However the GPR R H polymorphism

However, the GPR40 R211H polymorphism was reported to affect the variation of insulin secretory capacity in other ethnic groups. The allele frequency of H211 in Japanese was 78.4%.102, 103 By comparing clinical and metabolic parameters among Japanese men, Ogawa et al. found that histidine homozygotes have significantly higher serum insulin levels, homeostasis model of insulin resistance, and pancreatic β-cell function than arginine homozygotes do. Therefore, the authors suggested that genetic variation of GPR40 might alter the insulin secretory capacity. Another GPR40 mutation, G180S located in TM5, was identified in heterozygous form in the Sicilian population in Italy. The frequency of G180S is 0.75%, which, interestingly, increases with the severity of obesity. Subjects carrying GPR40 G180S mutation have significantly decreased insulin secretion than those carrying wild-type GPR40 during oral glucose tolerance test. Functional studies showed that G180S mutants have similar expression levels (both total and cell surface) as the wild-type receptor but diminished increase of intracellular Ca concentrations in response to oleic acid. Whether this defect is due to ligand binding or G protein coupling/activation is not clear. Binding experiments were not performed.
Conclusions GPCRs are versatile signaling molecules regulating almost all physiological processes, including Okadaic acid homeostasis and glucose homeostasis.105, 106 They also prove to be important therapeutic targets. Drugs targeting GPCRs account for 30% of current pharmaceutical sales. GPR40 is a member of family A GPCRs. Since the deorphanization of GPR40 in 2003, various functions of GPR40 have been identified and characterized, including insulin secretion, incretin secretion, glucagon secretion, immune inflammation, bone density, neurogenesis, pain control, taste preference, and cell proliferation. Tremendous progress has been made on the development of GPR40 agonists in the treatment of T2DM, and most importantly, one of these ligands, TAK-875, has been successfully tried in phase II clinical trials. However, our understanding of some functions of GPR40 and the underlying mechanisms are still controversial and incomplete. Further studies are warranted to address these questions.
Acknowledgments
Fibrosis is characterized by the excessive accumulation of extracellular matrix in damaged or inflamed tissues, and it is the common pathological outcome of many inflammatory and metabolic diseases. Numerous clinical conditions can lead to organ fibrosis and functional failure; in many disorders, acute or persistent inflammation is crucial to trigger the fibrotic response. The production of various profibrotic cytokines and growth factors by innate inflammatory cells results in the recruitment and activation of extracellular matrix–producing myofibroblasts. There is currently a great need for therapies that could effectively target pathophysiological pathways involved in fibrosis. Free fatty acids (FFAs) are essential nutrients that exert various biological effects and have been implicated in many diseases, playing protective or harmful roles depending on the context. Besides their effects on intracellular metabolism and nuclear receptors, studies in the past 15 years have shown that FFAs can activate several cell surface G protein–coupled receptors, including FFA receptor 1 (GPR40) and GPR84. GPR40 and GPR84 show distinct characteristics in both fatty acid binding and biological effects. GPR40 is activated by both medium-chain FFAs (eg, decanoic acid) and long-chain FFAs (eg, linoleic acid), and is coupled to G or G proteins. GPR84 is responsive to medium-chain FFAs only and activates almost exclusively pertussis toxin–sensitive G signaling pathways. In addition, GPR40 and GPR84 exhibit distinct tissue distribution profiles. GPR40 is abundantly expressed in pancreatic β cells, where it enhances glucose-mediated insulin secretion. Accordingly, several GPR40 agonists have advanced to clinical trials for type 2 diabetes. However, the actions of GPR40 may not be limited to insulin secretion. GPR40 is also expressed in enteroendocrine cells of the gastrointestinal tract and may mediate release of glucagon-like peptide-1 and cholecystokinin secretion., In addition, GPR40 is expressed in murine skin and may serve to limit and attenuate inflammation. Recent studies have also involved GPR40 in regulation of pain perception and sensing taste of fatty acids. Finally, GPR40 has been shown to be expressed in the rat kidney and in a subset of murine kidney tubules, including the cortical collecting duct. Moreover, in human renal proximal tubule epithelial HK-2 cells, activation of GPR40 with the synthetic agonist GW9508 reduced cisplatin-induced apoptosis.