G-protein-coupled receptor GPR40 (also known as Free fatty acid receptor 1(FFAR1)) is a seven trans-membrane domain receptor which is predominantly expressed in pancreatic beta cells. It plays an essential role in fatty acid ampli�cation of glucose induced insulin secretion. GPR40 agonists are in second phase of preclinical trials for treatment of diabetes because of their role in improved glucose control. Binding of free fatty acids to GPR40 initiates a downstream signaling cascade which involves activation of a transducer protein “guanine nucleotide-binding protein subunit alpha-11� (GNA11). Next phospholipase c (PLC) hormone is activated which hydrolyzes membrane phospholipids (such as phosphatidylinositol-4-5-biphosphate) into second messenger molecules inositol-1-4-5-trophosphate (IP3) and Diacylglycerol (DAG). IP3 initiates calcium efflux from endoplasmic reticulum and increase intracellular calcium concentration. Increased intracellular calcium concentration is involved in activating the insulin exocytosis machinery. DAG on the other hand activates PKD1. PKD1 initiates F-actin remodeling and supports second phase of insulin exocytosis. a5f cb2 a5f cb2 a5f cb2 a5f cb2 a5f cb2 a5f cb2 a5f cb2 a5f cb2 a5f cb2 G protein mediated signaling pathway PW:0000125 Pathway Ontology signaling pathway PW:0000003 Pathway Ontology insulin secretion pathway PW:0000674 Pathway Ontology 24051395 PubMed Modulating GPR40: therapeutic promise and potential in diabetes 2013 Poitout V Lin DC 23631851 PubMed The fatty acid receptor FFA1/GPR40 a decade later: how much do we know? Mancini AD1, Poitout V. 2013 Mancini AD Poitout V