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  • Opinion
  • Published:

G protein-coupled receptors as targets for anti-diabetic therapeutics

Nature Reviews Drug Discovery volume 15, pages 161–172 (2016)Cite this article

Subjects

This article has been updated

Key Points

  • G protein-coupled receptors (GPCRs) can affect insulin action, insulin secretion and β-cell expansion, and certain GPCRs have emerged as potential drug targets for the development of anti-diabetic therapeutics.

  • Decreased insulin sensitivity is a major metabolic defect in the great majority of individualswith type 2 diabetes (T2D), and one of the key mechanisms underlying insulin resistance is chronic tissue inflammation.

  • Leukotriene B4 (LTB4) receptor 1 (LTB4R1) inhibitors may be anti-diabetic insulin sensitizers, as they inhibit inflammation and directly block the capacity of LTB4 to impair cellular insulin signalling in hepatocytes and myocytes.

  • The long-chain fatty acid receptors, free fatty acid receptor 1 (FFAR1, also known as GPR40) and FFAR4 (also known as GPR120), mediate beneficial effects by promoting glucose-induced insulin secretion or by inhibiting inflammatory signalling in immune cells, respectively.

  • The stimulation of β-cell glucose-dependent insulinotropic receptor (GPR119) leads directly to an increase in insulin secretion, and agonism of GPR119 on enteroendocrine cells promotes both glucagon-like peptide 1 (GLP1) and gastric inhibitory polypeptide (GIP) release. Therefore, GPR119 could be an important anti-diabetic drug target to promote insulin secretion.

  • Administration of exogenous CX3C-chemokine ligand 1 (CX3CL1, also known as fractalkine) to mice strikingly improves glucose tolerance and enhances β-cell insulin secretion. CX3CL1 and its receptor, CX3CR1, could be new targets used to positively influence β-cell function, and CX3CL1-based reagents might be future therapeutic approaches to anti-diabetes therapy.

Abstract

The prevalence of obesity and type 2 diabetes (T2D) is increasing worldwide, and these two metabolic disorders are closely linked. Lifestyle modification, including weight loss and exercise, are effective treatments for T2D, but, unfortunately, most patients are unsuccessful at maintaining durable weight reduction and recidivism is all too common. Therefore, safe and efficacious drugs are required for the successful treatment of T2D in a large proportion of patients. Targeting G protein-coupled receptors (GPCRs) in metabolic tissues — such as adipose tissue, liver, muscle, pancreatic islets, immune cells and the central nervous system — has emerged as a key target for current and future anti-diabetic compounds. This Opinion focuses on the potential of GPCRs as targets for the discovery of new drugs to successfully treat T2D.

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Figure 1: Pathophysiology, obesity and type 2 diabetes.
Figure 2: Leukotriene B4 system.
Figure 3: Stimulation of free fatty acid receptor 4 signalling pathways produces anti-inflammatory, insulin-sensitizing effects.
Figure 4: G protein-coupled receptor-dependent signalling pathways regulate insulin release from pancreatic β-cells.

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Change history

  • 17 February 2016

    In the original article, α-linolenic acid was incorrectly written. The error has been corrected in the print and online versions of the article.

References

  1. Kahn, S. E., Hull, R. L. & Utzschneider, K. M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846 (2006).

    CAS  PubMed  Google Scholar 

  2. Olefsky, J. M. & Courtney, C. H. in Textook of Endocrinology 5th edn (eds De Groot, J.& Jameson, J. L.) 1093–1117 (W. B. Saunders and Company, 2005).

  3. Stumvoll, M., Goldstein, B. J. & van Haeften, T. W. Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365, 1333–1346 (2005).

    CAS  PubMed  Google Scholar 

  4. Barnes, A. S. The epidemic of obesity and diabetes: trends and treatments. Tex. Heart Inst. J. 38, 142–144 (2011).

    PubMed  PubMed Central  Google Scholar 

  5. Cerf, M. E. Beta cell dysfunction and insulin resistance. Front. Endocrinol. (Lausanne) 4, 37 (2013).

    Google Scholar 

  6. Nolan, C. J. & Prentki, M. The islet β-cell: fuel responsive and vulnerable. Trends Endocrinol. Metab. 19, 285–291 (2008).

    CAS  PubMed  Google Scholar 

  7. Prentki, M. & Nolan, C. J. Islet β cell failure in type 2 diabetes. J. Clin. Invest. 116, 1802–1812 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bornfeldt, K. E. & Tabas, I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 14, 575–585 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Imai, Y., Dobrian, A. D., Morris, M. A. & Nadler, J. L. Islet inflammation: a unifying target for diabetes treatment? Trends Endocrinol. Metab. 24, 351–360 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Johnson, A. M. & Olefsky, J. M. The origins and drivers of insulin resistance. Cell 152, 673–684 (2013).

    CAS  PubMed  Google Scholar 

  11. Robertson, R. P. β-cell deterioration during diabetes: what's in the gun? Trends Endocrinol. Metab. 20, 388–393 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Saltiel, A. R. Insulin resistance in the defense against obesity. Cell Metab. 15, 798–804 (2012).

    CAS  PubMed  Google Scholar 

  13. Samuel, V. T. & Shulman, G. I. Mechanisms for insulin resistance: common threads and missing links. Cell 148, 852–871 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Gether, U. Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endocr. Rev. 21, 90–113 (2000).

    CAS  PubMed  Google Scholar 

  15. Katritch, V., Cherezov, V. & Stevens, R. C. Structure-function of the G protein-coupled receptor superfamily. Annu. Rev. Pharmacol. Toxicol. 53, 531–556 (2013).

