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

Keiichi Katsumoto (), Siham Yennek, Chunguang Chen, Luis Fernando Delgadillo Silva, Sofia Traikov, Dror Sever, Ajuna Azad, Jingdong Shan, Seppo Vainio, Nikolay Ninov, Stephan Speier and Anne Grapin-Botton ()
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Keiichi Katsumoto: Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG)
Siham Yennek: University of Copenhagen
Chunguang Chen: Technische Universität Dresden
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
Stephan Speier: Technische Universität Dresden
Anne Grapin-Botton: Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG)

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33841-5

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