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Wnt4 is heterogeneously activated in maturing β-cells to control calcium signaling, metabolism and function

Author

Listed:
  • Keiichi Katsumoto

    (Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG)
    University of Copenhagen)

  • Siham Yennek

    (University of Copenhagen)

  • Chunguang Chen

    (Technische Universität Dresden
    Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München
    German Center for Diabetes Research)

  • Luis Fernando Delgadillo Silva

    (Center for Regenerative Therapies (CRTD))

  • Sofia Traikov

    (Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG))

  • Dror Sever

    (University of Copenhagen)

  • Ajuna Azad

    (University of Copenhagen)

  • Jingdong Shan

    (University of Oulu)

  • Seppo Vainio

    (University of Oulu)

  • Nikolay Ninov

    (Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München
    Center for Regenerative Therapies (CRTD))

  • Stephan Speier

    (Technische Universität Dresden
    Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München
    German Center for Diabetes Research)

  • Anne Grapin-Botton

    (Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG)
    University of Copenhagen
    Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München)

Abstract

Diabetes is a multifactorial disorder characterized by loss or dysfunction of pancreatic β-cells. β-cells are heterogeneous, exhibiting different glucose sensing, insulin secretion and gene expression. They communicate with other endocrine cell types via paracrine signals and between β-cells via gap junctions. Here, we identify the importance of signaling between β-cells via the extracellular signal WNT4. We show heterogeneity in Wnt4 expression, most strikingly in the postnatal maturation period, Wnt4-positive cells, being more mature while Wnt4-negative cells are more proliferative. Knock-out in adult β-cells shows that WNT4 controls the activation of calcium signaling in response to a glucose challenge, as well as metabolic pathways converging to lower ATP/ADP ratios, thereby reducing insulin secretion. These results reveal that paracrine signaling between β-cells is important in addition to gap junctions in controling insulin secretion. Together with previous reports of WNT4 up-regulation in obesity our observations suggest an adaptive insulin response coordinating β-cells.

Suggested Citation

  • Keiichi Katsumoto & Siham Yennek & Chunguang Chen & Luis Fernando Delgadillo Silva & Sofia Traikov & Dror Sever & Ajuna Azad & Jingdong Shan & Seppo Vainio & Nikolay Ninov & Stephan Speier & Anne Grap, 2022. "Wnt4 is heterogeneously activated in maturing β-cells to control calcium signaling, metabolism and function," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33841-5
    DOI: 10.1038/s41467-022-33841-5
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    1. Craig Dorrell & Jonathan Schug & Pamela S. Canaday & Holger A. Russ & Branden D. Tarlow & Maria T. Grompe & Tamara Horton & Matthias Hebrok & Philip R. Streeter & Klaus H. Kaestner & Markus Grompe, 2016. "Human islets contain four distinct subtypes of β cells," Nature Communications, Nature, vol. 7(1), pages 1-9, September.
    2. Eiji Yoshihara & Carolyn O’Connor & Emanuel Gasser & Zong Wei & Tae Gyu Oh & Tiffany W. Tseng & Dan Wang & Fritz Cayabyab & Yang Dai & Ruth T. Yu & Christopher Liddle & Annette R. Atkins & Michael Dow, 2020. "Immune-evasive human islet-like organoids ameliorate diabetes," Nature, Nature, vol. 586(7830), pages 606-611, October.
    3. Sumeet Pal Singh & Sharan Janjuha & Theresa Hartmann & Özge Kayisoglu & Judith Konantz & Sarah Birke & Priyanka Murawala & Ezzaldin Ahmed Alfar & Kei Murata & Anne Eugster & Naoki Tsuji & Edward R. Mo, 2017. "Different developmental histories of beta-cells generate functional and proliferative heterogeneity during islet growth," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
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    1. Laura M. Mueller & Abigail Isaacson & Heather Wilson & Anna Salowka & Isabel Tay & Maolian Gong & Nancy Samir Elbarbary & Klemens Raile & Francesca M. Spagnoli, 2024. "Heterozygous missense variant in GLI2 impairs human endocrine pancreas development," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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