Inhibiting or antagonizing glucagon: making progress in diabetes care.
Absolute or relative hyperglucagonaemia has been recognized for years in all experimental or clinical forms of diabetes. It has been suggested that excess secretion of glucagon by the islet α cells is a direct consequence of intra-islet insulin secretory defects. Recent studies have shown that knockout of the glucagon receptor or administration of a monoclonal specific glucagon receptor antibody make insulin-deficient type 1 diabetic rodents thrive without insulin. These observations suggest that glucagon plays an essential role in the pathophysiology of diabetes and that targeting the α cell and glucagon are innovative approaches in the management of diabetes. Despite active research and identification of promising compounds, no one selective glucagon antagonist is presently used in the treatment of diabetes. Interestingly, besides insulin, several drugs used today in the management of diabetes appear to exert their effects, in part, by inhibiting glucagon secretion (glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors and, possibly, sulphonylureas) or glucagon action (metformin). The potential risks associated with total glucagon suppression include α-cell hyperplasia, increased mass of the pancreas, increased susceptibility to hepatosteatosis and hepatocellular injury and increased risk of hypoglycaemia, and these should be considered in the search and development of new compounds reducing glucagon receptor signalling. More than 40 years after its initial description, hyperglucagonaemia in diabetes can no longer be ignored or minimized, and its correction represents an attractive way to improve diabetes management.
Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, University of Liège, Liège, Belgium.
P J
PJ
Lefèbvre
Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, University of Liège, Liège, Belgium.
N
N
Paquot
Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, University of Liège, Liège, Belgium.|Division of Clinical Pharmacology, Department of Medicine, University of Liège, Liège, Belgium.
A J
AJ
Scheen
D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000503:physiopathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use; D005934:Glucagon / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000378:metabolism; D065089:Glycoside Hydrolase Inhibitors / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D010179:Pancreas / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
D054873:Dipeptidyl-Peptidase IV Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D005934:Glucagon; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
diabetes; glucagon