DC2420 - The long-chain fatty-acid receptor FFA4 stimulates Insulin secretion via inhibition of Somatostatin release from Delta cells

Blinded Abstract: The fatty-acid receptor FFA4 is expressed in islets, but its mechanisms of action remains unknown. Our previous studies suggest that FFA4 regulates somatostatin (SST) secretion from delta-cells.
Hypothesis: FFA4 agonists indirectly stimulate insulin secretion via inhibition of SST release.

Methods: SST-null (insertion of Cre into Sst gene; SSTKO),delta-cell-ablated (expressing diptheria toxin receptor in delta cells; SST-iDTR), and G protein Gα(z)-null (GnazKO) mice were used. Hormone secretion was assessed in 1-h-static incubations of isolated islets in response to 2.8 or 16.7mM glucose +/- the FFA4 agonists CpdA (20-50 μM) or AZ13581837 (10 μM).

Results: In WT islets, CpdA potentiated glucose-stimulated insulin secretion (GSIS) (179 ± 63 % of the 16.7 mM glucose condition, n=8, p< 0.05) and decreased SST secretion (33 ± 13 vs. 58 ± 21 pM in the glucose alone condition, n=8, p< 0.01). CpdA had no effect in SSTKO or SST-iDTR islets (92 ± 44 % and 122 ± 14 % of the 16.7 mM glucose condition respectively, n=6 each, NS). CpdA did not inhibit SST secretion in Gnaz KO islets (35 ± 23 pM vs. 48 ± 16 in the glucose alone condition, n=8, NS). As FFAR4 expression is elevated in human beta cells, we investigated FFA4 activation in EndoCβH5 cells. AZ13581837 potentiated GSIS (149 ± 25 % of the 16.7 mM glucose condition, n=5-6, P< 0.01), suggesting a direct action on human beta cells.

Conclusion: FFA4 agonists stimulate rodent insulin secretion indirectly via FFA4-Gα(z)-mediated inhibition of delta-cell SST secretion, a mechanism different in human islets.