{"doi":"10.1101/2020.05.12.081588","title":"Testosterone enhances GLP-1 efficacy at the plasma membrane and endosomes to augment insulin secretion in male pancreatic β cells","abstract":"Abstract Male mice with elimination of the androgen receptor (AR) in islet β cells (βARKO) exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hypoinsulinemia and hyperglycemia when challenged with a Western diet. Testosterone activation of an extranuclear AR in β cells potentiates GSIS by amplifying the insulinotropic action of glucagon-like peptide-1 (GLP-1). Here, using a combination of βARKO and β cell-selective GLP-1 receptor knockout mice and their islets, we show that AR activation in β cells amplifies the insulinotropic effect of islet-derived GLP-1. In β cell models expressing cAMP sensors, testosterone enhances the ability of GLP-1, but not that of glucose-dependent insulinotropic polypeptide or glucagon, to produce cAMP. Accordingly, testosterone selectively enhances the ability of GLP-1 to potentiate GSIS. Notably, testosterone enhances GLP-1 production of cAMP at the plasma membrane and endosomes. In male mouse and human islets, the insulinotropic effect of testosterone is abolished following inhibition of the membrane and endosomal cAMP-dependent protein kinase A and exchange protein activated by cAMP islet 2 pathways. Thus, membrane localization of AR enhances the ability of the GLP-1 receptor to produce cAMP, thus increasing glucose-stimulated insulin exocytosis. Significance Statement This study reveals that testosterone, acting on the androgen receptor (AR) in insulin-producing β cells amplifies the insulinotropic action of glucagon-like peptide-1 (GLP-1) by increasing GLP-1-mediated production of cAMP at the plasma membrane and endosomal compartments, to promote insulin vesicles exocytosis in human β cells. This study establishes a novel biological paradigm in which membrane location of a steroid nuclear receptor enhances the ability of a G protein-coupled receptor to produce cAMP. It has exceptional clinical significance for targeted delivery of testosterone to β cells in the large population of aging and androgen-deficient men who are at increased risk of diabetes.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":129622,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9482,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":260258,"name":"Fiona Ashford","orcid":"0000-0002-2946-3864","position":1,"is_corresponding":false},{"id":581258,"name":"Stavroula Bitsi","orcid":"0000-0001-5536-7123","position":2,"is_corresponding":false},{"id":504660,"name":"Lina Schiffer","orcid":"0000-0001-8540-4861","position":3,"is_corresponding":false},{"id":251235,"name":"Mirza Muhammad Fahd Qadir","orcid":"0000-0002-6764-6151","position":4,"is_corresponding":false},{"id":239621,"name":"Wiebke Arlt","orcid":"0000-0001-5106-9719","position":5,"is_corresponding":false},{"id":260266,"name":"Alejandra Tomás","orcid":"0000-0002-2290-8453","position":6,"is_corresponding":false},{"id":236999,"name":"David J. Hodson","orcid":"0000-0002-8641-8568","position":7,"is_corresponding":false},{"id":104951,"name":"Franck Mauvais‐Jarvis","orcid":"0000-0002-0874-0754","position":8,"is_corresponding":false},{"id":581257,"name":"Weiwei Xu","orcid":"0000-0002-8723-0778","position":0,"is_corresponding":true}],"reference_count":28,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:15:49.682497Z","pmid":null,"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":[]}