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 δ cells, deletion of SST and deletion of the G protein Gαz (Gnaz -/-), in purified mouse β and δ cells, in human EndoC-bH5 cells, and in human islets. Ca++ dynamics in response to Cpd A were measured in δ cells from Gnaz -/- mouse islets and in human islets. The insulinotropic effect of Cpd A was lost in δ cell-ablated and SST-deficient mouse islets and was absent in purified mouse β cells. Gαz deletion prevented Cpd A inhibition of SST secretion but not the potentiation of insulin release. Cpd A diminished Ca++ transients in mouse δ 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 β cells, Cpd A potentiated insulin secretion in human EndoC-βH5 cells. We conclude that FFAR4 activation stimulates insulin secretion from mouse islets indirectly via Gαz-coupled inhibition of SST secretion from δ cells, while in human islets, it stimulates insulin release via a direct effect on β cells. These key species-related differences are to be taken into account as FFAR4 is considered a potential therapeutic target for metabolic diseases.