3117-LB: A Novel SSTR2a, ZT-01, Enhances First-Phase Insulin Secretion from Pancreatic Islets Isolated from Healthy Male Mice

Introduction and Objective: Pharmacological blockade of somatostatin receptor 2 (SSTR2a) enhances glucagon secretion during hypoglycemia in diabetic rats. However, the effect of SSTR2a on insulin secretion at physiological postprandial glucose levels remains unclear. Here, we investigated the effect of SSTR2 antagonism on insulin secretion dynamics in healthy mouse islets via the islets-on-a-chip technique and examined whether this effect is mediated by glucagon signalling via GLP1R on β-cells. Methods: Islets isolated from male FVB/NJ mice (n=1-2 mice, 10-12 weeks old) were treated +/- SSTR2a (ZT-01, 300 nM) and GLP1R antagonist (Exendin 9-39, 1 μM) at 2 mM and 8 mM glucose. Fluorescent anisotropy of C-peptide secretion from individual islets was employed to investigate the effect of each treatment on insulin secretion dynamics. Results: Treatment of islets with ZT-01 led to a 3-fold increase in first-phase insulin (FPIR) secretion compared to control islets. This effect was found to be mediated by glucagon signalling via GLP1R on β-cells, as addition of Exendin 9-39 attenuated the FPIR response comparable to that of the control group. Conclusion: Removing the inhibitory effect of somatostatin from pancreatic α-cells enhances glucagon secretion, which in turn amplifies FPIR via the GLP1Rs signaling pathway in β-cells. This work suggests that SST modulates the temporal dynamics of insulin secretion via a glucagon-dependent GLP-1R mechanism. Disclosure S. Fatehi: None. N. Gulati: None. Y. Wang: None. R. Liggins: Employee; Current; Zucara Therapeutics. M. Riddell: Research Support; Ended; Dexcom, Inc. Speaker's Bureau; Current; Dexcom, Inc., Novo Nordisk. Consultant; Current; Jaeb Center for Health Research. Advisory Panel; Current; Zucara Therapeutics. J.V. Rocheleau: None.