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Optical tools for understanding the complexity of β-cell signalling and insulin release

Nature Reviews Endocrinology volume 14, pages 721–737 (2018)Cite this article

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Abstract

Following stimulation, pancreatic β-cells must orchestrate a plethora of signalling events to ensure the appropriate release of insulin and maintenance of normal glucose homeostasis. Failure at any point in this cascade leads to impaired insulin secretion, elevated blood levels of glucose and eventually type 2 diabetes mellitus. Likewise, β-cell replacement or regeneration strategies for the treatment of both type 1 and type 2 diabetes mellitus might fail if the correct cell signalling phenotype cannot be faithfully recreated. However, current understanding of β-cell function is complicated because of the highly dynamic nature of their intracellular and intercellular signalling as well as insulin release itself. β-Cells must precisely integrate multiple signals stemming from multiple cues, often with differing intensities, frequencies and cellular and subcellular localizations, before converging these signals onto insulin exocytosis. In this respect, optical approaches with high resolution in space and time are extremely useful for properly deciphering the complexity of β-cell signalling. An increased understanding of β-cell signalling might identify new mechanisms underlying insulin release, with relevance for future drug therapy and de novo stem cell engineering of functional islets.

Key points

  • β-Cells are capable of integrating signals that vary over space and time.

  • The conventional view of β-cells does not fully consider the dynamic nature of β-cell stimulus–secretion coupling and insulin secretion.

  • The mechanisms by which β-cells dynamically integrate multiple signals or cues might be implicated in metabolic disease.

  • Optical approaches possess the necessary spatial and temporal resolution to unravel the complexity of β-cell signalling.

  • Restoring normal β-cell signalling dynamics might allow improved treatment of type 2 diabetes mellitus (T2DM).

  • β-Cell engineering, reprogramming or regeneration studies should consider the normal signalling phenotype to provide optimal type 1 diabetes mellitus and T2DM therapies.

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Fig. 1: β-Cell signalling is dynamic and localized.
Fig. 2: β-Cells receive and integrate multiple signalling inputs.
Fig. 3: β-Cell signalling is shaped by the islet context.
Fig. 4: Methods for optically reporting β-cell signalling and secretion.
Fig. 5: Methods for optical control of β-cell signalling and secretion.
Fig. 6: Schematic of all-optical interrogation of β-cell signalling and secretion.

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Acknowledgements

D.J.H. was supported by a Diabetes UK R. D. Lawrence (12/0004431) Fellowship, a Wellcome Trust Institutional Support Award and Medical Research Council (MR/N00275X/1) and Diabetes UK (17/0005681) Project Grants. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Starting Grant 715884 to D.J.H. and Advanced Grant 268795 to D.T.). C.S. is supported by TRR186 of the German Research Council (DFG). The authors apologize to the many authors whose studies could not be cited owing to space limitations.

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Nature Reviews Endocrinology thanks D. Eizirik and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Author notes

  1. These authors contributed equally: James A. Frank, Johannes Broichhagen.

Authors and Affiliations

  1. Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, USA

    James A. Frank & Dirk Trauner

  2. Department of Chemical Biology, Max Planck Institute for Medical Research, Heidelberg, Germany

    Johannes Broichhagen

  3. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic

    Dmytro A. Yushchenko

  4. Department of Chemistry, New York University, New York, NY, USA

    Dirk Trauner

  5. European Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics Unit, Heidelberg, Germany

    Carsten Schultz

  6. Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR, USA

    Carsten Schultz

  7. Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK

    David J. Hodson

  8. Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK

    David J. Hodson

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Contributions

J.A.F., J.B., D.Y. and D.J.H. researched the data for the article, contributed to discussion of content and reviewed and edited the article before submission. C.S. and D.T. contributed to discussion of content and reviewed and edited the article before submission. D.J.H. wrote the article with input from all the authors.

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Frank, J.A., Broichhagen, J., Yushchenko, D.A. et al. Optical tools for understanding the complexity of β-cell signalling and insulin release. Nat Rev Endocrinol 14, 721–737 (2018). https://doi.org/10.1038/s41574-018-0105-2

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