{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T21:14:47Z","timestamp":1770326087132,"version":"3.49.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T00:00:00Z","timestamp":1669075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>The free fatty acid receptor 1 (FFAR1\/GPR40) mediates fatty acid-induced insulin secretion from pancreatic \u03b2-cells. At least 3 distinct binding sites exist on the FFAR1 receptor and numerous synthetic ligands have been investigated for their anti-diabetic actions. Fasiglifam, binds to site-1 and stimulates intra-cellular calcium release and improves glycemic control in diabetic patients. Recently, small molecule FFAR1 agonists were discovered which bind to site-3, stimulating both intra-cellular calcium and cAMP, resulting in insulin and glucagon-like peptide-1 (GLP-1) secretion. The ability of our site-3 FFAR1 agonist (compound A) to control blood glucose was evaluated in spontaneously diabetic cynomolgus monkeys during an oral glucose tolerance test. In type-2 diabetic (T2D) animals, significant reductions in blood glucose and insulin were noted. To better understand the mechanism of these <jats:italic>in vivo<\/jats:italic> findings, we evaluated the effect of compound A in islets under several conditions of dysfunction. First, healthy human and non-human primate islets were treated with compound A and showed potentiation of insulin and glucagon secretion from both species. Next, we determined glucose-responsive insulin secretion under gluco-lipotoxic conditions and from islets isolated from type-2 diabetic humans. Despite a dysfunctional phenotype that failed to secrete insulin in response to glucose, site-3 FFAR1 agonism not only enhanced insulin secretion, but restored glucose responsiveness across a range of glucose concentrations. Lastly, we treated <jats:italic>ex vivo<\/jats:italic> human islets chronically with a sulfonylurea to induce secondary beta-cell failure. Again, this model showed reduced glucose-responsive insulin secretion that was restored and potentiated by site-3 FFAR1 agonism. Together these data suggest a mechanism for FFAR1 where agonists have direct effects on islet hormone secretion that can overcome a dysfunctional T2D phenotype. These unique characteristics of FFAR1 site-3 agonists make them an appealing potential therapy to treat type-2 diabetes.<\/jats:p>","DOI":"10.3389\/fendo.2022.1061688","type":"journal-article","created":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T07:29:14Z","timestamp":1669102154000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["A FFAR1 full agonist restores islet function in models of impaired glucose-stimulated insulin secretion and diabetic non-human primates"],"prefix":"10.3389","volume":"13","author":[{"given":"Brian","family":"Rady","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianying","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivona","family":"Bakaj","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenson","family":"Qi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. P.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tonya","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Norquay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Player","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Pocai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211495200","article-title":"The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids","volume":"278","author":"Briscoe","year":"2003","journal-title":"J Biol Chem"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01478","article-title":"Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40","volume":"422","author":"Itoh","year":"","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2337\/db08-0307","article-title":"Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion","volume":"57","author":"Edfalk","year":"2008","journal-title":"Diabetes"},{"key":"B4","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.molmet.2014.10.002","article-title":"GPR40 (FFAR1) - Combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo","volume":"4","author":"Hauge","year":"2014","journal-title":"Mol Metab"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1021\/ml1000855","article-title":"Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist","volume":"1","author":"Negoro","year":"2010","journal-title":"ACS Med Chem Lett"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2011.10.118","article-title":"AMG 837: a potent, orally bioavailable GPR40 agonist","volume":"22","author":"Houze","year":"2012","journal-title":"Bioorg Med Chem Lett"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12467","article-title":"Efficacy and safety of fasiglifam (TAK-875), a G protein-coupled receptor 40 agonist, in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise: a randomized, double-blind, placebo-controlled, phase III trial","volume":"17","author":"Kaku","year":"2015","journal-title":"Diabetes Obes Metab"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.2337\/dc12-0872","article-title":"Randomized, double-blind, dose-ranging study of TAK-875, a novel GPR40 agonist, in Japanese patients with inadequately controlled type 2 diabetes","volume":"36","author":"Kaku","year":"2013","journal-title":"Diabetes Care"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfx040","article-title":"Fasiglifam (TAK-875): Mechanistic Investigation and Retrospective Identification of Hazards for Drug Induced Liver Injury","volume":"163","author":"Otieno","year":"2018","journal-title":"Toxicol Sci"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1124\/mol.112.079640","article-title":"Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor","volume":"82","author":"Lin","year":"2012","journal-title":"Mol Pharmacol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1124\/mol.116.105940","article-title":"Pluridimensional View of Biased Agonism","volume":"90","author":"Costa-Neto","year":"2016","journal-title":"Mol Pharmacol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.3417","article-title":"Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40","volume":"24","author":"Lu","year":"2017","journal-title":"Nat Struct Mol