Pancreatic insulin-producing β-cells have a long lifespan, such that in healthy conditions they replicate little during a lifetime. Nevertheless, they show increased self-duplication after increased metabolic demand or after injury (that is, β-cell loss). It is not known whether adult mammals can differentiate (regenerate) new β-cells after extreme, total β-cell loss, as in diabetes. This would indicate differentiation from precursors or another heterologous (non-β-cell) source. Here we show β-cell regeneration in a transgenic model of diphtheria-toxin-induced acute selective near-total β-cell ablation. If given insulin, the mice survived and showed β-cell mass augmentation with time. Lineage-tracing to label the glucagon-producing α-cells before β-cell ablation tracked large fractions of regenerated β-cells as deriving from α-cells, revealing a previously disregarded degree of pancreatic cell plasticity. Such inter-endocrine spontaneous adult cell conversion could be harnessed towards methods of producing β-cells for diabetes therapies, either in differentiation settings in vitro or in induced regeneration.

An investigation of the influence of age on the generation of insulin-producing cells after β-cell loss in mice reveals that, whereas α-cells can reprogram to produce insulin from puberty to adulthood, efficient reconstitution in the very young is through δ-cell reprogramming, leading to complete diabetes recovery. It has been shown previously that adult mouse pancreas can regenerate new insulin-producing cells after their near-total ablation, through a process in which glucagon-producing α-cells become insulin producers, and there is evidence to suggest that such reprogramming also occurs in humans. This study reports an age-dependent switch between two mechanisms of regeneration of insulin production following β-cell loss in mice: a robust and efficient regeneration during youth, involving de-differentiation and proliferation of δ-cells, and a less efficient process of α-cell conversion that begins post-puberty and persists throughout life. The authors suggest that these phenomena may be translatable to humans and that the existence of alternatives modes of insulin production holds promise for therapeutic developments. Total or near-total loss of insulin-producing β-cells occurs in type 1 diabetes1,2. 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 autoimmunity3. 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 proliferation3. 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.