity

  • Islet composition, cell polarity, cell-to-cell adhesion and cell-to-matrix adhesion all contribute to β-cell heterogeneity, as does the interaction of endocrine cells with vessels, nerves and the microenvironment

  • Plasticity allows islet cells to adapt to physiological changes, such as pregnancy; this process might also be triggered by pathological insults, such as prolonged exposure to hyperglycaemia

  • Heterogeneous subpopulations of β cells can be recognized by the expression of specific markers, including insulin, PDX1, E-Cadherin, Flattop, PSA-NCAM, DKK3, ST8SIA1 and CD9

  • Flattop is a novel Wnt/PCP effector that can discriminate between proliferative and mature β cells

  • Targeting specific β-cell subpopulations could advance efforts to induce therapeutic regeneration of endogenous islet cells among individuals with diabetes mellitus

Abstract

Although β-cell heterogeneity was discovered more than 50 years ago, the underlying principles have been explored only during the past decade. Islet-cell heterogeneity arises during pancreatic development and might reflect the existence of distinct populations of progenitor cells and the developmental pathways of endocrine cells. Heterogeneity can also be acquired in the postnatal period owing to β-cell plasticity or changes in islet architecture. Furthermore, β-cell neogenesis, replication and dedifferentiation represent alternative sources of β-cell heterogeneity. In addition to a physiological role, β-cell heterogeneity influences the development of diabetes mellitus and its response to treatment. Identifying phenotypic and functional markers to discriminate distinct β-cell subpopulations and the mechanisms underpinning their regulation is warranted to advance current knowledge of β-cell function and to design novel regenerative strategies that target subpopulations of β cells. In this context, the Wnt/planar cell polarity (PCP) effector molecule Flattop can distinguish two unique β-cell subpopulations with specific transcriptional signatures, functional properties and differential responses to environmental stimuli. In vivo targeting of these β-cell subpopulations might, therefore, represent an alternative strategy for the future treatment of diabetes mellitus.

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Figure 1: A 3D model of functional β-cell heterogeneity.

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Acknowledgements

A.M. is sponsored by the Helmholtz Postdoctoral Fellowship Program. The authors' research is funded by an Emmy-Noether Fellowship; the European Union (grant agreement No. 602587); the Helmholtz Alliance 'Imaging and Curing Environmental Metabolic Diseases'; the Helmholtz Association; the Helmholtz Society; the Helmholtz Portfolio Theme 'Metabolic Dysfunction and Common Disease'; the German Research Foundation; and the German Center for Diabetes Research. The authors thank A. Bortolon from Science Vision for the islet graphic and E. Bader (Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Germany) for carefully reading the manuscript.

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S.S.R. researched the data for the article. S.S.R and H.L. provided a substantial contribution to discussions of the content. S.S.R., A.M. and M.G. wrote the article. S.S.R., A.M., M.G. and H.L. contributed equally to review and/or editing of the manuscript before submission.

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Correspondence to Heiko Lickert.

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Roscioni, S., Migliorini, A., Gegg, M. et al. Impact of islet architecture on β-cell heterogeneity, plasticity and function. Nat Rev Endocrinol 12, 695–709 (2016). https://doi.org/10.1038/nrendo.2016.147

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