Department of Genetic Medicine and Development of the Faculty of Medicine, University of Geneva, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland; Centre facultaire du diabète, University of Geneva, Geneva, Switzerland
Fabrizio Thorel
Department of Genetic Medicine and Development of the Faculty of Medicine, University of Geneva, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland; Centre facultaire du diabète, University of Geneva, Geneva, Switzerland
Julie S Moyers
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States
Maureen J Charron
Departments of Biochemistry, Medicine, and Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, United States
Patricia M Vuguin
Pediatric Endocrinology, Women's and Childrens Health, College of Physicians & Surgeons, Columbia University, New York, United States
Alvin C Powers
Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Department of Molecular Physiology, Vanderbilt University, Nashville, United States; VA Tennessee Valley Healthcare System, Nashville, United States
Department of Genetic Medicine and Development of the Faculty of Medicine, University of Geneva, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland; Centre facultaire du diabète, University of Geneva, Geneva, Switzerland
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.
