200-OR: Role of Delta Cell Gpr120 in the Regulation of Islet Function and Glucose Control

Gpr120 is a long-chain fatty acid receptor expressed in pancreatic islets, where it inhibits the secretion of somatostatin (SST) by the δ cell. SST is a negative regulator of glucoregulatory hormone secretion. However, the precise role of Gpr120 in the regulation of insulin and glucagon secretion is still unclear, as well as the specific islet cell(s) type(s) involved. Objective: This study aimed at defining the role of pancreatic δ-cell Gpr120 signaling in the regulation of islet function and glucose homeostasis. Methods: Insulin and SST secretion was measured in isolated islets from WT, Gpr120 KO and Gpr40 KO mice in 1h static incubation in the presence of 2.8 or 16.7 mM glucose with or without synthetic (Compound A, Cpd A) or endogenous (alpha-linolenic, eicosapentaenoic or docosahexaenoic acid) Gpr120 agonists. Glucagon and SST secretion was measured after 1h static incubation in response to arginine with or without Cpd A. Cpd A was administered orally to WT male mice before an oral Glucose Tolerance Test or an Arginine Test, and blood glucose and insulin or glucagon plasma levels were measured. Results: In isolated islets from WT mice, activation of Gpr120 with either Cpd A or endogenous agonists dose-dependently inhibited glucose-stimulated SST secretion, and concomitantly increased glucose-stimulated insulin secretion. Cpd A also inhibited SST secretion and potentiated glucagon secretion in response to arginine in low glucose conditions. The effects of Cpd A were unaltered in Gpr40 KO islets but disappeared in Gpr120 KO islets. Oral administration of Cpd A improved glucose tolerance and potentiated both glucose-induced insulin secretion and arginine-induced glucagon secretion. Conclusion: The results demonstrate that Gpr120 activation in islets inhibits SST secretion, potentiates insulin and glucagon secretion, and improves glycemic control.