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

eLife

Julie S Moyers¹  Alvin C Powers¹  Fabrizio Thorel²  Patricia M Vuguin²  Nicolas Damond³  Maureen J Charron³  Pedro L Herrera⁴ 

[1] Centre facultaire du diabète, University of Geneva, Geneva, Switzerland;Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland;Department of Genetic Medicine and Development of the Faculty of Medicine, University of Geneva, Geneva, Switzerland;Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States;

关键词: glucagon;    glucagon receptor;    insulin;    type 1 diabetes;    hyperglycemia;    glucose homeostasis;   

DOI  :  10.7554/eLife.13828

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown