The glucagon-like peptide-1 (GLP-1) receptor is one of the best validated therapeutic targets for the treatment of type 2 diabetes\nmellitus (T2DM). Over several years, the accumulation of basic, translational, and clinical research helped define the physiologic\nroles of GLP-1 and its receptor in regulating glucose homeostasis and energy metabolism. These efforts provided much of the\nfoundation for pharmaceutical development of the GLP-1 receptor peptide agonists, exenatide and liraglutide, as novel medicines\nfor patients suffering from T2DM. Now, much attention is focused on better understanding the molecular mechanisms involved\nin ligand induced signaling of the GLP-1 receptor. For example, advancements in biophysical and structural biology techniques\nare being applied in attempts to more precisely determine ligand binding and receptor occupancy characteristics at the atomic\nlevel. These efforts should better inform three-dimensional modeling of the GLP-1 receptor that will help inspire more rational\napproaches to identify and optimize small molecule agonists or allosteric modulators targeting the GLP-1 receptor. This article\nreviews GLP-1 receptor physiology with an emphasis on GLP-1 induced signaling mechanisms in order to highlight new molecular\nstrategies that help determine desired pharmacologic characteristics for guiding development of future nonpeptide GLP-1 receptor\nactivators.
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