Glucagon receptor modulation: Its role in diabetes care

Abstract

Abstract The metabolic changes attributable to diabetes are due to both deficiency of insulin as well as excess glucagon (GC). The glucagon receptor (GCGR) is a G protein-coupled receptor. GC is predominantly found in the liver. GC exerts its action both at the GCGR and the glucagon-like peptide receptor (GLP1R). Knockout studies as well as human mutation analysis have indicated therapeutic potential as well as concerns of modulation of the GCGR as a potential target for diabetes therapies. Three approaches to GCGR antagonism—small molecules, monoclonal antibodies, and antisense oligonucleotides—have demonstrated an impressive reduction in HbA1C in preclinical and clinical studies. However, adverse events such as an increase in weight cholesterol liver enzymes and alpha cell hyperplasia have stalled further clinical development. On the other hand, balancing the hyperglycemic effect of glucagon and retaining their beneficial effects, especially with weight loss and decrease in weight loss and hepatic steatosis by use of unimolecular coagonists with GLP1 and GIP have shown considerable promise in clinical trials.