Blockade of glucagon signaling prevents or reverses diabetes onset only if residual β-cells persist
- University of Geneva, Switzerland
- Eli Lilly and Company, United States
- Albert Einstein College of Medicine, United States
- Columbia University, United States
- Vanderbilt University, United States
Abstract
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 ncy did not impair the natural capacity 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.
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Ethics
Animal experimentation: All mice were housed and treated in accordance with the guidelines and regulations of the Direction Générale de la Santé, state of Geneva (license number GE/103/14).
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© 2016, Damond et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Blockade of glucagon signaling prevents or reverses diabetes onset only if residual β-cells persist
eLife 5:e13828.
https://doi.org/10.7554/eLife.13828
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