Iron deficiency induces maturation-dependent loss of pancreatic β-cells
Pancreatic β-cells maintain glucose homeostasis by secreting insulin in response to rising blood glucose, a process fueled by mitochondrial ATP production. Iron, a core cofactor in the electron transport chain, is essential for this metabolic coupling. While the cytotoxic effects of iron overload are well known, the role of iron sufficiency during β-cell development remains unclear. Here, we identify a maturation-dependent requirement for iron in mouse and human β-cells. Using chemical chelation and genetic disruption of transferrin receptor (TFRC)-mediated uptake, we show that immature β-cells depend on iron during metabolic transition to functional maturity. Iron restriction at this stage impairs oxidative metabolism and compromises survival. In contrast, mature β-cells remain resilient to iron depletion, revealing a developmental switch in iron dependency. These findings establish iron as a key metabolic cue in β-cell development and suggest strategies to generate fully functional stem cell-derived β-cells for diabetes modeling and cell replacement therapy.
Authors
- Ann Massie (ORCID: https://orcid.org/0000-0002-8418-5879)
- MIRIAM CNOP
- Chiara Vinci (ORCID: https://orcid.org/0000-0002-5730-9186)
- Annelore Van Mulders (ORCID: https://orcid.org/0000-0002-7889-6893)
- Françoise Carlotti (ORCID: https://orcid.org/0000-0001-7929-8468)
- Willem Staels (ORCID: https://orcid.org/0000-0001-8259-3329)
- Nico De Leu (ORCID: https://orcid.org/0000-0002-0542-5708)
- Stephanie Bourgeois (ORCID: https://orcid.org/0000-0003-3494-0108)
- Yves Heremans (ORCID: https://orcid.org/0000-0002-2608-974X)
- Bart Ghesquière (ORCID: https://orcid.org/0000-0002-9247-0821)
- Sophie Coenen (ORCID: https://orcid.org/0000-0002-0491-4059)
- Laure Degroote (ORCID: https://orcid.org/0000-0001-7310-6103)
- Julie Pierreux (ORCID: https://orcid.org/0000-0003-3292-6214)
- Lien Willems (ORCID: https://orcid.org/0000-0002-5226-664X)
- Thomas Rolf Mandrup-Poulsen
- Gamze Ates
- Xiaoyan Yi
- Gunter Leuckx
- Clara Zelinsky
- Raphael Scharfmann
- Eelco de Koning
- Toshiaki Sawatani
- Steven Goderis
- Yue Tong
Institutions
- University of Copenhagen (DK)
- Centre National de la Recherche Scientifique (FR)
- Université Libre de Bruxelles (BE)
- Vrije Universiteit Brussel (BE)
- Inserm (FR)
- Leiden University Medical Center (NL)
- Erasmus Hospital (BE)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Institut Cochin (FR)
- Walloon Excellence in Lifesciences and Biotechnology (BE)
- Flanders Environment Agency (BE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-02-16
- DOI
- https://doi.org/10.1038/s41467-026-69574-y
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 0.00