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

Abstract
Article and author information
Metrics

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

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.
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.
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.
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.
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.
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.
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).

Copyright

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.