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Free fatty acid receptor 4 agonism stimulates insulin secretion via different mechanisms in mouse vs human islets

Year: 2026

Type: article

Abstract: Activation of the free fatty acid receptor FFAR4 in pancreatic islets potentiates insulin and inhibits somatostatin (SST) secretion. Here, we investigated the relative roles of δ and β 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 δ cells and deletion of SST and the G protein Gαz (Gnaz-/-), in purified mouse β and δ cells, in mouse β cell-only pseudo-islets, and in human islets and EndoC-βH5 cells. Ca++ dynamics were measured in δ cells from Gnaz-/- mouse islets and β cells from dissociated mouse islets and human islets. The insulinotropic effect of FFAR4 activation was lost in δ cell-ablated and SST-deficient mouse islets, purified mouse β cells, and β cell-only pseudo-islets. FFAR4 activation did not increase β-cell Ca++ transients in dissociated mouse islets. Gαz 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 δ cells, an effect that was partially lost in Gαz deficient islets. In human islets, Cpd A increased insulin secretion and intracellular Ca++ without affecting SST secretion. AZ13581827 potentiated insulin secretion in human EndoC-βH5 cells. We conclude that FFAR4 activation stimulates insulin secretion from mouse islets indirectly, in part via Gαz-coupled inhibition of SST secretion from δ cells, while in human islets, it directly stimulates insulin release from β cells.

Source: Endocrinology

DOI: 10.1210/endocr/bqag111