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

Damond N, Thorel F, Moyers JS, Charron MJ, Vuguin PM, Powers AC, Herrera PL
Elife. 2016 5

PMID: 27092792 · PMCID: PMC4871705 · DOI:10.7554/eLife.13828

Glucagon secretion dysregulation in diabetes fosters hyperglycemia. Recent studies report that mice lacking glucagon receptor (Gcgr(-/-)) do not develop diabetes following streptozotocin (STZ)-mediated ablation of insulin-producing β-cells. Here, we show that diabetes prevention in STZ-treated Gcgr(-/-) animals requires remnant insulin action originating from spared residual β-cells: these mice indeed became hyperglycemic after insulin receptor blockade. Accordingly, Gcgr(-/-) mice developed hyperglycemia after induction of a more complete, diphtheria toxin (DT)-induced β-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 α-cells to reprogram into insulin production after extreme β-cell loss. α-to-β-cell conversion was improved in Gcgr(-/-) mice as a consequence of α-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 β-cell regeneration therapies relying upon α-cell reprogramming.

MeSH Terms (10)

Animals Diabetes Mellitus, Experimental Gastrointestinal Agents Glucagon Insulin Insulin-Secreting Cells Mice Mice, Knockout Receptors, Glucagon Signal Transduction

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