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Nature. 2014 Oct 23;514(7523):503-7. doi: 10.1038/nature13633. Epub 2014 Aug 20.

Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers.

Author information

1
Department of Genetic Medicine &Development, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, 1211 Geneva-4, Switzerland.
2
Novo Nordisk A/S, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark.
3
Cell and Developmental Biology, Vanderbilt University Medical Center, 465 21st Av. South, Nashville, Tennessee 37232, USA.
4
Cambridge Institute for Medical Research, Hills Road, Cambridge CB2 0XY, UK.

Abstract

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.

PMID:
25141178
PMCID:
PMC4209186
DOI:
10.1038/nature13633
[Indexed for MEDLINE]
Free PMC Article

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