Blockade of glucagon signaling prevents or reverses diabetes onset only if residual β-cells persist.
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.
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.
Nicolas
0000-0003-3027-8989
N
Damond
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
F
Thorel
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States.
Julie S
JS
Moyers
Departments of Biochemistry, Medicine, and Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, United States.
Maureen J
MJ
Charron
Pediatric Endocrinology, Women's and Childrens Health, College of Physicians & Surgeons, Columbia University, New York, United States.
Patricia M
PM
Vuguin
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.
Alvin C
AC
Powers
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.
Pedro L
0000-0003-0771-9504
PL
Herrera
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D005765:Gastrointestinal Agents / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018027:Receptors, Glucagon / Q000172:deficiency; D015398:Signal Transduction
D005765:Gastrointestinal Agents; D007328:Insulin; D018027:Receptors, Glucagon; D005934:Glucagon
glucagon; glucagon receptor; glucose homeostasis; human biology; hyperglycemia; insulin; medicine; mouse; type 1 diabetes