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Here, we investigated the relative roles of \u03b4 and \u03b2 cells in the insulinotropic effect of FFAR4 activation in mouse and human islets. The effects of the FFAR4 agonists Compound A (Cpd A) and AZ13581827 on insulin and SST secretion were investigated in islets from mice following ablation of \u03b4 cells and deletion of SST and the G protein G\u03b1z (Gnaz\u2212\/\u2212), in purified mouse \u03b2 and \u03b4 cells, in mouse \u03b2 cell-only pseudo-islets, and in human islets and EndoC-\u03b2H5 cells. Ca++ dynamics were measured in \u03b4 cells from Gnaz\u2212\/\u2212 mouse islets and \u03b2 cells from dissociated mouse islets and human islets. The insulinotropic effect of FFAR4 activation was lost in \u03b4 cell-ablated and SST-deficient mouse islets, purified mouse \u03b2 cells, and \u03b2 cell-only pseudo-islets. FFAR4 activation did not increase \u03b2-cell Ca++ transients in dissociated mouse islets. G\u03b1z deletion in mice partially blunted Cpd A inhibition of SST secretion but not the potentiation of insulin release. Cpd A diminished Ca++ transients in mouse \u03b4 cells, an effect that was partially lost in G\u03b1z deficient islets. In human islets, Cpd A increased insulin secretion and intracellular Ca++ without affecting SST secretion. AZ13581827 potentiated insulin secretion in human EndoC-\u03b2H5 cells. We conclude that FFAR4 activation stimulates insulin secretion from mouse islets indirectly, in part via G\u03b1z-coupled inhibition of SST secretion from \u03b4 cells, while in human islets, it directly stimulates insulin release from \u03b2 cells.<\/jats:p>","DOI":"10.1210\/endocr\/bqag111","type":"journal-article","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T12:29:35Z","timestamp":1790425775000},"source":"Crossref","is-referenced-by-count":2,"title":["Free fatty acid receptor 4 agonism stimulates insulin secretion via different mechanisms in mouse vs human islets"],"prefix":"10.1210","volume":"167","author":[{"given":"Laura","family":"Reininger","sequence":"first","affiliation":[{"name":"University of Montreal Hospital Research Center (CRCHUM) , Montreal, QC H2X 0A9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Rehman","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Physiology & Behavior, College of Biological Sciences, University of California Davis , Davis, CA 95616 ,","place":["USA"]},{"name":"Department of Physiology and Membrane Biology, School of Medicine, University of California Davis , Davis, CA 95616 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Hart","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Physiology & Behavior, College of Biological Sciences, University of California Davis , Davis, CA 95616 ,","place":["USA"]},{"name":"Department of Physiology and Membrane Biology, School of Medicine, University of California Davis , Davis, CA 95616 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Ferragne","sequence":"additional","affiliation":[{"name":"University of Montreal Hospital Research Center (CRCHUM) , Montreal, QC H2X 0A9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Tremblay","sequence":"additional","affiliation":[{"name":"University of Montreal Hospital Research Center (CRCHUM) , Montreal, QC H2X 0A9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lanie","family":"Ethier","sequence":"additional","affiliation":[{"name":"University of Montreal Hospital Research Center (CRCHUM) , Montreal, QC H2X 0A9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Am\u00e9lia","family":"Bouabcha","sequence":"additional","affiliation":[{"name":"University of Montreal Hospital Research Center (CRCHUM) , Montreal, QC H2X 0A9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Kimple","sequence":"additional","affiliation":[{"name":"University of Wisconsin School of Medicine and Public Health , Madison, WI 53705 ,","place":["USA"]},{"name":"Research Service, William S. Middleton Memorial Veterans Hospital , Madison, WI 53705 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Ghislain","sequence":"additional","affiliation":[{"name":"University of Montreal Hospital Research Center (CRCHUM) , Montreal, QC H2X 0A9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark O","family":"Huising","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Physiology & Behavior, College of Biological Sciences, University of California Davis , Davis, CA 95616 ,","place":["USA"]},{"name":"Department of Physiology and Membrane Biology, School of Medicine, University of California Davis , Davis, CA 95616 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6555-5053","authenticated-orcid":false,"given":"Vincent","family":"Poitout","sequence":"additional","affiliation":[{"name":"University of Montreal 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