GPR40 agonists for the treatment of type 2 diabetes mellitus: Benefits and challenges

Current Drug Targets

Volumn 17, Issue 11, 2016, Pages 1292-1300

  Mohammad, Sameer ^a  

^a KING SAUD BIN ABDULAZIZ UNIVERSITY FOR HEALTH SCIENCES   (Saudi Arabia)

Author keywords

Free fatty acid receptors; G protein coupled receptors; GPR40; Insulin resistance; Pancreatic cell dysfunction; Type 2 diabetes

Indexed keywords

ANTIDIABETIC AGENT; FASIGLIFAM; FATTY ACID; G PROTEIN COUPLED RECEPTOR 40; G PROTEIN COUPLED RECEPTOR 40 AGONIST; UNCLASSIFIED DRUG; AMG 837; BENZOFURAN DERIVATIVE; BIPHENYL DERIVATIVE; FFAR1 PROTEIN, HUMAN; G PROTEIN COUPLED RECEPTOR; INSULIN; SULFONE; TAK-875;

AGONIST; ARTICLE; GENE OVEREXPRESSION; GLUCOSE TOLERANCE; GLYCEMIC CONTROL; HOMEOSTASIS AND REGULATION; HUMAN; IN VITRO STUDY; INSULIN RELEASE; INSULIN RESISTANCE; LIVER TOXICITY; MULTICENTER STUDY (TOPIC); NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; RANDOMIZED CONTROLLED TRIAL (TOPIC); AGONISTS; ANIMAL; DIABETES MELLITUS, TYPE 2; DRUG DESIGN; METABOLISM; PATHOPHYSIOLOGY;

ANIMALS; BENZOFURANS; BIPHENYL COMPOUNDS; DIABETES MELLITUS, TYPE 2; DRUG DESIGN; FATTY ACIDS, NONESTERIFIED; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN; RECEPTORS, G-PROTEIN-COUPLED; SULFONES;

EID: 84983776364     PISSN: 13894501     EISSN: 18735592     Source Type: Journal    
DOI: 10.2174/1389450117666151209122702     Document Type: Article

References (103)

1. IDF Diabetes Atlas Group. Update of mortality attributable to diabetes for the IDF Diabetes Atlas: estimates for the year 2011. Diabetes Res Clin Pract 2013; 100(2): 277-9.
2. Guariguata L. By the numbers: new estimates from the IDF Diabetes Atlas Update for 2012. Diabetes Res Clin Pract 2012; 98(3): 524-5.
3. Zhang P, Zhang X, Brown J, et al. Global healthcare expenditure on diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010; 87(3): 293-301.
4. Ng CS, Lee JY, Toh MP, Ko Y. Cost-of-illness studies of diabetes mellitus: A systematic review. Diabetes Res Clin Pract 2014; 105(2): 151-63.
5. Ettaro L, Songer TJ, Zhang P, Engelgau MM. Cost-of-illness studies in diabetes mellitus. Pharmacoeconomics 2004; 22(3): 149-64.
6. Update of ADA's major position statement, “Standards of Medical Care in Diabetes”. Introduction. Diabetes Care 2011; 34 (Suppl 1): S1-2.
7. Standards of medical care in diabetes-2011. Diabetes Care 2011; 34 (Suppl 1): S11-61.
8. Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabet Med 1997; 14 (Suppl 5): S1-85.
9. Cohen FJ, Neslusan CA, Conklin JE, Song X. Recent antihyperglycemic prescribing trends for US privately insured patients with type 2 diabetes. Diabetes Care 2003; 26(6): 1847-51.
10. Smith NL, Heckbert SR, Bittner VA, et al. Antidiabetic treatment trends in a cohort of elderly people with diabetes. The cardiovascular health study, 1989-1997. Diabetes Care 1999; 22(5): 736-42.
11. George MM, Copeland KC. Current treatment options for type 2 diabetes mellitus in youth: today's realities and lessons from the TODAY study. Curr Diab Rep 2013; 13(1): 72-80.
12. Morgan NG, Dhayal S. G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic β-cell. Biochem Pharmacol 2009; 78(12): 1419-27.
13. Civelli O. GPCR deorphanizations: the novel, the known and the unexpected transmitters. Trends Pharmacol Sci 2005; 26(1): 15-9.
14. Oh DY, Lagakos WS. The role of G-protein-coupled receptors in mediating the effect of fatty acids on inflammation and insulin sensitivity. Curr Opin Clin Nutr Metab Care 2011; 14(4): 322-7.
15. Yonezawa T, Kurata R, Yoshida K, Murayama MA, Cui X, Hasegawa A. Free fatty acids-sensing G protein-coupled receptors in drug targeting and therapeutics. Curr Med Chem 2013; 20(31): 3855-71.
16. Talukdar S, Olefsky JM, Osborn O. Targeting GPR120 and other fatty acid-sensing GPCRs ameliorates insulin resistance and inflammatory diseases. Trends Pharmacol Sci 2011; 32(9): 543-50.
17. Mohammad S. Role of Free Fatty Acid Receptor 2 (FFAR2) in the Regulation of Metabolic Homeostasis. Curr Drug Targets 2015; 16(7): 771-5.
18. Negoro N, Sasaki S, Mikami S, et al. Discovery of TAK-875: A potent, selective, and orally bioavailable GPR40 agonist. ACS Med Chem Lett 2010; 1(6): 290-4.
19. Vettor R, Granzotto M, De Stefani D, 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 2008; 93(9): 3541-50.
20. Kebede M, Alquier T, Latour MG, Semache M, Tremblay C, Poitout V. The fatty acid receptor GPR40 plays a role in insulin secretion in vivo after high-fat feeding. Diabetes 2008; 57(9): 2432-7.
21. Edfalk S, Steneberg P, Edlund H. Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes 2008; 57(9): 2280-7.
22. Schnell S, Schaefer M, Schofl C. Free fatty acids increase cytosolic free calcium and stimulate insulin secretion from β-cells through activation of GPR40. Mol Cell Endocrinol 2007; 263(12): 173-80.
23. Tomita T, Masuzaki H, Noguchi M, et al. GPR40 gene expression in human pancreas and insulinoma. Biochem Biophys Res Commun 2005; 338(4): 1788-90.
