Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules

• Published in: British journal of pharmacology 2006-07, Vol.148 (5), p.619-628
• Main Authors: Briscoe, Celia P, Peat, Andrew J, McKeown, Stephen C, Corbett, David F, Goetz, Aaron S, Littleton, Thomas R, McCoy, David C, Kenakin, Terry P, Andrews, John L, Ammala, Carina, Fornwald, James A, Ignar, Diane M, Jenkinson, Stephen
• Format: Article
• Language: English
• Subjects: agonist; Animals; antagonist; Benzoates - pharmacology; Biological and medical sciences; Cell Line; Cells, Cultured; CHO Cells; Cricetinae; Diabetes. Impaired glucose tolerance; Drug Evaluation, Preclinical; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose - pharmacology; GPCR; GPR120; GPR40; Humans; Hypoglycemic Agents - pharmacology; Hypolipidemic Agents - pharmacology; insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Medical sciences; Methylamines - pharmacology; Mice; MIN6; Models, Biological; Pharmacology. Drug treatments; Potassium Chloride - pharmacology; Propionates - pharmacology; Pyrimidines - pharmacology; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - antagonists & inhibitors; small molecule; Spodoptera - cytology; Type 2 diabetes
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0706770

1 Long chain fatty acids have recently been identified as agonists for the G protein‐coupled receptors GPR40 and GPR120. Here, we present the first description of GW9508, a small‐molecule agonist of the fatty acid receptors GPR40 and GPR120. In addition, we also describe the pharmacology of GW1100, a selective GPR40 antagonist. These molecules were used to further investigate the role of GPR40 in glucose‐stimulated insulin secretion in the MIN6 mouse pancreatic β‐cell line. 2 GW9508 and linoleic acid both stimulated intracellular Ca2+ mobilization in human embryonic kidney (HEK)293 cells expressing GPR40 (pEC50 values of 7.32±0.03 and 5.65±0.06, respectively) or GPR120 (pEC50 values of 5.46±0.09 and 5.89±0.04, respectively), but not in the parent HEK‐293 cell line. 3 GW1100 dose dependently inhibited GPR40‐mediated Ca2+ elevations stimulated by GW9508 and linoleic acid (pIC50 values of 5.99±0.03 and 5.99±0.06, respectively). GW1100 had no effect on the GPR120‐mediated stimulation of intracellular Ca2+ release produced by either GW9508 or linoleic acid. 4 GW9508 dose dependently potentiated glucose‐stimulated insulin secretion in MIN6 cells, but not in primary rat or mouse islets. Furthermore, GW9508 was able to potentiate the KCl‐mediated increase in insulin secretion in MIN6 cells. The effects of GW9508 on insulin secretion were reversed by GW1100, while linoleic acid‐stimulated insulin secretion was partially attenuated by GW1100. 5 These results add further evidence to a link between GPR40 and the ability of fatty acids to acutely potentiate insulin secretion and demonstrate that small‐molecule GPR40 agonists are glucose‐sensitive insulin secretagogues. British Journal of Pharmacology (2006) 148, 619–628. doi:10.1038/sj.bjp.0706770