@Article{IPB-2574, author = {Abbas, G. and Haq, Q. M. I. and Hamaed, A. and Al-Sibani, M. and Hussain, H.}, title = {{Glucagon and Glucagon-like Peptide-1 Receptors: Promising Therapeutic Targets for an Effective Management of Diabetes Mellitus}}, year = {2020}, pages = {501-508}, journal = {Curr Pharm Des}, doi = {10.2174/1381612826666200131143231}, url = {https://dx.doi.org/10.2174/1381612826666200131143231}, volume = {26}, abstract = {G-protein-coupled receptors (GPCRs) are membrane-bound proteins which are responsible for the detection of extracellular stimuli and the origination of intracellular responses. Both glucagon and glucagon-like peptide-1 (GLP-1) receptors belong to G protein-coupled receptor (GPCR) superfamily. Along with insulin, glucagon and GLP-1 are critical hormones for maintaining normal serum glucose within human body. Glucagon generally plays its role in the liver through cyclic adenosine monophosphate (cAMP), where it compensates the action of insulin. GLP-1 is secreted by the L-cells of the small intestine to stimulate insulin secretion and inhibit glucagon action. Despite the extensive research efforts and the multiple approaches adopted, the glycemic control in the case of type-2 diabetes mellitus remains a major challenge. Therefore, a deep understanding of the structure-function relationship of these receptors will have great implications on future therapies in order to maintain a normal glucose level for an extended period of time. The antagonists of glucagon receptor that can effectively block the hepatic glucose production, as a result of glucagon action, are highly desirable for the tuning of the hyperglycemic state in type 2 diabetes mellitus. In the same manner, GLP-1R agonists act as important treatment modalities thanks to their multiple anti-diabetic actions to attain normal glucose level. In this review article, the structural diversity of glucagon and GLP-1 receptors along with their signaling pathways, site-directed mutations and significance in drug discovery against type-2 diabetes will be illustrated. Moreover, the promising non-peptide antagonists of glucagon receptor and agonists of GLP-1 receptor, for the management of diabetes will be presented with elaboration on the structure-activity relationship (SAR).} }