Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers
Open accessAbstract
Total or near-total loss of insulin-producing β-cells occurs in type 1 diabetes. Restoration of insulin production in type 1 diabetes is thus a major medical challenge. We previously observed in mice in which β-cells are completely ablated that the pancreas reconstitutes new insulin-producing cells in the absence of autoimmunity. The process involves the contribution of islet non-β-cells; specifically, glucagon-producing α-cells begin producing insulin by a process of reprogramming (transdifferentiation) without proliferation. Here we show the influence of age on β-cell reconstitution from heterologous islet cells after near-total β-cell loss in mice. We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through to adulthood, and also in aged individuals, even a long time after β-cell loss. In contrast, before puberty there is no detectable α-cell conversion, although β-cell reconstitution after injury is more efficient, always leading to diabetes recovery. This process occurs through a newly discovered mechanism: the spontaneous en masse reprogramming of somatostatin-producing δ-cells. The juveniles display 'somatostatin-to-insulin' δ-cell conversion, involving dedifferentiation, proliferation and re-expression of islet developmental regulators. This juvenile adaptability relies, at least in part, upon the combined action of FoxO1 and downstream effectors. Restoration of insulin producing-cells from non-β-cell origins is thus enabled throughout life via δ- or α-cell spontaneous reprogramming. A landscape with multiple intra-islet cell interconversion events is emerging, offering new perspectives for therapy.
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Reprogramming of differentiated cells into progenitor-like cells is an important injury-repair paradigm independent of adult stem cells in various epithelial tissues in mammals.
“The reprogramming of differentiated cells into progenitor-like cells has recently been discovered as an important injury-repair paradigm independent of adult stem cells in a variety of epithelial tissues in mammals, 1 such as the lung, 2 intestine, 3 pancreas, 4 and liver.5,6”
From Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers (2023) · cites this paper as [4]
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- Authors
- Chera, S., Baronnier, D., Ghila, L., Cigliola, V., Jensen, J. N., Gu, G., Furuyama, K., Thorel, F., Gribble, F. M., Reimann, F., & Herrera, P. L.
- Affiliations
- University of Geneva (CH)
- Novo Nordisk (Denmark) (DK)
- Vanderbilt University Medical Center (US)
- University of Cambridge (GB)
- Corresponding author
- Herrera, Pedro L.
- ORCID
- Venue
- Nature
- Published
- 2014-08-20
- Volume
- 514
- Issue
- 7523
- Pages
- 503-507
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4209186
- OpenAlex
- W2081490620
- Cited by
- 410
- References
- 3
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 32 · 2023: 40 · 2022: 30 · 2021: 46 · 2020: 37 · 2019: 31 · 2018: 47 · 2017: 38 · 2016: 42 · 2015: 36 · 2014: 5 · 2013: 1
- FWCI
- 40.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- National Science Foundation
- Wellcome Trust (WT088357Z/09/Z, 088357, WT084210Z/07/Z)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (NRP 63)
- National Institutes of Health (WT084210/Z/07/Z, WT088357/Z/09/Z)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK072522, R01DK065949, U01DK089566)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- type 1 diabetes, pancreatic delta cells, alpha cells, transdifferentiation, beta cell regeneration, age-dependent plasticity, dedifferentiation, FOXO1, pancreatic islets, beta-cell ablation, puberty, senescence, insulin-producing cells
- MeSH terms
- Forkhead Box Protein O1, Insulin Secretion, Aging, Animals, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Humans, Insulin, Regeneration, Sexual Maturation, Somatostatin, Somatostatin-Secreting Cells, Cell Proliferation, Glucagon-Secreting Cells, Insulin-Secreting Cells, Mice, Forkhead Transcription Factors, Cell Dedifferentiation, Cell Transdifferentiation
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