24. Steneberg P, Rubins N, Bartoov-Shifman R, Walker MD, Edlund H. The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse. Cell Metab 2005; 1(4): 245-58.
25. 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 2005; 289(4): E670-7.
26. Briscoe CP, Tadayyon M, Andrews JL, et al. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem 2003; 278(13): 11303-11.
27. Itoh Y, Kawamata Y, Harada M, et al. Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40. Nature 2003; 422(6928): 173-6.
28. Nagasumi K, Esaki R, Iwachidow K, et al. Overexpression of GPR40 in pancreatic _-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice. Diabetes 2009; 58(5): 1067-76.
29. Briscoe CP, Peat AJ, McKeown SC, et al. Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules. Br J Pharmacol 2006; 148(5): 619-28.
30. Tomita T, Hosoda K, Fujikura J, Inagaki N, Nakao K. The Gprotein-coupled long-chain fatty acid receptor GPR40 and glucose metabolism. Front Endocrinol (Lausanne) 2014; 5: 152.
31. Xiong Y, Swaminath G, Cao Q, et al. Activation of FFA1 mediates GLP-1 secretion in mice. Evidence for allosterism at FFA1. Mol Cell Endocrinol 2013; 369(1-2): 119-29.
32. Parker HE, Habib AM, Rogers GJ, Gribble FM, Reimann F. Nutrient-dependent secretion of glucose-dependent insulinotropic polypeptide from primary murine K cells. Diabetologia 2009; 52(2): 289-98.
33. Habib AM, Richards P, Rogers GJ, Reimann F, Gribble FM. Colocalisation and secretion of glucagon-like peptide 1 and peptide YY from primary cultured human L cells. Diabetologia 2013; 56(6): 1413-6.
34. Yamashima T. 'PUFA-GPR40-CREB signaling' hypothesis for the adult primate neurogenesis. Prog Lipid Res 2012; 51(3): 221-31.
35. Boneva NB, Kikuchi M, Minabe Y, Yamashima T. Neuroprotective and ameliorative actions of polyunsaturated fatty acids against neuronal diseases: implication of fatty acid-binding proteins (FABP) and G protein-coupled receptor 40 (GPR40) in adult neurogenesis. J Pharmacol Sci 2011; 116(2): 163-72.
36. Boneva NB, Yamashima T. New insights into “GPR40-CREB interaction in adult neurogenesis” specific for primates. Hippocampus 2012; 22(4): 896-905.
37. Ma D, Zhang M, Larsen CP, et al. DHA promotes the neuronal differentiation of rat neural stem cells transfected with GPR40 gene. Brain Res 2010; 1330: 1-8.
38. Ma D, Tao B, Warashina S, et al. Expression of free fatty acid receptor GPR40 in the central nervous system of adult monkeys. Neurosci Res 2007; 58(4): 394-401.
39. Honore JC, Kooli A, Hamel D, et al. Fatty acid receptor Gpr40 mediates neuromicrovascular degeneration induced by transarachidonic acids in rodents. Arterioscler Thromb Vasc Biol 2013; 33(5): 954-61.
40. Khan MZ, He L. The role of polyunsaturated fatty acids and GPR40 receptor in brain. Neuropharmacology 2015; pii: S0028-3908(15)00194-X.
41. Yamashima T. Dual effects of the non-esterified fatty acid receptor 'GPR40' for human health. Prog Lipid Res 2015; 58: 40-50.
42. Nakamoto K, Nishinaka T, Sato N, Mankura M, Koyama Y, Tokuyama S. Antinociceptive effect of docosahexaenoic acid (DHA) through long fatty acid receptor G protein-coupled receptor 40 (GPR40). Yakugaku Zasshi 2014; 134(3): 397-403.
43. Nakamoto K, Tokuyama S. A long chain fatty acid receptor GPR40 as a novel pain control system. Nihon Shinkei Seishin Yakurigaku Zasshi 2012; 32(4): 233-7.
44. Skov V, Glintborg D, Knudsen S, et al. Pioglitazone enhances mitochondrial biogenesis and ribosomal protein biosynthesis in skeletal muscle in polycystic ovary syndrome. PLoS One 2008; 3(6): e2466.
45. Skov V, Glintborg D, Knudsen S, et al. Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulin-resistant women with polycystic ovary syndrome. Diabetes 2007; 56(9): 2349-55.
