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

ABSTRACT: Total or near-total loss of insulin-producing ?-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 ?-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-?-cells; specifically, glucagon-producing ?-cells begin producing insulin by a process of reprogramming (transdifferentiation) without proliferation. Here we show the influence of age on ?-cell reconstitution from heterologous islet cells after near-total ?-cell loss in mice. We found that senescence does not alter ?-cell plasticity: ?-cells can reprogram to produce insulin from puberty through to adulthood, and also in aged individuals, even a long time after ?-cell loss. In contrast, before puberty there is no detectable ?-cell conversion, although ?-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 ?-cells. The juveniles display 'somatostatin-to-insulin' ?-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-?-cell origins is thus enabled throughout life via ?- or ?-cell spontaneous reprogramming. A landscape with multiple intra-islet cell interconversion events is emerging, offering new perspectives for therapy.

SUBMITTER: Chera S 

PROVIDER: S-EPMC4209186 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature