{"doi":"10.1126/scitranslmed.adi6148","title":"G6PC2 controls glucagon secretion by defining the set point for glucose in pancreatic α cells","abstract":"Elevated glucagon concentrations have been reported in patients with type 2 diabetes (T2D). A critical role for α cell–intrinsic mechanisms in regulating glucagon secretion was previously established through genetic manipulation of the glycolytic enzyme glucokinase (GCK) in mice. Genetic variation at the glucose-6-phosphatase catalytic subunit 2 ( G6PC2 ) locus, encoding an enzyme that opposes GCK, has been reproducibly associated with fasting blood glucose and hemoglobin A1c. Here, we found that trait-associated variants in the G6PC2 promoter are located in open chromatin not just in β but also in α cells and documented allele-specific G6PC2 expression of linked variants in human α cells. Using α cell–specific gene ablation of G6pc2 in mice, we showed that this gene plays a critical role in controlling glucose suppression of amino acid–stimulated glucagon secretion independent of alterations in insulin output, islet hormone content, or islet morphology, findings that we confirmed in primary human α cells. Collectively, our data demonstrate that G6PC2 affects glycemic control via its action in α cells and possibly suggest that G6PC2 inhibitors might help control blood glucose through a bihormonal mechanism.","journal":"Science Translational Medicine","year":2025,"id":529683,"datarank":0.31191623125197543,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.0,"self_endowment_contribution":0.31191623125197543,"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":0.9521,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1172301,"name":"Reut Rifkind","orcid":null,"position":1,"is_corresponding":false},{"id":1172300,"name":"Eric Waite","orcid":null,"position":2,"is_corresponding":false},{"id":1172302,"name":"Zenab Hamdan","orcid":null,"position":3,"is_corresponding":false},{"id":276651,"name":"Catherine Lee May","orcid":null,"position":4,"is_corresponding":false},{"id":14811,"name":"Elisabetta Manduchi","orcid":"0000-0002-4110-3714","position":5,"is_corresponding":false},{"id":45188,"name":"Benjamin F. Voight","orcid":"0000-0002-6205-9994","position":6,"is_corresponding":false},{"id":650172,"name":"Michelle Y. Y. Lee","orcid":"0000-0002-5574-8011","position":7,"is_corresponding":false},{"id":1172303,"name":"Mark Tigue","orcid":null,"position":8,"is_corresponding":false},{"id":1171934,"name":"Nicholas Manuto","orcid":"0009-0009-0783-8782","position":9,"is_corresponding":false},{"id":1152,"name":"Benjamin Gläser","orcid":"0000-0003-4711-5000","position":10,"is_corresponding":false},{"id":853761,"name":"Dana Avrahami","orcid":null,"position":11,"is_corresponding":false},{"id":250526,"name":"Klaus H. Kaestner","orcid":"0000-0002-1228-021X","position":12,"is_corresponding":false},{"id":650173,"name":"Varun Bahl","orcid":"0000-0002-0789-8613","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:51:01.235017Z","pmid":"39742505","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":[]}