Diabetes Recovery By Age-Dependent Conversion of Pancreatic δ-Cells Into Insulin Producers

Total or near-total loss of insulin-producing β-cells is a situation found in diabetes (Type 1, T1D) (1,2). Restoration of insulin production in T1D 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 absence of autoimmunity (3). 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 (3). Here we studied the influence of age on β-cell reconstitution from heterologous islet cells after near-total β-cell loss. We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through adulthood, and also in aged individuals, even a long-time after β-cell loss. In contrast, prior to puberty there is no detectable α-cell conversion, although β-cell reconstitution after injury is more efficient, always leading to diabetes recovery; it occurs through a newly discovered mechanism: the spontaneous en masse reprogramming of somatostatin-producing δ-cells. The younglings display “somatostatin-to-insulin” δ-cell conversion, involving de-differentiation, proliferation and re-expression of islet developmental regulators. This juvenile adaptability relies, at least in part, upon 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, thus offering new perspectives.