46. Timmers S, Konings E, Bilet L, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab 2011; 14(5): 612-22.
47. Tateno C, Miya F, Wake K, et al. Morphological and microarray analyses of human hepatocytes from xenogeneic host livers. Lab Invest 2013; 93(1): 54-71.
48. Affo S, Dominguez M, Lozano JJ, et al. Transcriptome analysis identifies TNF superfamily receptors as potential therapeutic targets in alcoholic hepatitis. Gut 2013; 62(3): 452-60.
49. van Dijk SJ, Feskens EJ, Bos MB, et al. A saturated fatty acid-rich diet induces an obesity-linked proinflammatory gene expression profile in adipose tissue of subjects at risk of metabolic syndrome. Am J Clin Nutr 2009; 90(6): 1656-64.
50. She X, Rohl CA, Castle JC, Kulkarni AV, Johnson JM, Chen R. Definition, conservation and epigenetics of housekeeping and tissue-enriched genes. BMC Genomics 2009; 10: 269.
51. Hardy OT, Perugini RA, Nicoloro SM, et al. Body mass indexindependent inflammation in omental adipose tissue associated with insulin resistance in morbid obesity. Surg Obes Relat Dis 2011; 7(1): 60-7.
52. Keller P, Gburcik V, Petrovic N, et al. Gene-chip studies of adipogenesis-regulated microRNAs in mouse primary adipocytes and human obesity. BMC Endocr Disord 2011; 11: 7.
53. Wu HT, Chen W, Cheng KC, Ku PM, Yeh CH, Cheng JT. Oleic acid activates peroxisome proliferator-activated receptor delta to compensate insulin resistance in steatotic cells. J Nutr Biochem 2012; 23(10): 1264-70.
54. Suh HN, Huong HT, Song CH, Lee JH, Han HJ. Linoleic acid stimulates gluconeogenesis via Ca2+/PLC, cPLA2, and PPAR pathways through GPR40 in primary cultured chicken hepatocytes. Am J Physiol Cell Physiol 2008; 295(6): C1518-27.
55. Ou HY, Wu HT, Hung HC, Yang YC, Wu JS, Chang CJ. Multiple mechanisms of GW-9508, a selective G protein-coupled receptor 40 agonist, in the regulation of glucose homeostasis and insulin sensitivity. Am J Physiol Endocrinol Metab 2013; 304(6): E668-76.
56. Lin DC, Zhang J, Zhuang R, et al. AMG 837: a novel GPR40/FFA1 agonist that enhances insulin secretion and lowers glucose levels in rodents. PLoS One 2011; 6(11): e27270.
57. Houze JB, Zhu L, Sun Y, et al. AMG 837: a potent, orally bioavailable GPR40 agonist. Bioorg Med Chem Lett 2012; 22(2): 1267-70.
58. Yazaki R, Kumagai N, Shibasaki M. Enantioselective synthesis of a GPR40 agonist AMG 837 via catalytic asymmetric conjugate addition of terminal alkyne to α,β-unsaturated thioamide. Org Lett 2011; 13(5): 952-5.
59. Tan CP, Feng Y, Zhou YP, et al. Selective small-molecule agonists of G protein-coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice. Diabetes 2008; 57(8): 2211-9.
60. Song F, Lu S, Gunnet J, et al. Synthesis and biological evaluation of 3-aryl-3-(4-phenoxy)-propionic acid as a novel series of G protein-coupled receptor 40 agonists. J Med Chem 2007; 50(12): 2807-17.
61. Stoddart LA, Brown AJ, 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 2007; 71(4): 994-1005.
62. Tanaka H, Yoshida S, Minoura H, et al. Novel GPR40 agonist AS2575959 exhibits glucose metabolism improvement and synergistic effect with sitagliptin on insulin and incretin secretion. Life Sci 2014; 94(2): 115-21.
63. Fujita T, Matsuoka T, Honda T, Kabashima K, Hirata T, Narumiya S. A GPR40 agonist GW9508 suppresses CCL5, CCL17, and CXCL10 induction in keratinocytes and attenuates cutaneous immune inflammation. J Invest Dermatol 2011; 131(8): 1660-7.
64. Christiansen E, Hansen SV, Urban C, et al. Discovery of TUG-770: A highly potent free fatty acid receptor 1 (FFA1/GPR40) agonist for treatment of type 2 diabetes. ACS Med Chem Lett 2013; 4(5): 441-5.
