Dual role for glucagon-producing α-cells in diabetes: contribution to disease progression and to restoration of insulin production

In type 1 diabetes massive loss of insulin-producing β-cells results in a severely impaired glycemic control. Here, we study glucagon-producing α-cells, which present a double interest in this context. First, glucagon secretion is exacerbated in diabetes, which worsens hyperglycemia. Second, a fraction of α-cells reprogram toward insulin production after massive β-cell loss, thus contributing to β-cell regeneration. Recent studies suggest that mice do not develop diabetes after β-cell loss if glucagon signaling is interrupted. On the contrary, we show that when β-cell loss is near complete, glucagon signaling blockade does not prevent diabetes. Maintenance of normoglycemia in previous models depends on the action of insulin secreted by residual β-cells escaping ablation. We also investigate the role of the chromatin-modifying enzymes DNMT1 and Ezh2 in α-to-β-cell conversion. Finally, we implement methods to study human islet cell plasticity, which we use to show that human α-cells can become insulin producers. Altogether, these results offer new insights into the role of α-cells and glucagon in diabetes