    CAS  PubMed  Google Scholar 

  16. Kobilka, B. K. G protein coupled receptor structure and activation. Biochim. Biophys. Acta 1768, 794–807 (2007).

    CAS  PubMed  Google Scholar 

  17. Claing, A., Laporte, S. A., Caron, M. G. & Lefkowitz, R. J. Endocytosis of G protein-coupled receptors: roles of G protein-coupled receptor kinases and beta-arrestin proteins. Prog. Neurobiol. 66, 61–79 (2002).

    CAS  PubMed  Google Scholar 

  18. Hall, R. A. & Lefkowitz, R. J. Regulation of G protein-coupled receptor signaling by scaffold proteins. Circ. Res. 91, 672–680 (2002).

    CAS  PubMed  Google Scholar 

  19. Pierce, K. L. et al. Epidermal growth factor (EGF) receptor-dependent ERK activation by G protein-coupled receptors: a co-culture system for identifying intermediates upstream and downstream of heparin-binding EGF shedding. J. Biol. Chem. 276, 23155–23160 (2001).

    CAS  PubMed  Google Scholar 

  20. Zhang, J. et al. Molecular mechanisms of G protein-coupled receptor signaling: role of G protein-coupled receptor kinases and arrestins in receptor desensitization and resensitization. Recept. Channels 5, 193–199 (1997).

    CAS  PubMed  Google Scholar 

  21. Ahren, B. Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes. Nat. Rev. Drug Discov. 8, 369–385 (2009).

    CAS  PubMed  Google Scholar 

  22. Berger, M. et al. Gαi/o-coupled receptor signaling restricts pancreatic β-cell expansion. Proc. Natl Acad. Sci. USA 112, 2888–2893 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Kim, H. et al. Serotonin regulates pancreatic β-cell mass during pregnancy. Nat. Med. 16, 804–808 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. McArdle, M. A., Finucane, O. M., Connaughton, R. M., McMorrow, A. M. & Roche, H. M. Mechanisms of obesity-induced inflammation and insulin resistance: insights into the emerging role of nutritional strategies. Front. Endocrinol. (Lausanne) 4, 52 (2013).

    Google Scholar 

  25. Shoelson, S. E., Lee, J. & Goldfine, A. B. Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Chawla, A., Nguyen, K. D. & Goh, Y. P. Macrophage-mediated inflammation in metabolic disease. Nat. Rev. Immunol. 11, 738–749 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Li, P. et al. Functional heterogeneity of CD11c-positive adipose tissue macrophages in diet-induced obese mice. J. Biol. Chem. 285, 15333–15345 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Lumeng, C. N., Bodzin, J. L. & Saltiel, A. R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Olefsky, J. M. & Glass, C. K. Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010).

    CAS  PubMed  Google Scholar 

  32. Talukdar, S. et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat. Med. 18, 1407–1412 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Winer, D. A. et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat. Med. 17, 610–617 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Gerner, R. R., Wieser, V., Moschen, A. R. & Tilg, H. Metabolic inflammation: role of cytokines in the crosstalk between adipose tissue and liver. Can. J. Physiol. Pharmacol. 91, 867–872 (2013).

    CAS  PubMed  Google Scholar 

  35. Wieser, V., Moschen, A. R. & Tilg, H. Inflammation, cytokines and insulin resistance: a clinical perspective. Arch. Immunol. Ther. Exp. (Warsz) 61, 119–125 (2013).

    CAS  Google Scholar 

  36. Folco, G. & Murphy, R. C. Eicosanoid transcellular biosynthesis: from cell–cell interactions to in vivo tissue responses. Pharmacol. Rev. 58, 375–388 (2006).

    CAS  PubMed  Google Scholar 

  37. Samuelsson, B. & Funk, C. D. Enzymes involved in the biosynthesis of leukotriene B4 . J. Biol. Chem. 264, 19469–19472 (1989).

    CAS  PubMed  Google Scholar 

  38. Dixon, R. A. et al. Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature 343, 282–284 (1990).

    CAS  PubMed  Google Scholar 

  39. Peters-Golden, M. & Henderson, W. R. Jr. Leukotrienes. N. Engl. J. Med. 357, 1841–1854 (2007).

    CAS  PubMed  Google Scholar 

  40. Radmark, O. & Samuelsson, B. 5-lipoxygenase: mechanisms of regulation. J. Lipid Res. 50, S40–S45 (2009).

    PubMed  PubMed Central  Google Scholar 

  41. Afonso, P. V. et al. LTB4 is a signal-relay molecule during neutrophil chemotaxis. Dev. Cell 22, 1079–1091 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kavelaars, A. et al. Increased acute inflammation, leukotriene B4-induced chemotaxis, and signaling in mice deficient for G protein-coupled receptor kinase 6. J. Immunol. 171, 6128–6134 (2003).

    CAS  PubMed  Google Scholar 

  43. Rankin, J. A., Sylvester, I., Smith, S., Yoshimura, T. & Leonard, E. J. Macrophages cultured in vitro release leukotriene B4 and neutrophil attractant/activation protein (interleukin 8) sequentially in response to stimulation with lipopolysaccharide and zymosan. J. Clin. Invest. 86, 1556–1564 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Tian, W. et al. Blocking macrophage leukotriene B4 prevents endothelial injury and reverses pulmonary hypertension. Sci. Transl. Med. 5, 200ra117 (2013).

    PubMed  PubMed Central  Google Scholar 

  45. Tong, W. G. et al. Leukotriene B4 receptor antagonist LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Clin. Cancer Res. 8, 3232–3242 (2002).

    CAS  PubMed  Google Scholar 

  46. Yokomizo, T., Izumi, T., Chang, K., Takuwa, Y. & Shimizu, T. A. G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 387, 620–624 (1997).

