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Ghrelin receptor, a growth hormone secretagogue receptor (GHS-R), is expressed in the pancreas. Emerging evidence indicates that GHS-R is involved in the regulation of glucose-stimulated insulin secretion (GSIS), but the mechanism by which GHS-R regulates GSIS in the pancreas is unclear. In this study, we investigated the role of GHS-R on GSIS in detail using global <i>Ghsr</i>^−/− mice (in vivo) and <i>Ghsr</i>-ablated pancreatic islets (ex vivo). GSIS was attenuated in both <i>Ghsr</i>^−/− mice and <i>Ghsr</i>-ablated islets, while the islet morphology was similar between WT and <i>Ghsr</i>^−/− mice. To elucidate the mechanism underpinning <i>Ghsr</i>-mediated GSIS, we investigated the key steps of the GSIS signaling cascade. The gene expression of glucose transporter 2 (<i>Glut2</i>) and the glucose-metabolic intermediate—glucose-6-phosphate (G6P) were reduced in <i>Ghsr</i>-ablated islets, supporting decreased glucose uptake. There was no difference in mitochondrial DNA content in the islets of WT and <i>Ghsr</i>^−/− mice, but the ATP/ADP ratio in <i>Ghsr</i>^−/− islets was significantly lower than that of WT islets. Moreover, the expression of pancreatic and duodenal homeobox 1 (Pdx1), as well as insulin signaling genes of insulin receptor (IR) and insulin receptor substrates 1 and 2 (IRS1/IRS2), was downregulated in <i>Ghsr</i>^−/− islets. Akt is the key mediator of the insulin signaling cascade. Concurrently, Akt phosphorylation was reduced in the pancreas of <i>Ghsr</i>^−/− mice under both insulin-stimulated and homeostatic conditions. These findings demonstrate that GHS-R ablation affects key components of the insulin signaling pathway in the pancreas, suggesting the existence of a cross-talk between GHS-R and the insulin signaling pathway in pancreatic islets, and GHS-R likely regulates GSIS via the Akt-Pdx1-GLUT2 pathway.