Free fatty acid receptor 4 agonists stimulate insulin secretion via different mechanisms in mouse versus human islets

The free fatty acid receptor FFAR4 is expressed in pancreatic islets, and its activation potentiates insulin and inhibits somatostatin (SST) secretion. We investigated the mechanisms of action of FFAR4 on hormone secretion in mouse and human islets. The effects of the FFAR4 agonist Compound A (Cpd A) on insulin and SST secretion were investigated in islets from mice following ablation of delta cells, deletion of SST and deletion of the G protein Gαz (Gnaz-/-), in purified mouse beta and delta cells, in human EndoC-bH5 cells, and in human islets. Ca++ dynamics in response to Cpd A were measured in delta cells from Gnaz-/- mouse islets and in human islets. The insulinotropic effect of Cpd A was lost in delta cell-ablated and SST-deficient mouse islets and was absent in purified mouse beta cells. Gαz deletion prevented Cpd A inhibition of SST secretion but not the potentiation of insulin release. Cpd A diminished Ca++ transients in mouse delta cells, an effect that was lost in Gαz deficient islets. In human islets, FFAR4 activation increased insulin secretion and intracellular Ca++ transient independent of SST secretion. Consistent with a direct effect on beta cells, Cpd A potentiated insulin secretion in human EndoC-bH5 cells. We conclude that FFAR4 activation stimulates insulin secretion from mouse islets indirectly via Gαz-coupled inhibition of SST secretion from delta cells, while in human islets, it stimulates insulin release via a direct effect on beta cells. These key species-related differences are to be taken into account as FFAR4 is considered a potential therapeutic target for metabolic diseases.