    CAS  PubMed  Google Scholar 

  47. Yokomizo, T., Kato, K., Terawaki, K., Izumi, T. & Shimizu, T. A second leukotriene B4 receptor, BLT2: a new therapeutic target in inflammation and immunological disorders. J. Exp. Med. 192, 421–432 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Hill, A. T., Bayley, D. & Stockley, R. A. The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am. J. Respir. Crit. Care Med. 160, 893–898 (1999).

    CAS  PubMed  Google Scholar 

  49. Montuschi, P., Kharitonov, S. A., Ciabattoni, G. & Barnes, P. J. Exhaled leukotrienes and prostaglandins in COPD. Thorax 58, 585–588 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Chen, M. et al. Neutrophil-derived leukotriene B4 is required for inflammatory arthritis. J. Exp. Med. 203, 837–842 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Xu, S., Lu, H., Lin, J., Chen, Z. & Jiang, D. Regulation of TNFα and IL1β in rheumatoid arthritis synovial fibroblasts by leukotriene B4. Rheumatol. Int. 30, 1183–1189 (2010).

    CAS  PubMed  Google Scholar 

  52. Beeh, K. M. et al. Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4 . Chest 123, 1240–1247 (2003).

    CAS  PubMed  Google Scholar 

  53. Crooks, S. W., Bayley, D. L., Hill, S. L. & Stockley, R. A. Bronchial inflammation in acute bacterial exacerbations of chronic bronchitis: the role of leukotriene B4. Eur. Respir. J. 15, 274–280 (2000).

    CAS  PubMed  Google Scholar 

  54. Hicks, A., Monkarsh, S. P., Hoffman, A. F. & Goodnow, R. Jr. Leukotriene B4 receptor antagonists as therapeutics for inflammatory disease: preclinical and clinical developments. Expert Opin. Investig. Drugs 16, 1909–1920 (2007).

    CAS  PubMed  Google Scholar 

  55. Nancey, S. et al. Blockade of LTB4 /BLT1 pathway improves CD8+ T-cell-mediated colitis. Inflamm. Bowel Dis. 17, 279–288 (2011).

    PubMed  Google Scholar 

  56. Showell, H. J., Breslow, R., Conklyn, M. J., Hingorani, G. P. & Koch, K. Characterization of the pharmacological profile of the potent LTB4 antagonist CP-105,696 on murine LTB4 receptors in vitro. Br. J. Pharmacol. 117, 1127–1132 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Gronke, L. et al. Effect of the oral leukotriene B4 receptor antagonist LTB019 on inflammatory sputum markers in patients with chronic obstructive pulmonary disease. Pulm. Pharmacol. Ther. 21, 409–417 (2008).

    CAS  PubMed  Google Scholar 

  58. Spite, M. et al. Deficiency of the leukotriene B4 receptor, BLT-1, protects against systemic insulin resistance in diet-induced obesity. J. Immunol. 187, 1942–1949 (2011).

    CAS  PubMed  Google Scholar 

  59. Li, P. et al. LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes. Nat. Med. 21, 239–247 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. González- Périz, A. et al. Obesity-induced insulin resistance and hepatic steatosis are alleviated by ω-3 fatty acids: a role for resolvins and protectins. Faseb J. 23, 1946–1957 (2009).

    Google Scholar 

  61. Proudman, S. M., Cleland, L. G. & James, M. J. Dietary omega-3 fats for treatment of inflammatory joint disease: efficacy and utility. Rheum. Dis. Clin. North Am. 34, 469–479 (2008).

    PubMed  Google Scholar 

  62. Sijben, J. W. & Calder, P. C. Differential immunomodulation with long-chain n-3 PUFA in health and chronic disease. Proc. Nutr. Soc. 66, 237–259 (2007).

    CAS  PubMed  Google Scholar 

  63. Calder, P. C. Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? Br. J. Clin. Pharmacol. 75, 645–662 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Sorensen, L. S. et al. Rapid incorporation of ω-3 fatty acids into colonic tissue after oral supplementation in patients with colorectal cancer: a randomized, placebo-controlled intervention trial. J. Parenter. Enteral Nutr. 38, 617–624 (2013).

    Google Scholar 

  65. Sorensen, L. S. et al. Randomized clinical trial of perioperative omega-3 fatty acid supplements in elective colorectal cancer surgery. Br. J. Surg. 101, 33–42 (2014).

    CAS  PubMed  Google Scholar 

  66. Yates, C. M., Calder, P. C. & Ed Rainger, G. Pharmacology and therapeutics of omega-3 polyunsaturated fatty acids in chronic inflammatory disease. Pharmacol. Ther. 141, 272–282 (2014).

    CAS  PubMed  Google Scholar 

  67. Yusof, H. M. et al. Limited impact of 2 g/day omega-3 fatty acid ethyl esters (Omacor®) on plasma lipids and inflammatory markers in patients awaiting carotid endarterectomy. Mar. Drugs 11, 3569–3581 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Cintra, D. E. et al. Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity. PLoS ONE 7, e30571 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Oh, D. Y. et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142, 687–698 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Williams-Bey, Y. et al. Omega-3 free fatty acids suppress macrophage inflammasome activation by inhibiting NF-κB activation and enhancing autophagy. PLoS ONE 9, e97957 (2014).

    PubMed  PubMed Central  Google Scholar 

  71. Yan, Y. et al. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity 38, 1154–1163 (2013).

    CAS  PubMed  Google Scholar 

  72. Hirasawa, A. et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat. Med. 11, 90–94 (2005).

    CAS  PubMed  Google Scholar 

  73. Gotoh, C. et al. The regulation of adipogenesis through GPR120. Biochem. Biophys. Res. Commun. 354, 591–597 (2007).

    CAS  PubMed  Google Scholar 

  74. Christiansen, E. et al. Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases. Br. J. Nutr. 113, 1677–1688 (2015).

