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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 the human body. Glucagon
generally plays its role in the liver through cyclic adenosine monophosphate (cAMP), where it compensates for
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 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 for future therapies in order to
maintain a normal glucose level for an extended period of time. The antagonists of glucagon receptors 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 levels.
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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 are illustrated. Moreover,
the promising non-peptide antagonists of glucagon receptor and agonists of GLP-1 receptor, for the management
of diabetes are presented with elaboration on the structure-activity relationship (SAR).
G protein-coupled receptor 119 agonist DS-8500a effects on pancreatic β-cells in Japanese type 2 diabetes mellitus patients