65. Brown SP, Dransfield PJ, Vimolratana M, et al. Discovery of AM-1638: A potent and orally bioavailable GPR40/FFA1 full agonist. ACS Med Chem Lett 2012; 3(9): 726-30.
66. Gowda N, Dandu A, Singh J, et al. Treatment with CNX-011-67, a novel GPR40 agonist, delays onset and progression of diabetes and improves β cell preservation and function in male ZDF rats. BMC Pharmacol Toxicol 2013; 14(1): 28.
67. Doshi LS, Brahma MK, Sayyed SG, et al. Acute administration of GPR40 receptor agonist potentiates glucose-stimulated insulin secretion in vivo in the rat. Metabolism 2009; 58(3): 333-43.
68. Ito R, Tsujihata Y, Matsuda-Nagasumi K, Mori I, Negoro N, Takeuchi K. TAK-875, a GPR40/FFAR1 agonist, in combination with metformin prevents progression of diabetes and β-cell dysfunction in Zucker diabetic fatty rats. Br J Pharmacol 2013; 170(3): 568-80.
69. Luo J, Swaminath G, Brown SP, et al. A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents. PLoS One 2012; 7(10): e46300.
70. Tanaka H, Yoshida S, Oshima H, et al. Chronic treatment with novel GPR40 agonists improve whole-body glucose metabolism based on the glucose-dependent insulin secretion. J Pharmacol Exp Ther 2013; 346(3): 443-52.
71. Zhao YF, Wang L, Zha D, et al. GW9508 inhibits insulin secretion by activating ATP-sensitive potassium channels in rat pancreatic β-cells. J Mol Endocrinol 2013; 51(1): 69-77.
72. Philippe C, Wauquier F, Leotoing L, Coxam V, Wittrant Y. GW9508, a free fatty acid receptor agonist, specifically induces cell death in bone resorbing precursor cells through increased oxidative stress from mitochondrial origin. Exp Cell Res 2013; 319(19): 3035-41.
73. Christiansen E, Urban C, Merten N, et al. Discovery of potent and selective agonists for the free fatty acid receptor 1 (FFA(1)/GPR40), a potential target for the treatment of type II diabetes. J Med Chem 2008; 51(22): 7061-4.
74. Christiansen E, Due-Hansen ME, Urban C, et al. Free fatty acid receptor 1 (FFA1/GPR40) agonists: mesylpropoxy appendage lowers lipophilicity and improves ADME properties. J Med Chem 2012; 55(14): 6624-8.
75. Urban C, Hamacher A, Partke HJ, et al. In vitro and mouse in vivo characterization of the potent free fatty acid 1 receptor agonist TUG-469. Naunyn Schmiedebergs Arch Pharmacol 2013; 386(12): 1021-30.
76. Wagner R, Kaiser G, Gerst F, et al. Reevaluation of fatty acid receptor 1 as a drug target for the stimulation of insulin secretion in humans. Diabetes 2013; 62(6): 2106-11.
77. Naik H, Vakilynejad M, Wu J, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamic properties of the GPR40 agonist TAK-875: results from a double-blind, placebo-controlled single oral dose rising study in healthy volunteers. J Clin Pharmacol 2012; 52(7): 1007-16.
78. Leifke E, Naik H, Wu J, et al. A multiple-ascending-dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of a novel GPR40 agonist, TAK-875, in subjects with type 2 diabetes. Clin Pharmacol Ther 2012; 92(1): 29-39.
79. Kaku K, Araki T, Yoshinaka R. Randomized, double-blind, doseranging study of TAK-875, a novel GPR40 agonist, in Japanese patients with inadequately controlled type 2 diabetes. Diabetes Care 2013; 36(2): 245-50.
80. Burant CF, Viswanathan P, Marcinak J, et al. TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2012; 379(9824): 1403-11.
81. Araki T, Hirayama M, Hiroi S, Kaku K. GPR40-induced insulin secretion by the novel agonist TAK-875: first clinical findings in patients with type 2 diabetes. Diabetes Obes Metab 2012; 14(3): 271-8.