    CAS  PubMed  Google Scholar 

  75. Burns, R. N. & Moniri, N. H. Agonism with the omega-3 fatty acids α-linolenic acid and docosahexaenoic acid mediates phosphorylation of both the short and long isoforms of the human GPR120 receptor. Biochem. Biophys. Res. Commun. 396, 1030–1035 (2010).

    CAS  PubMed  Google Scholar 

  76. Hudson, B. D. et al. The pharmacology of TUG-891, a potent and selective agonist of the free fatty acid receptor 4 (FFA4/GPR120), demonstrates both potential opportunity and possible challenges to therapeutic agonism. Mol. Pharmacol. 84, 710–725 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Li, X., Yu, Y. & Funk, C. D. Cyclooxygenase-2 induction in macrophages is modulated by docosahexaenoic acid via interactions with free fatty acid receptor 4 (FFA4). FASEB J. 27, 4987–4997 (2013).

    CAS  PubMed  Google Scholar 

  78. Liu, Y. et al. The fish oil ingredient, docosahexaenoic acid, activates cytosolic phospholipase A2 via GPR120 receptor to produce prostaglandin E2 and plays an anti-inflammatory role in macrophages. Immunology 143, 81–95 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Liu, Z. et al. Omega-3 fatty acids and other FFA4 agonists inhibit growth factor signaling in human prostate cancer cells. J. Pharmacol. Exp. Ther. 352, 380–394 (2015).

    PubMed  PubMed Central  Google Scholar 

  80. Raptis, D. A. et al. GPR120 on Kupffer cells mediates hepatoprotective effects of ω3-fatty acids. J. Hepatol 60, 625–632 (2014).

    CAS  PubMed  Google Scholar 

  81. Wellhauser, L. & Belsham, D. D. Activation of the omega-3 fatty acid receptor GPR120 mediates anti-inflammatory actions in immortalized hypothalamic neurons. J. Neuroinflamm. 11, 60 (2014).

    Google Scholar 

  82. Watson, S. J., Brown, A. J. & Holliday, N. D. Differential signaling by splice variants of the human free fatty acid receptor GPR120. Mol. Pharmacol. 81, 631–642 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Burns, R. N., Singh, M., Senatorov, I. S. & Moniri, N. H. Mechanisms of homologous and heterologous phosphorylation of FFA receptor 4 (GPR120): GRK6 and PKC mediate phosphorylation of Thr347, Ser350, and Ser357 in the C-terminal tail. Biochem. Pharmacol. 87, 650–659 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Ichimura, A. et al. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483, 350–354 (2012).

    CAS  PubMed  Google Scholar 

  85. Bonnefond, A. et al. Contribution of the low-frequency, loss-of-function p.R270H mutation in FFAR4 (GPR120) to increased fasting plasma glucose levels. J. Med. Genet. 52, 595–598 (2015).

    CAS  PubMed  Google Scholar 

  86. de Git, K. C. & Adan, R. A. Leptin resistance in diet-induced obesity: the role of hypothalamic inflammation. Obes. Rev. 16, 207–224 (2015).

    CAS  PubMed  Google Scholar 

  87. Milanski, M. et al. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J. Neurosci. 29, 359–370 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Suckow, A. T. et al. Alteration of the glucagon axis in GPR120 (FFAR4) knockout mice: a role for GPR120 in glucagon secretion. J. Biol. Chem. 289, 15751–15763 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Yore, M. M. et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159, 318–332 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Oh da, Y. et al. A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice. Nat. Med. 20, 942–947 (2014).

    PubMed  Google Scholar 

  91. Meier, J. J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat. Rev. Endocrinol. 8, 728–742 (2012).

    CAS  PubMed  Google Scholar 

  92. Peters, A. Incretin-based therapies: review of current clinical trial data. Am. J. Med. 123, S28–S37 (2010).

    CAS  PubMed  Google Scholar 

  93. Tzefos, M., Harris, K. & Brackett, A. Clinical efficacy and safety of once-weekly glucagon-like peptide-1 agonists in development for treatment of type 2 diabetes mellitus in adults. Ann. Pharmacother. 46, 68–78 (2012).

    CAS  PubMed  Google Scholar 

  94. Fonseca, V. A. et al. Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy: a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes (GetGoal-Mono). Diabetes Care 35, 1225–1231 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Grunberger, G. et al. Monotherapy with the once-weekly GLP-1 analogue dulaglutide for 12 weeks in patients with Type 2 diabetes: dose-dependent effects on glycaemic control in a randomized, double-blind, placebo-controlled study. Diabet. Med. 29, 1260–1267 (2012).

    CAS  PubMed  Google Scholar 

  96. Cuthbertson, J., Patterson, S., O'Harte, F. P. & Bell, P. M. Addition of metformin to exogenous glucagon-like peptide-1 results in increased serum glucagon-like peptide-1 concentrations and greater glucose lowering in type 2 diabetes mellitus. Metabolism 60, 52–56 (2011).

    CAS  PubMed  Google Scholar 

  97. Migoya, E. M. et al. Dipeptidyl peptidase-4 inhibitors administered in combination with metformin result in an additive increase in the plasma concentration of active GLP-1. Clin. Pharmacol. Ther. 88, 801–808 (2010).

    CAS  PubMed  Google Scholar 

  98. Zander, M., Taskiran, M., Toft-Nielsen, M. B., Madsbad, S. & Holst, J. J. Additive glucose-lowering effects of glucagon-like peptide-1 and metformin in type 2 diabetes. Diabetes Care 24, 720–725 (2001).

