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

Total or near-total loss of insulin-producing beta-cells occurs in type 1 diabetes(1,2). Restoration of insulin production in type 1 diabetes is thus a major medical challenge. We previously observed in mice in which beta-cells are completely ablated that the pancreas reconstitutes new insulin-producing cells in the absence of autoimmunity(3). The process involves the contribution of islet non-beta-cells; specifically, glucagon-producing alpha-cells begin producing insulin by a process of reprogramming (transdifferentiation) without proliferation(3). Here we show the influence of age on beta-cell reconstitution from heterologous islet cells after near-total beta-cell loss in mice. We found that senescence does not alter alpha-cell plasticity: alpha-cells can reprogram to produce insulin from puberty through to adulthood, and also in aged individuals, even a long time after beta-cell loss. In contrast, before puberty there is no detectable alpha-cell conversion, although beta-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 delta-cells. The juveniles display somatostatin-to-insulin delta-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-beta-cell origins is thus enabled throughout life via delta- or alpha-cell spontaneous reprogramming. A landscape with multiple intra-islet cell interconversion events is emerging, offering new perspectives for therapy.