Targeting GPCRs Activated by Fatty Acid-Derived Lipids in Type 2 Diabetes

G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, because of their diversity, cell-specific expression, and druggable sites accessible at the cell surface. Preclinical and clinical studies suggest that targeting GPCRs activated by fatty acid-derived lipids may have potential to improve glucose homeostasis and reduce complications in patients with type 2 diabetes (T2D). Despite the discontinued development of fasiglifam (TAK-875), the first FFA1 agonist to reach late-stage clinical trials, lipid-sensing receptors remain a viable target, albeit with a need for further characterization of their binding mode, intracellular signaling, and toxicity. Herein, we analyze general discovery trends, various signaling pathways, as well as possible challenges following activation of GPCRs that have been validated clinically to control blood glucose levels.