82. Molecule of the Month. TAK-875. Drug News Perspect 2010; 23(10): 667.
83. Yashiro H, Tsujihata Y, Takeuchi K, Hazama M, Johnson PR, Rorsman P. 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 2012; 340(2): 483-9.
84. Tsujihata Y, Ito R, Suzuki M, 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 2011; 339(1): 228-37.
85. Lead GPR40 agonist bites the dust. Nat Rev Drug Discov 2014; 13(2): 91.
86. Wang Y, Liu JJ, Dransfield PJ, et al. Discovery and optimization of potent GPR40 full agonists containing tricyclic spirocycles. ACS Med Chem Lett 2013; 4(6): 551-5.
87. Du X, Dransfield PJ, Lin DC, et al. Improving the pharmacokinetics of GPR40/FFA1 full agonists. ACS Med Chem Lett 2014; 5(4): 384-9.
88. Chang-Chen KJ, Mullur R, Bernal-Mizrachi E. β-cell failure as a complication of diabetes. Rev Endocr Metab Disord 2008; 9(4): 329-43.
89. Meidute Abaraviciene S, Lundquist I, Galvanovskis J, Flodgren E, Olde B, Salehi A. Palmitate-induced β-cell dysfunction is associated with excessive NO production and is reversed by thiazolidinedione-mediated inhibition of GPR40 transduction mechanisms. PLoS One 2008; 3(5): e2182.
90. Wu J, Sun P, Zhang X, et al. Inhibition of GPR40 protects MIN6 β cells from palmitate-induced ER stress and apoptosis. J Cell Biochem 2012; 113(4): 1152-8.
91. Kristinsson H, Smith DM, Bergsten P, Sargsyan E. FFAR1 is involved in both the acute and chronic effects of palmitate on insulin secretion. Endocrinology 2013; 154(11): 4078-88.
92. Natalicchio A, Labarbuta R, Tortosa F, et al. Exendin-4 protects pancreatic β cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway. Diabetologia 2013; 56(11): 2456-66.
93. Latour MG, Alquier T, Oseid E, et al. GPR40 is necessary but not sufficient for fatty acid stimulation of insulin secretion in vivo. Diabetes 2007; 56(4): 1087-94.
94. 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 2014; 24(14): 2991-3000.
95. Brownlie R, Mayers RM, Pierce JA, Marley AE, Smith DM. The long-chain fatty acid receptor, GPR40, and glucolipotoxicity: investigations using GPR40-knockout mice. Biochem Soc Trans 2008; 36(5): 950-4.
96. Lan H, Hoos LM, Liu L, et al. Lack of FFAR1/GPR40 does not protect mice from high-fat diet-induced metabolic disease. Diabetes 2008; 57(11): 2999-3006.
97. Alquier T, Poitout V. GPR40: good cop, bad cop? Diabetes 2009; 58(5): 1035-6.
98. Tomita T, Masuzaki H, Iwakura H, et al. Expression of the gene for a membrane-bound fatty acid receptor in the pancreas and islet cell tumours in humans: evidence for GPR40 expression in pancreatic _ cells and implications for insulin secretion. Diabetologia 2006; 49(5): 962-8.
99. Matsuda-Nagasumi K, Takami-Esaki R, Iwachidow K, et al. Lack of GPR40/FFAR1 does not induce diabetes even under insulin resistance condition. Diabetes Obes Metab 2013; 15(6): 538-45.
100. Nakashima R, Yano T, Ogawa J, et al. Potentiation of insulin secretion and improvement of glucose intolerance by combining a novel G protein-coupled receptor 40 agonist DS-1558 with glucagon-like peptide-1 receptor agonists. Eur J Pharmacol 2014; 737: 194-201.
101. Zhang X, Yan G, Li Y, Zhu W, Wang H. DC260126, a smallmolecule antagonist of GPR40, improves insulin tolerance but not glucose tolerance in obese Zucker rats. Biomed Pharmacother 2010; 64(9): 647-51.
102. Sun P, Wang T, Zhou Y, et al. DC260126: a small-molecule antagonist of GPR40 that protects against pancreatic β-Cells dysfunction in db/db mice. PLoS One 2013; 8(6): e66744.
103. Srivastava A, Yano J, Hirozane Y, et al. High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature 2014; 513(7516): 124-7.