    CAS  PubMed  Google Scholar 

  99. Vella, A. Common genetic variation influences the heterogeneity of response to oral glucose. Curr. Diab. Rep. 10, 249–251 (2010).

    PubMed  PubMed Central  Google Scholar 

  100. Drucker, D. J. Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis. Mol. Endocrinol. 17, 161–171 (2003).

    CAS  PubMed  Google Scholar 

  101. Drucker, D. J. The biology of incretin hormones. Cell Metab. 3, 153–165 (2006).

    CAS  PubMed  Google Scholar 

  102. Drucker, D. J. The role of gut hormones in glucose homeostasis. J. Clin. Invest. 117, 24–32 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Ahren, B. & Schmitz, O. GLP-1 receptor agonists and DPP-4 inhibitors in the treatment of type 2 diabetes. Horm. Metab. Res. 36, 867–876 (2004).

    CAS  PubMed  Google Scholar 

  104. Brown, D. X. & Evans, M. Choosing between GLP-1 receptor agonists and DPP-4 inhibitors: a pharmacological perspective. J. Nutr. Metab. 2012, 381713 (2012).

    PubMed  PubMed Central  Google Scholar 

  105. Brunton, S. GLP-1 receptor agonists versus DPP-4 inhibitors for type 2 diabetes: is one approach more successful or preferable than the other? Int. J. Clin. Pract. 68, 557–567 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Unger, J. R. & Parkin, C. G. Glucagon-like peptide-1 (GLP-1) receptor agonists: differentiating the new medications. Diabetes Ther. 2, 29–39 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Dicker, D. DPP-4 inhibitors: impact on glycemic control and cardiovascular risk factors. Diabetes Care 34, S276–S278 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Doyle, M. E. & Egan, J. M. Mechanisms of action of glucagon-like peptide 1 in the pancreas. Pharmacol. Ther. 113, 546–593 (2007).

    CAS  PubMed  Google Scholar 

  109. Sonoda, N. et al. β-arrestin-1 mediates glucagon-like peptide-1 signaling to insulin secretion in cultured pancreatic β cells. Proc. Natl Acad. Sci. USA 105, 6614–6619 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Deacon, C. F., Pridal, L., Klarskov, L., Olesen, M. & Holst, J. J. Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig. Am. J. Physiol. 271, E458–E464 (1996).

    CAS  PubMed  Google Scholar 

  111. Hansen, L., Deacon, C. F., Orskov, C. & Holst, J. J. Glucagon-like peptide-1-(7–36)amide is transformed to glucagon-like peptide-1-(9–36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 140, 5356–5363 (1999).

    CAS  PubMed  Google Scholar 

  112. Vilsboll, T., Agerso, H., Krarup, T. & Holst, J. J. Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects. J. Clin. Endocrinol. Metab. 88, 220–224 (2003).

    CAS  PubMed  Google Scholar 

  113. Farre, R. & Tack, J. Food and symptom generation in functional gastrointestinal disorders: physiological aspects. Am. J. Gastroenterol. 108, 698–706 (2013).

    PubMed  Google Scholar 

  114. Richards, P. et al. Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model. Diabetes 63, 1224–1233 (2014).

    CAS  PubMed  Google Scholar 

  115. Sisley, S. et al. Neuronal GLP1R mediates liraglutide's anorectic but not glucose-lowering effect. J. Clin. Invest. 124, 2456–2463 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Lamont, B. J. et al. Pancreatic GLP-1 receptor activation is sufficient for incretin control of glucose metabolism in mice. J. Clin. Invest. 122, 388–402 (2012).

    CAS  PubMed  Google Scholar 

  117. Buteau, J., Foisy, S., Joly, E. & Prentki, M. Glucagon-like peptide 1 induces pancreatic β-cell proliferation via transactivation of the epidermal growth factor receptor. Diabetes 52, 124–132 (2003).

    CAS  PubMed  Google Scholar 

  118. Wang, Q. & Brubaker, P. L. Glucagon-like peptide-1 treatment delays the onset of diabetes in 8 week-old db/db mice. Diabetologia 45, 1263–1273 (2002).

    CAS  PubMed  Google Scholar 

  119. Fehmann, H. C., Goke, R. & Goke, B. Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide. Endocr. Rev. 16, 390–410 (1995).

    CAS  PubMed  Google Scholar 

  120. Holst, J. J. The physiology of glucagon-like peptide 1. Physiol. Rev. 87, 1409–1439 (2007).

    CAS  PubMed  Google Scholar 

  121. Orskov, C., Holst, J. J. & Nielsen, O. V. Effect of truncated glucagon-like peptide-1 [proglucagon-(78–107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology 123, 2009–2013 (1988).

    CAS  PubMed  Google Scholar 

  122. Baynes, K. C. The evolving world of GLP-1 agonist therapies for type 2 diabetes. Ther. Adv. Endocrinol. Metab. 1, 61–67 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Secher, A. et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J. Clin. Invest. 124, 4473–4488 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Buse, J. B. et al. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann. Intern. Med. 154, 103–112 (2011).

    PubMed  Google Scholar 

  125. Madsbad, S. Exenatide and liraglutide: different approaches to develop GLP-1 receptor agonists (incretin mimetics) — preclinical and clinical results. Best Pract. Res. Clin. Endocrinol. Metab. 23, 463–477 (2009).

    CAS  PubMed  Google Scholar 

  126. Stonehouse, A., Walsh, B. & Cuddihy, R. Exenatide once-weekly clinical development: safety and efficacy across a range of background therapies. Diabetes Technol. Ther. 13, 1063–1069 (2011).

