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

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 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.DOI: http://dx.doi.org/10.7554/eLife.13828.001

A first‐in‐human pharmacodynamic and pharmacokinetic study of a fully human anti‐glucagon receptor monoclonal antibody in normal healthy volunteers

“…Studies in glucagon receptor knockout mice rendered insulin deficient by streptozotocin have firmly demonstrated the metabolic benefits of absence of glucagon action without insulin administration . In addition, we have shown in mice with near absence of insulin receptor signaling that REGN1193 treatment is able to lower glucose to near normal ranges .…”

“…Studies in glucagon receptor knockout mice rendered insulin deficient by streptozotocin have firmly demonstrated the metabolic benefits of absence of glucagon action without insulin administration. [18][19][20] In addition, we have shown in mice with near absence of insulin receptor signaling that REGN1193 treatment is able to lower glucose to near normal ranges. 21 Thus, patients with insulin receptor loss of function mutations, manifested as severe insulin resistance and diabetes, ie, Rabson-Mendenhall syndrome and other related diseases, may benefit from anti-glucagon receptor therapy.…”

Hypoglycemic Effect of Combined Ghrelin and Glucagon Receptor Blockade

“…In particular, genetic deletion of insulin (49) or the use of diphtheria toxin to induce near complete ablation of β-cells (50) in Gcgr −/− mice nonetheless induced full-blown diabetes. Thus, it has been suggested that a retained low level of insulin, as occurs in the STZ type 1 diabetes model, may be permissive for the blood glucose–lowering effect observed with GcgR antagonism.…”

Glucagon receptor signalling – backwards and forwards

“…However, in the case of complete lack of insulin (e.g. induction of complete loss of β-cells and deletion of the insulin gene), these effects are less prominent, suggesting that some residual β-cell function is critical to maintaining the metabolic phenotype of GCGr knockout mice [10,11]. Notably, deletion of the GCGr gene or blockade of GCGr signalling is accompanied by marked changes in other metabolic regulators, including GLP-1, which complicate elucidation of the mechanisms that contribute to glucose lowering [12].…”