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  • br Conflicts of interest br Funding This work


    Conflicts of interest
    Funding This work was supported by the National Natural Science Foundation of China (No.81670558; 81800542), and the Science & Technology Development Fund of Tianjin Education Commission for Higher Education (No.2017KJ221).
    Introduction Free fatty acids (FFAs) are an essential energy source, especially during starvation, exercise, and pregnancy, and they are also important modulators of various physiological responses. For pancreatic β-cells, FFAs are required for both basal and glucose-stimulated insulin secretion (GSIS).2, 3, 4 The insulinotropic effect of FFAs depends on the chain length and the degree of saturation; the less saturated long-chain FFAs have a greater effect. However, chronically elevated plasma FFA concentrations, which are closely associated with obesity and type 2 PHA-848125 australia (T2DM), may lead to insulin resistance in the skeletal muscle and liver and pancreatic β-cell dysfunction and apoptosis.1, 6, 7 The effects of FFAs on insulin secretion are traditionally believed to be related to the malonyl-CoA/long-chain acyl-CoA signaling network and glucose-responsive triglyceride/FFA cycling. However, the deorphanization of G protein-coupled receptor 40 (GPR40) suggests the existence of a different mechanism. Activation of GPR40 in the presence of glucose increases cytosolic Ca concentrations mainly through Gq/11–phospholipase C (PLC) pathway and eventually amplifies GSIS. Therefore, GPR40 has become an attractive therapeutic target for T2DM, and numerous ligands of GPR40 have been developed. GPR40, which is also known as FFA receptor 1 (FFAR1 or FFA1), was identified as an orphan receptor in the search for novel human galanin receptor (GALR) subtypes in 1997. Using reverse pharmacology approaches measuring calcium transients, GPR40 were deorphanized and characterized as being activated by saturated and unsaturated medium- and long-chain fatty acids at physiologically relevant concentrations.9, 11 It was independently deorphanized using high-throughput reporter screening assay by a third group. Of the saturated FFAs, pentadecanoic (C15) and palmitic (C16) acids are the most potent, whereas for the unsaturated FFAs, there is no major effect in chain length and/or degree of saturation on binding affinity or potency. GPR40 is a promiscuous receptor that can be activated by several endogenous ligands, different from most of the typical GPCRs that are activated by one or a few endogenous ligands. In the primary sequence, GPR40 is highly related to other receptors within the same family, exhibiting high homology with GPR41 (FFAR3) and GPR43 (FFAR2),10, 14 whereas it has little homology with GPR119 and GPR120 (FFAR4).
    Molecular Cloning and Tissue Distribution of GPR40
    Physiology of GPR40
    Pharmacology of GPR40
    Pathophysiology of GPR40 Up to now, human genomic studies have identified three nucleotide substitutions in GPR40 that result in coding variations, including one polymorphism, R211H, and two mutations, D175N and G180S (Fig. 3.2). In 2005, Hamid et al. studied the potential relationship between human GPR40 gene variation and insulin resistance in T2DM patients. Using direct sequencing in Danish Caucasian subjects, they identified two single nucleotide substitutions in GPR40 that result in R211H polymorphism located in the third intracellular loop and D175N mutation located in the second extracellular loop. The D175N mutation was found in heterozygous form in both normal glucose tolerance subjects and T2DM patients. Further sequence analysis of the family members of one T2DM patient harboring the D175N mutation found three more members carrying the heterozygous mutation and observed no cosegregation of this mutation with T2DM. The R211H polymorphism, detected in both T2DM patients and control subjects with a similar frequency (24%), was found to not associate with changes in insulin secretion or pancreatic β-cell function. Functional studies by measuring inositol phosphate turnover showed that R211H GPR40 has similar signaling properties (EC50 and maximal response) as the wild-type receptor, whereas D175N mutant has decreased maximal signaling in response to eicosatriynoic acid by 39%, although the EC50 is similar to wild-type receptor. No data on the expression and ligand binding properties of these receptors were reported.