    PubMed  PubMed Central  Google Scholar 

  127. Freyse, E. J., Berg, S., Kohnert, K. D., Heinke, P. & Salzsieder, E. DPP-4 inhibition increases GIP and decreases GLP-1 incretin effects during intravenous glucose tolerance test in Wistar rats. Biol. Chem. 392, 209–215 (2011).

    CAS  PubMed  Google Scholar 

  128. Kazafeos, K. Incretin effect: GLP-1, GIP, DPP4. Diabetes Res. Clin. Pract. 93, S32–S36 (2011).

    CAS  PubMed  Google Scholar 

  129. Nikolaidis, L. A. et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 109, 962–965 (2004).

    CAS  PubMed  Google Scholar 

  130. Read, P. A. et al. A pilot study to assess whether glucagon-like peptide-1 protects the heart from ischemic dysfunction and attenuates stunning after coronary balloon occlusion in humans. Circ. Cardiovasc. Interv. 4, 266–272 (2011).

    CAS  PubMed  Google Scholar 

  131. Sokos, G. G. et al. Effect of glucagon-like peptide-1 (GLP-1) on glycemic control and left ventricular function in patients undergoing coronary artery bypass grafting. Am. J. Cardiol. 100, 824–829 (2007).

    CAS  PubMed  Google Scholar 

  132. Stranges, P. & Khanderia, U. Diabetes and cardiovascular disease: focus on glucagon-like peptide-1 based therapies. Ther. Adv. Drug Saf. 3, 185–201 (2012).

    PubMed  PubMed Central  Google Scholar 

  133. Crespin, S. R., Greenough, W. B. 3rd & Steinberg, D. Stimulation of insulin secretion by long-chain free fatty acids. A direct pancreatic effect. J. Clin. Invest. 52, 1979–1984 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Stein, D. T. et al. Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat. J. Clin. Invest. 97, 2728–2735 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Briscoe, C. P. et al. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J. Biol. Chem. 278, 11303–11311 (2003).

    CAS  PubMed  Google Scholar 

  136. Itoh, Y. et al. Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40. Nature 422, 173–176 (2003).

    CAS  PubMed  Google Scholar 

  137. Latour, M. G. et al. GPR40 is necessary but not sufficient for fatty acid stimulation of insulin secretion in vivo. Diabetes 56, 1087–1094 (2007).

    CAS  PubMed  Google Scholar 

  138. Stoddart, L. A., Brown, A. J. & Milligan, G. Uncovering the pharmacology of the G protein-coupled receptor GPR40: high apparent constitutive activity in guanosine 5′-O-(3-[35S]thio)triphosphate binding studies reflects binding of an endogenous agonist. Mol. Pharmacol. 71, 994–1005 (2007).

    CAS  PubMed  Google Scholar 

  139. Poitout, V. & Robertson, R. P. Glucolipotoxicity: fuel excess and β-cell dysfunction. Endocr. Rev. 29, 351–366 (2008).

    CAS  PubMed  Google Scholar 

  140. Yaney, G. C. & Corkey, B. E. Fatty acid metabolism and insulin secretion in pancreatic beta cells. Diabetologia 46, 1297–1312 (2003).

    CAS  PubMed  Google Scholar 

  141. Alquier, T. et al. Deletion of GPR40 impairs glucose-induced insulin secretion in vivo in mice without affecting intracellular fuel metabolism in islets. Diabetes 58, 2607–2615 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Kebede, M. et al. The fatty acid receptor GPR40 plays a role in insulin secretion in vivo after high-fat feeding. Diabetes 57, 2432–2437 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Lan, H. et al. Lack of FFAR1/GPR40 does not protect mice from high-fat diet-induced metabolic disease. Diabetes 57, 2999–3006 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Nagasumi, K. et al. Overexpression of GPR40 in pancreatic β-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice. Diabetes 58, 1067–1076 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Vettor, R. et al. Loss-of-function mutation of the GPR40 gene associates with abnormal stimulated insulin secretion by acting on intracellular calcium mobilization. J. Clin. Endocrinol. Metab. 93, 3541–3550 (2008).

    CAS  PubMed  Google Scholar 

  146. Doshi, L. S. et al. Acute administration of GPR40 receptor agonist potentiates glucose-stimulated insulin secretion in vivo in the rat. Metabolism 58, 333–343 (2009).

    CAS  PubMed  Google Scholar 

  147. Luo, J. et al. A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents. PLoS ONE 7, e46300 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Tan, C. P. et al. Selective small-molecule agonists of G protein-coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice. Diabetes 57, 2211–2219 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Tsujihata, Y. et al. TAK-875, an orally available G protein-coupled receptor 40/free fatty acid receptor 1 agonist, enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats. J. Pharmacol. Exp. Ther. 339, 228–237 (2011).

    CAS  PubMed  Google Scholar 

  150. Ferdaoussi, M. et al. G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1. Diabetologia 55, 2682–2692 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Fujiwara, K., Maekawa, F. & Yada, T. Oleic acid interacts with GPR40 to induce Ca2+ signaling in rat islet β-cells: mediation by PLC and L-type Ca2+ channel and link to insulin release. Am. J. Physiol. Endocrinol. Metab. 289, E670–E677 (2005).

    CAS  PubMed  Google Scholar 

  152. Shapiro, H., Shachar, S., Sekler, I., Hershfinkel, M. & Walker, M. D. Role of GPR40 in fatty acid action on the β cell line INS-1E. Biochem. Biophys. Res. Commun. 335, 97–104 (2005).

    CAS  PubMed  Google Scholar 

  153. Edfalk, S., Steneberg, P. & Edlund, H. Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes 57, 2280–2287 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Flodgren, E. et al. GPR40 is expressed in glucagon producing cells and affects glucagon secretion. Biochem. Biophys. Res. Commun. 354, 240–245 (2007).

