Type 2 diabetes (T2D) has reached epidemic proportions, and there is an unmet medical need for orally effective agents that regulate glucose homeostasis. GPR119, a class-A (rhodopsin-like) G protein-coupled receptor expressed primarily in the pancreas and gastrointestinal tract, has attracted considerable interest as a T2D drug target in recent years. The activation of GPR119 increases the intracellular accumulation of cAMP, leading to enhanced glucose-dependent insulin secretion from pancreatic β-cells and increased release of the gut peptides GLP-1 (glucagon-like peptide 1), GIP (glucose-dependent insulinotropic peptide) and PYY (polypeptide YY). Oral administration of small molecule GPR119 agonists has been shown to improve glucose tolerance in both rodents and humans. This review summarizes the research leading to the identification of GPR119 as a potential drug target for T2D and related metabolic disorders, and provides an overview of the recent progress made in the discovery of orally active GPR119 agonists.
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