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PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

Author

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  • Daniela Nasteska

    (Institute of Metabolism and Systems Research (IMSR), University of Birmingham
    University of Birmingham and University of Nottingham
    Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners)

  • Nicholas H. F. Fine

    (Institute of Metabolism and Systems Research (IMSR), University of Birmingham
    University of Birmingham and University of Nottingham
    Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners)

  • Fiona B. Ashford

    (Institute of Metabolism and Systems Research (IMSR), University of Birmingham
    University of Birmingham and University of Nottingham
    Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners)

  • Federica Cuozzo

    (Institute of Metabolism and Systems Research (IMSR), University of Birmingham
    University of Birmingham and University of Nottingham
    Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners)

  • Katrina Viloria

    (Institute of Metabolism and Systems Research (IMSR), University of Birmingham
    University of Birmingham and University of Nottingham
    Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners)

  • Gabrielle Smith

    (Institute of Metabolism and Systems Research (IMSR), University of Birmingham
    Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners)

  • Aisha Dahir

    (Institute of Metabolism and Systems Research (IMSR), University of Birmingham
    Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners)

  • Peter W. J. Dawson

    (University of Birmingham
    University of Birmingham)

  • Yu-Chiang Lai

    (Institute of Metabolism and Systems Research (IMSR), University of Birmingham
    University of Birmingham
    University of Birmingham)

  • Aimée Bastidas-Ponce

    (Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München
    German Center for Diabetes Research (DZD)
    Institute of Stem Cell Research, Helmholtz Zentrum München
    Technical University of Munich, School of Medicine)

  • Mostafa Bakhti

    (Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München
    German Center for Diabetes Research (DZD)
    Institute of Stem Cell Research, Helmholtz Zentrum München)

  • Guy A. Rutter

    (Imperial College London
    Nanyang Technological University)

  • Remi Fiancette

    (University of Birmingham)

  • Rita Nano

    (San Raffaele Diabetes Research Institute, IRCCS Ospedale
    Vita-Salute San Raffaele University)

  • Lorenzo Piemonti

    (San Raffaele Diabetes Research Institute, IRCCS Ospedale
    Vita-Salute San Raffaele University)

  • Heiko Lickert

    (Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München
    German Center for Diabetes Research (DZD)
    Institute of Stem Cell Research, Helmholtz Zentrum München
    Technical University of Munich, School of Medicine)

  • Qiao Zhou

    (Weill Cornell Medical College)

  • Ildem Akerman

    (Institute of Metabolism and Systems Research (IMSR), University of Birmingham
    Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners)

  • David J. Hodson

    (Institute of Metabolism and Systems Research (IMSR), University of Birmingham
    University of Birmingham and University of Nottingham
    Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners)

Abstract

Transcriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.

Suggested Citation

  • Daniela Nasteska & Nicholas H. F. Fine & Fiona B. Ashford & Federica Cuozzo & Katrina Viloria & Gabrielle Smith & Aisha Dahir & Peter W. J. Dawson & Yu-Chiang Lai & Aimée Bastidas-Ponce & Mostafa Bakh, 2021. "PDX1LOW MAFALOW β-cells contribute to islet function and insulin release," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20632-z
    DOI: 10.1038/s41467-020-20632-z
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    Cited by:

    1. Chien-Wen Chen & Bo-Jhih Guan & Mohammed R. Alzahrani & Zhaofeng Gao & Long Gao & Syrena Bracey & Jing Wu & Cheikh A. Mbow & Raul Jobava & Leena Haataja & Ajay H. Zalavadia & Ashleigh E. Schaffer & Hu, 2022. "Adaptation to chronic ER stress enforces pancreatic β-cell plasticity," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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