GPR40 role in insulin secretion (Homo sapiens)

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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 amplification 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. This hydrolyzes membrane phospholipids such as phosphatidylinositol-4-5-biphosphate into second messenger molecules inositol-1-4-5-triphosphate (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 the second phase of insulin exocytosis.