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Elife. 2016 Apr 19;5. pii: e13828. doi: 10.7554/eLife.13828.

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

Author information

1
Department of Genetic Medicine and Development of the Faculty of Medicine, University of Geneva, Geneva, Switzerland.
2
Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland.
3
Centre facultaire du diabète, University of Geneva, Geneva, Switzerland.
4
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States.
5
Departments of Biochemistry, Medicine, and Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, United States.
6
Pediatric Endocrinology, Women's and Childrens Health, College of Physicians & Surgeons, Columbia University, New York, United States.
7
Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Department of Molecular Physiology, Vanderbilt University, Nashville, United States.
8
VA Tennessee Valley Healthcare System, Nashville, 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 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.

KEYWORDS:

glucagon; glucagon receptor; glucose homeostasis; human biology; hyperglycemia; insulin; medicine; mouse; type 1 diabetes

PMID:
27092792
PMCID:
PMC4871705
DOI:
10.7554/eLife.13828
[Indexed for MEDLINE]
Free PMC Article

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