Biol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2337\/db09-9028","article-title":"Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus","volume":"58","author":"Defronzo","year":"2009","journal-title":"Diabetes"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-0150","article-title":"Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin","volume":"89","author":"Marchetti","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-004-1381-z","article-title":"Beta cell function and its relation to insulin action in humans: a critical appraisal","volume":"47","author":"Ferrannini","year":"2004","journal-title":"Diabetologia"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.3.727","article-title":"Functional and molecular defects of pancreatic islets in human type 2 diabetes","volume":"54","author":"Del Guerra","year":"2005","journal-title":"Diabetes"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-2860","article-title":"Evidence of \u03b2-Cell Dedifferentiation in Human Type 2 Diabetes","volume":"101","author":"Cinti","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"B18","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1021\/acsmedchemlett.8b00444","article-title":"Discovery of a GPR40 Superagonist: The Impact of Aryl Propionic Acid \u03b1-Fluorination","volume":"10","author":"Huang","year":"2018","journal-title":"ACS Med Chem Lett"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1021\/ml300133f","article-title":"Discovery of AM-1638: A Potent and Orally Bioavailable GPR40\/FFA1 Full Agonist","volume":"3","author":"Brown","year":"2012","journal-title":"ACS Med Chem Lett"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.12.193","article-title":"GPR40 is expressed in glucagon producing cells and affects glucagon secretion","volume":"354","author":"Flodgren","year":"2007","journal-title":"Biochem Biophys Res Commun"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-11-0132","article-title":"Acute stimulation of glucagon secretion by linoleic acid results from GPR40 activation and [Ca2+] increase in pancreatic islet {alpha}-cells","volume":"210","author":"Wang","year":"2011","journal-title":"J Endocrinol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.2337\/db21-0451","article-title":"SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans","volume":"70","author":"Nishizaki","year":"2021","journal-title":"Diabetes"},{"key":"B23","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1002\/ddr.21416","article-title":"Free fatty acid receptor 1 agonist, MR1704, lowers blood glucose levels in rats unresponsive to the sulfonylurea, glibenclamide","volume":"79","author":"Tsuda","year":"2018","journal-title":"Drug Dev Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1172\/JCI45680","article-title":"Dynamics of insulin secretion and the clinical implications for obesity and diabetes","volume":"121","author":"Seino","year":"2011","journal-title":"J Clin Invest."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1210\/me.2002-0333","article-title":"Glucose-stimulated insulin secretion is coupled to the interaction of actin with the t-SNARE (target membrane soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein) complex","volume":"17","author":"Thurmond","year":"2003","journal-title":"Mol Endocrinol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1242\/jcs.034355","article-title":"Mechanisms of biphasic insulin-granule exocytosis - roles of the cytoskeleton, small GTPases and SNARE proteins","volume":"122","author":"Wang","year":"2009","journal-title":"J Cell Sci"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.279885","article-title":"Novel mechanistic link between focal adhesion remodeling and glucose-stimulated insulin secretion","volume":"287","author":"Rondas","year":"2012","journal-title":"J Biol Chem"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-012-2650-x","article-title":"G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1","volume":"55","author":"Ferdaoussi","year":"2012","journal-title":"Diabetologia"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s00592-012-0446-6","article-title":"Ultrastructural morphometric analysis of insulin secretory granules in human type 2 diabetes","author":"Masini","year":"2012","journal-title":"Acta Diabetol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0186033","article-title":"GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent","volume":"12","author":"Pachanski","year":"2017","journal-title":"PloS One"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/8.5.535","article-title":"Metabolic Effects of Glucagon in the Wistar Rat","volume":"8","author":"Salter","year":"1960","journal-title":"Am J Clin Nutr"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM196105042641801","article-title":"Depression of food intake induced in healthy subjects by glucagon","volume":"264","author":"Penick","year":"1961","journal-title":"N Engl J Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1957.11.3.419","article-title":"Effect of glucagon on food intake and body weight in man","volume":"11","author":"JL","year":"1957","journal-title":"J Appl Physiol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00435.2016","article-title":"GPR40 reduces food intake and body weight through GLP-1","volume":"313","author":"Gorski","year":"2017","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(21)00203-5","article-title":"Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials","volume":"9","author":"Sattar","year":"2021","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2028395","article-title":"NN9931-4296 Investigators. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis","volume":"384","author":"Newsome","year":"2021","journal-title":"N Engl J Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.121.055459","article-title":"Effect of the Glucagon-Like Peptide-1 Receptor Agonists Semaglutide and Liraglutide on Kidney Outcomes in Patients With Type 2 Diabetes: Pooled Analysis of SUSTAIN 6 and LEADER","volume":"145","author":"Shaman","year":"2022","journal-title":"Circulation"},{"key":"B38","year":""}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.1061688\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T07:29:16Z","timestamp":1669102156000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.1061688\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,22]]},"references-count":38,"alternative-id":["10.3389\/fendo.2022.1061688"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2022.1061688","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,22]]},"article-number":"1061688"}}