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

  1. Nicolas Damond
  2. Fabrizio Thorel
  3. Julie S Moyers
  4. Maureen J Charron
  5. Patricia M Vuguin
  6. Alvin C Powers
  7. Pedro L Herrera  Is a corresponding author
  1. University of Geneva, Switzerland
  2. Eli Lilly and Company, United States
  3. Albert Einstein College of Medicine, United States
  4. Columbia University, United States
  5. 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.

Article and author information

Author details

  1. Nicolas Damond

    Department of Genetic Medicine, Development of the Faculty of Medicine, Institute of Genetics and Genomics in Geneva, Centre facultaire du diabète, University of Geneva, Geneva, Switzerland
    Competing interests
    No competing interests declared.
  2. Fabrizio Thorel

    Department of Genetic Medicine, Development of the Faculty of Medicine, Institute of Genetics and Genomics in Geneva, Centre facultaire du diabète, University of Geneva, Geneva, Switzerland
    Competing interests
    No competing interests declared.
  3. Julie S Moyers

    Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States
    Competing interests
    Julie S Moyers, J.S.M. is an employee and shareholder of Eli Lilly and Company.
  4. Maureen J Charron

    Departments of Biochemistry, Medicine, and Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    No competing interests declared.
  5. Patricia M Vuguin

    Pediatric Endocrinology, Women's and Childrens Health, College of Physicians & Surgeons, Columbia University, New York, United States
    Competing interests
    No competing interests declared.
  6. Alvin C Powers

    Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Department of Molecular Physiology, Vanderbilt University, Nashville, United States
    Competing interests
    No competing interests declared.
  7. Pedro L Herrera

    Department of Genetic Medicine, Development of the Faculty of Medicine, Institute of Genetics and Genomics in Geneva, Centre facultaire du diabète, University of Geneva, Geneva, Switzerland
    For correspondence
    Pedro.Herrera@unige.ch
    Competing interests
    No competing interests declared.

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).

Reviewing Editor

  1. Guy Rutter

Publication history

  1. Received: December 18, 2015
  2. Accepted: April 7, 2016
  3. Accepted Manuscript published: April 19, 2016 (version 1)
  4. Version of Record published: May 18, 2016 (version 2)

Copyright

© 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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  1. Nicolas Damond
  2. Fabrizio Thorel
  3. Julie S Moyers
  4. Maureen J Charron
  5. Patricia M Vuguin
  6. Alvin C Powers
  7. Pedro L Herrera
(2016)
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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