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Title

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

Authors
Jensen, Jan N
Gu, Guoqiang
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Published in Nature. 2014, vol. 514, no. 7523, p. 503-7
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/physiologyAnimalsCell DedifferentiationCell ProliferationCell TransdifferentiationDiabetes Mellitus, Experimental/pathology/therapyDiabetes Mellitus, Type 1/pathology/therapyForkhead Transcription Factors/metabolismGlucagon-Secreting Cells/cytology/secretionHumansInsulin/biosynthesis/secretionInsulin-Secreting Cells/cytology/secretionMiceRegenerationSexual MaturationSomatostatin/biosynthesis/secretionSomatostatin-Secreting Cells/cytology/secretion
Identifiers
PMID: 25141178
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Structures
Research group Types cellulaires pancréatiques pendant l'ontogénèse (522)
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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. 503-7. https://archive-ouverte.unige.ch/unige:55456

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Deposited on : 2015-04-13

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