1825-P: Potentiation of Glucose-Stimulated Insulin Secretion by Free Fatty-Acid Receptor 4 Involves Distinct Mechanisms in Mouse vs. Human Islets

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Introduction and Objective: The long-chain fatty-acid receptor FFA4 exerts beneficial effects on glucose homeostasis and is considered a potential therapeutic target for type 2 diabetes. We previously showed in mouse islets that FFA4 activation potentiates glucose-stimulated insulin secretion indirectly via inhibition of somatostatin (SST) secretion from δ cells. However, the mechanism of action of FFA4 in human islets remains unknown. Here, we investigated the mechanism of FFA4 action in mouse islets and explored the hypothesis that FFA4 agonists directly stimulate insulin secretion in human β cells. Methods: One-hour static incubations were performed on isolated mouse and human islets exposed to the selective FFA4 agonist CpdA (20 μM). Insulin and SST were assessed by radioimmunoassay. Data are expressed as mean ± SEM. Significance was tested using two-way ANOVA with post-hoc adjustment (Tukey test). Results: In mouse islets, CpdA potentiated glucose-induced insulin secretion (2.0 ± 0.3 fold increase vs. glucose alone; n=6; p<0.05) and decreased SST secretion (34 ± 5 pM vs. 58 ± 7 pM in glucose alone; n=7; p<0.001). CpdA did not affect insulin secretion in SST-deficient islets (1.1 ± 0.1 fold increase vs. glucose alone; n=9; ns). As we previously showed that FFA4 does not couple to Gαi/o, we asked whether it couples to Gαz in δ cells. CpdA did not reduce SST secretion in Gnaz knockout (35 ± 23 pM vs. 47 ± 16 pM in glucose alone; n=8; ns) islets. In human islets, in line with the elevated expression of FFAR4 in β cells, CpdA potentiated insulin secretion (1.8 ± 0.2 fold increase vs. glucose alone; n=3; p>0.05) but had no effect on SST secretion (67 ± 12 pM vs. 74 ± 14 pM in glucose alone; n=4; ns). Conclusion: Our data suggest distinct mechanisms of action whereby FFA4-Gαz coupling indirectly increases insulin secretion via inhibition of SST secretion in rodent’s δ cells, whereas in humans, FFA4 activation in β cells directly increases insulin secretion. Disclosure L. Reininger: None. A. Bouabcha: None. M.H. Rehman: None. S. Ferragne: None. C. Tremblay: None. M. Ethier: None. J. Ghislain: None. M.E. Kimple: None. M.O. Huising: Research Support; Thermo Fisher. V. Poitout: Research Support; Biodexa. Funding NIH (R01DK132597)

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