{"doi":"10.3390/biom12030407","title":"Mechanistic Investigation of GHS-R Mediated Glucose-Stimulated Insulin Secretion in Pancreatic Islets","abstract":"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 Ghsr−/− mice (in vivo) and Ghsr-ablated pancreatic islets (ex vivo). GSIS was attenuated in both Ghsr−/− mice and Ghsr-ablated islets, while the islet morphology was similar between WT and Ghsr−/− mice. To elucidate the mechanism underpinning Ghsr-mediated GSIS, we investigated the key steps of the GSIS signaling cascade. The gene expression of glucose transporter 2 (Glut2) and the glucose-metabolic intermediate—glucose-6-phosphate (G6P) were reduced in Ghsr-ablated islets, supporting decreased glucose uptake. There was no difference in mitochondrial DNA content in the islets of WT and Ghsr−/− mice, but the ATP/ADP ratio in Ghsr−/− 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 Ghsr−/− islets. Akt is the key mediator of the insulin signaling cascade. Concurrently, Akt phosphorylation was reduced in the pancreas of Ghsr−/− 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.","journal":"Biomolecules","year":2022,"id":288740,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9611,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":747425,"name":"Jong Han Lee","orcid":"0000-0002-5614-1537","position":1,"is_corresponding":false},{"id":747423,"name":"Chia‐Shan Wu","orcid":"0000-0002-6034-939X","position":2,"is_corresponding":false},{"id":969479,"name":"Hongying Wang","orcid":"0000-0002-8107-3492","position":3,"is_corresponding":false},{"id":784543,"name":"Ligen Lin","orcid":"0000-0002-6799-5327","position":4,"is_corresponding":false},{"id":355552,"name":"Taraka Donti","orcid":"0000-0002-3830-155X","position":5,"is_corresponding":false},{"id":55850,"name":"Brett H. Graham","orcid":"0000-0001-8451-8154","position":6,"is_corresponding":false},{"id":969884,"name":"Arun S. Rajan","orcid":null,"position":7,"is_corresponding":false},{"id":249640,"name":"Ashok Balasubramanyam","orcid":"0000-0003-2093-5201","position":8,"is_corresponding":false},{"id":354478,"name":"Susan L. Samson","orcid":"0000-0002-8159-7093","position":9,"is_corresponding":false},{"id":695315,"name":"Shaodong Guo","orcid":"0000-0001-5126-731X","position":10,"is_corresponding":false},{"id":484733,"name":"Yuxiang Sun","orcid":"0000-0002-6656-3733","position":11,"is_corresponding":false},{"id":747909,"name":"Geetali Pradhan","orcid":null,"position":0,"is_corresponding":true}],"reference_count":115,"raw_metadata":null,"created_at":"2026-07-19T00:30:14.968626Z","pmid":"35327599","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}