    CAS  PubMed  Google Scholar 

  155. Wang, L. et al. Acute stimulation of glucagon secretion by linoleic acid results from GPR40 activation and [Ca2+]i increase in pancreatic islet α-cells. J. Endocrinol. 210, 173–179 (2011).

    CAS  PubMed  Google Scholar 

  156. Burant, C. F. et al. TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 379, 1403–1411 (2012).

    CAS  PubMed  Google Scholar 

  157. Yashiro, H. et al. The effects of TAK-875, a selective G protein-coupled receptor 40/free fatty acid 1 agonist, on insulin and glucagon secretion in isolated rat and human islets. J. Pharmacol. Exp. Ther. 340, 483–489 (2012).

    CAS  PubMed  Google Scholar 

  158. Hirasawa, A. et al. Production and characterization of a monoclonal antibody against GPR40 (FFAR1; free fatty acid receptor 1). Biochem. Biophys. Res. Commun. 365, 22–28 (2008).

    CAS  PubMed  Google Scholar 

  159. Ma, D. et al. Expression of free fatty acid receptor GPR40 in the central nervous system of adult monkeys. Neurosci. Res. 58, 394–401 (2007).

    CAS  PubMed  Google Scholar 

  160. Nakamoto, K. et al. Involvement of the long-chain fatty acid receptor GPR40 as a novel pain regulatory system. Brain Res. 1432, 74–83 (2012).

    CAS  PubMed  Google Scholar 

  161. Kebede, M. et al. Glucose activates free fatty acid receptor 1 gene transcription via phosphatidylinositol-3-kinase-dependent O-GlcNAcylation of pancreas-duodenum homeobox-1. Proc. Natl Acad. Sci. USA 109, 2376–2381 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Mancini, A. D. & Poitout, V. The fatty acid receptor FFA1/GPR40 a decade later: how much do we know? Trends Endocrinol. Metab. 24, 398–407 (2013).

    CAS  PubMed  Google Scholar 

  163. Li, Y. et al. β-cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1. Diabetes 54, 482–491 (2005).

    CAS  PubMed  Google Scholar 

  164. Kalis, M. et al. Variants in the FFAR1 gene are associated with beta cell function. PLoS ONE 2, e1090 (2007).

    PubMed  PubMed Central  Google Scholar 

  165. Dupuis, J. et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat. Genet. 42, 105–116 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Wagner, R. et al. Reevaluation of fatty acid receptor 1 as a drug target for the stimulation of insulin secretion in humans. Diabetes 62, 2106–2111 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Negoro, N. et al. Discovery of TAK-875: a potent, selective, and orally bioavailable GPR40 agonist. ACS Med. Chem. Lett. 1, 290–294 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Kaku, K., Araki, T. & Yoshinaka, R. Randomized, double-blind, dose-ranging study of TAK-875, a novel GPR40 agonist, in Japanese patients with inadequately controlled type 2 diabetes. Diabetes Care 36, 245–250 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Defossa, E. & Wagner, M. Recent developments in the discovery of FFA1 receptor agonists as novel oral treatment for type 2 diabetes mellitus. Bioorg. Med. Chem. Lett. 24, 2991–3000 (2014).

    CAS  PubMed  Google Scholar 

  170. Lin, D. C. et al. Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor. Mol. Pharmacol. 82, 843–859 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Xiong, Y. et al. Activation of FFA1 mediates GLP-1 secretion in mice. Evidence for allosterism at FFA1. Mol. Cell Endocrinol. 369, 119–129 (2013).

    CAS  PubMed  Google Scholar 

  172. Lin, D. C. et al. AMG 837: a novel GPR40/FFA1 agonist that enhances insulin secretion and lowers glucose levels in rodents. PLoS ONE 6, e27270 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Chu, Z. L. et al. A role for intestinal endocrine cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucagon-like peptide-1 and glucose-dependent insulinotropic Peptide release. Endocrinology 149, 2038–2047 (2008).

    CAS  PubMed  Google Scholar 

  174. Chu, Z. L. et al. A role for β-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release. Endocrinology 148, 2601–2609 (2007).

    CAS  PubMed  Google Scholar 

  175. Parker, H. E., Habib, A. M., Rogers, G. J., Gribble, F. M. & Reimann, F. Nutrient-dependent secretion of glucose-dependent insulinotropic polypeptide from primary murine K cells. Diabetologia 52, 289–298 (2009).

    CAS  PubMed  Google Scholar 

  176. Reimann, F. et al. Glucose sensing in L cells: a primary cell study. Cell Metab. 8, 532–539 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Hansen, K. B. et al. 2-oleoyl glycerol is a GPR119 agonist and signals GLP-1 release in humans. J. Clin. Endocrinol. Metab. 96, E1409–E1417 (2011).

    CAS  PubMed  Google Scholar 

  178. Overton, H. A. et al. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab. 3, 167–175 (2006).

    CAS  PubMed  Google Scholar 

  179. Soga, T. et al. Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor. Biochem. Biophys. Res. Commun. 326, 744–751 (2005).

    CAS  PubMed  Google Scholar 

  180. Hansen, H. S., Rosenkilde, M. M., Holst, J. J. & Schwartz, T. W. GPR119 as a fat sensor. Trends Pharmacol. Sci. 33, 374–381 (2012).

    CAS  PubMed  Google Scholar 

  181. Lauffer, L., Iakoubov, R. & Brubaker, P. L. GPR119: 'double-dipping' for better glycemic control. Endocrinology 149, 2035–2037 (2008).

    CAS  PubMed  Google Scholar 

  182. Lan, H. et al. GPR119 is required for physiological regulation of glucagon-like peptide-1 secretion but not for metabolic homeostasis. J. Endocrinol. 201, 219–230 (2009).

