Glucagon-based therapy: Past, present and future

Diabesity and its related cardio-hepato-renal complications are of absolute concern globally. Last decade has witnessed a growing interest in the scientific community in investigating novel pharmaco-therapies employing the pancreatic hormone, glucagon. Canonically, this polypeptide hormone is known for its use in rescue treatment for hypoglycaemic shocks owing to its involvement in the counter-regulatory feedback mechanism. However, substantial studies in the recent past elucidated the pleiotropic effects of glucagon in diabesity and related complications like non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD). Thus, the dual nature of this peptide has sparked the search for drugs that can modify glucagon signalling to combat hypoglycaemia or diabesity. Thus far, researchers have explored various pharmacological approaches to utilise this peptide in imminent modern therapies. The research endeavours in this segment led to explorations of stable glucagon formulations/analogues, glucagon receptor antagonism, glucagon receptor agonism, and incretin poly-agonism as new strategies for the management of hypoglycaemia or diabesity. This 'three-dimensional' research on glucagon resulted in the discovery of various drug candidates that proficiently modify glucagon signalling. Currently, several emerging glucagon-based therapies are under pre-clinical and clinical development. We sought to summarise the recent progress to comprehend glucagon-mediated pleiotropic effects, provide an overview of drug candidates currently being developed and future perspectives in this research domain.