Blockade of glucagon signaling prevents or reverses diabetes onset only if residual β-cells persist

Glucagon secretion dysregulation in diabetes fosters hyperglycemia. Recent studies report that mice lacking glucagon receptor (Gcgt(-/-)) do not develop diabetes following streptozotocin (STZ)-mediated ablation of insulin-producing beta-cells. Here, we show that diabetes prevention in STZ-treated Gcgt(-/-) animals requires remnant insulin action originating from spared residual beta-cells: these mice indeed became hyperglycemic after insulin receptor blockade. Accordingly, Gcgt(-/-) mice developed hyperglycemia after induction of a more complete, diphtheria toxin (DT)-induced beta-cell loss, a situation of near-absolute insulin deficiency similar to type 1 diabetes. In addition, glucagon deficiency did not impair the natural capacity of alpha-cells to reprogram into insulin production after extreme beta-cell loss. beta-to-beta-cell conversion was improved in Gcgt(-/-) mice as a consequence of alpha-cell hyperplasia. Collectively, these results indicate that glucagon antagonism could i) be a useful adjuvant therapy in diabetes only when residual insulin action persists, and ii) help devising future beta-cell regeneration therapies relying upon a -cell reprogramming.