    CAS  PubMed  Google Scholar 

  183. Soga, T. et al. Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor. Biochem. Biophys. Res. Commun. 326, 744–751 (2005).

    CAS  PubMed  Google Scholar 

  184. Jones, R. M., Leonard, J. N., Buzard, D. J. & Lehmann, J. GPR119 agonists for the treatment of type 2 diabetes. Expert Opin. Ther. Pat. 19, 1339–1359 (2009).

    CAS  PubMed  Google Scholar 

  185. Shah, U. & Kowalski, T. J. GPR119 agonists for the potential treatment of type 2 diabetes and related metabolic disorders. Vitam. Horm. 84, 415–448 (2010).

    CAS  PubMed  Google Scholar 

  186. Moran, B. M., Abdel-Wahab, Y. H., Flatt, P. R. & McKillop, A. M. Activation of GPR119 by fatty acid agonists augments insulin release from clonal β-cells and isolated pancreatic islets and improves glucose tolerance in mice. Biol. Chem. 395, 453–464 (2014).

    CAS  PubMed  Google Scholar 

  187. Lee, Y. S. et al. The fractalkine/CX3CR1 system regulates β cell function and insulin secretion. Cell 153, 413–425 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Aoyama, T., Inokuchi, S., Brenner, D. A. & Seki, E. CX3CL1–CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice. Hepatology 52, 1390–1400 (2010).

    CAS  PubMed  Google Scholar 

  189. Haskell, C. A., Cleary, M. D. & Charo, I. F. Molecular uncoupling of fractalkine-mediated cell adhesion and signal transduction. Rapid flow arrest of CX3CR1-expressing cells is independent of G-protein activation. J. Biol. Chem. 274, 10053–10058 (1999).

    CAS  PubMed  Google Scholar 

  190. Lucas, A. D. et al. The transmembrane form of the CX3CL1 chemokine fractalkine is expressed predominantly by epithelial cells in vivo. Am. J. Pathol. 158, 855–866 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Combadiere, C. et al. Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice. Circulation 107, 1009–1016 (2003).

    CAS  PubMed  Google Scholar 

  192. Imai, T. et al. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 91, 521–530 (1997).

    CAS  PubMed  Google Scholar 

  193. Zernecke, A., Shagdarsuren, E. & Weber, C. Chemokines in atherosclerosis: an update. Arterioscler. Thromb. Vasc. Biol. 28, 1897–1908 (2008).

    CAS  PubMed  Google Scholar 

  194. Cardona, A. E. et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat. Neurosci. 9, 917–924 (2006).

    CAS  PubMed  Google Scholar 

  195. Tacke, F. et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J. Clin. Invest. 117, 185–194 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Inoue, A. et al. Antagonist of fractalkine (CX3CL1) delays the initiation and ameliorates the progression of lupus nephritis in MRL/lpr mice. Arthritis Rheum. 52, 1522–1533 (2005).

    CAS  PubMed  Google Scholar 

  197. Garton, K. J. et al. Tumor necrosis factor-α-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). J. Biol. Chem. 276, 37993–38001 (2001).

    CAS  PubMed  Google Scholar 

  198. Hundhausen, C. et al. The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell–cell adhesion. Blood 102, 1186–1195 (2003).

    CAS  PubMed  Google Scholar 

  199. Shah, R. et al. Fractalkine is a novel human adipochemokine associated with type 2 diabetes. Diabetes 60, 1512–1518 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Sirois-Gagnon, D. et al. Association of common polymorphisms in the fractalkine receptor (CX3CR1) with obesity. Obes. (Silver Spring) 19, 222–227 (2011).

    CAS  Google Scholar 

  201. Cnop, M. Fatty acids and glucolipotoxicity in the pathogenesis of Type 2 diabetes. Biochem. Soc. Trans. 36, 348–352 (2008).

    CAS  PubMed  Google Scholar 

  202. van Raalte, D. H. & Diamant, M. Glucolipotoxicity and beta cells in type 2 diabetes mellitus: target for durable therapy? Diabetes Res. Clin. Pract. 93, S37–S46 (2011).

    CAS  PubMed  Google Scholar 

  203. Donath, M. Y., Dalmas, E., Sauter, N. S. & Boni-Schnetzler, M. Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. Cell Metab. 17, 860–872 (2013).

    CAS  PubMed  Google Scholar 

  204. Eguchi, K. & Manabe, I. Macrophages and islet inflammation in type 2 diabetes. Diabetes Obes. Metab. 15, 152–158 (2013).

    CAS  PubMed  Google Scholar 

  205. Ehses, J. A., Ellingsgaard, H., Boni-Schnetzler, M. & Donath, M. Y. Pancreatic islet inflammation in type 2 diabetes: from α and β cell compensation to dysfunction. Arch. Physiol. Biochem. 115, 240–247 (2009).

    CAS  PubMed  Google Scholar 

  206. Mancini, A. D. & Poitout, V. GPR40 agonists for the treatment of type 2 diabetes: life after 'TAKing' a hit. Diabetes Obes. Metab. 17, 622–629 (2015).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors' work is funded in part by NIH grants to J.M.O. (DK033651, DK074868, DK063491, DK09062), and an American Heart Association Scientist Development Grant to D.Y.O. (14SDG19880020). We thank Angela Tyler for editorial assistance.

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  1. Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, 92093, California, USA

    Da Young Oh & Jerrold M. Olefsky

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Oh, D., Olefsky, J. G protein-coupled receptors as targets for anti-diabetic therapeutics. Nat Rev Drug Discov 15, 161–172 (2016). https://doi.org/10.1038/nrd.2015.4

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