University of Oulu

Katsumoto, K., Yennek, S., Chen, C. et al. Wnt4 is heterogeneously activated in maturing β-cells to control calcium signaling, metabolism and function. Nat Commun 13, 6255 (2022).

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

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Author: Katsumoto, Keiichi1,2; Yennek, Siham2; Chen, Chunguang3,4,5;
Organizations: 1Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Dresden, Germany
2Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, Denmark
3Institute of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
4Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany
5German Center for Diabetes Research, München-Neuherberg, Germany
6Center for Regenerative Therapies (CRTD), TU Dresden, Germany
7Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 4.2 MB)
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Language: English
Published: Springer Nature, 2022
Publish Date: 2023-06-22


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.

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Series: Nature communications
ISSN: 2041-1723
ISSN-E: 2041-1723
ISSN-L: 2041-1723
Volume: 13
Issue: 1
Article number: 6255
DOI: 10.1038/s41467-022-33841-5
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
1182 Biochemistry, cell and molecular biology
Funding: This work was supported by Novo Nordisk Foundation Nordic Endocrinology grant numbers 10715-442 and NNF15OC0016168. The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) is supported by Novo Nordisk Foundation grant number NNF17CC0027852. Work in the Ninov group was supported by grants from the Deutsche Forschungsgemeinschaft (grants: NI 1495/5- 1; NI 1495/4-1; NI 1495/2-3; NI 1495/2-1 and JU 3081/4-1), the International Research Training Group (IRTG 2251): ‘Immunological and Cellular Strategies in Metabolic Disease’ [project number 288034826 – IRTG 2251 (N.N.)], the Deutsches Zentrum für Diabetesforschung and core funding from TU Dresden. Open Access funding enabled and organized by Projekt DEAL.
Dataset Reference: Transcriptome data are available at Geo under accession numbers: GSE210237 (P1 GFP+ vs GFP− samples) and GSE210267 (conditional inducible knock-out of Wnt4 in β-cells). Mass spectrometry data are available at MetaboLights under accession number: MTBLS6012. Source data are provided with this paper.
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