Inhibiting or antagonizing glucagon: making progress in diabetes care

Abstract

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.

Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies

“…a-Cell hyperplasia has been raised as a potential concern with pharmacologic antagonism of glucagon action (28). Mice with homozygous disruption of the glucagon receptor gene develop dramatic elevations in plasma glucagon levels (.1,000-fold), hyperplasia of a-cells (29), and even neuroendocrine tumors (30).…”

Unraveling the Regulation of Hepatic Metabolism by Insulin

“…However, antagonism of glucagon action in liver failed to prevent the ability of insulin to suppress HGP during hyperinsulinemic-euglycemic clamps in mice also lacking hepatic insulin signaling, indicating that peripheral actions of insulin to regulate HGP are independent of acute changes of liver glucagon signaling [37], consistent with older studies that show the extra-hepatic action of insulin suppresses HGP regardless of portal concentrations of glucagon [69]. Although insulin controls HGP independent of acute changes in glucagon, several clinical studies have demonstrated reductions in blood glucose levels with glucagon receptor antagonists [70]…”

Genetic Basis of Monogenic Diabetes

“…A few recent studies have shown the efficacy of GLP-1 receptor (GLP-1R) agonists 57,58 and dipeptidyl peptidase-IV (DPP IV) inhibitors in these patients. It is possible that these two drugs are efficacious in the treatment of patients with PAX4 mutations, through their action on glucagon inhibition 59 .…”