en
Scientific article
Letter
Open access
English

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

Published inNature, vol. 514, no. 7523, p. 503-507
Publication date2014
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.

Keywords
  • Aging/physiology
  • Animals
  • Cell Dedifferentiation
  • Cell Proliferation
  • Cell Transdifferentiation
  • Diabetes Mellitus, Experimental/pathology/therapy
  • Diabetes Mellitus, Type 1/pathology/therapy
  • Forkhead Transcription Factors/metabolism
  • Glucagon-Secreting Cells/cytology/secretion
  • Humans
  • Insulin/biosynthesis/secretion
  • Insulin-Secreting Cells/cytology/secretion
  • Mice
  • Regeneration
  • Sexual Maturation
  • Somatostatin/biosynthesis/secretion
  • Somatostatin-Secreting Cells/cytology/secretion
Citation (ISO format)
CHERA, Simona et al. Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers. In: Nature, 2014, vol. 514, n° 7523, p. 503–507. doi: 10.1038/nature13633
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Article (Published version)
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Identifiers
ISSN of the journal0028-0836
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