{"doi":"10.1172/jci156243","title":"α Cell dysfunction in islets from nondiabetic, glutamic acid decarboxylase autoantibody–positive individuals","abstract":"BACKGROUNDMultiple islet autoantibodies (AAbs) predict the development of type 1 diabetes (T1D) and hyperglycemia within 10 years. By contrast, T1D develops in only approximately 15% of individuals who are positive for single AAbs (generally against glutamic acid decarboxylase [GADA]); hence, the single GADA+ state may represent an early stage of T1D.METHODSHere, we functionally, histologically, and molecularly phenotyped human islets from nondiabetic GADA+ and T1D donors.RESULTSSimilar to the few remaining β cells in the T1D islets, GADA+ donor islets demonstrated a preserved insulin secretory response. By contrast, α cell glucagon secretion was dysregulated in both GADA+ and T1D islets, with impaired glucose suppression of glucagon secretion. Single-cell RNA-Seq of GADA+ α cells revealed distinct abnormalities in glycolysis and oxidative phosphorylation pathways and a marked downregulation of cAMP-dependent protein kinase inhibitor β (PKIB), providing a molecular basis for the loss of glucose suppression and the increased effect of 3-isobutyl-1-methylxanthine (IBMX) observed in GADA+ donor islets.CONCLUSIONWe found that α cell dysfunction was present during the early stages of islet autoimmunity at a time when β cell mass was still normal, raising important questions about the role of early α cell dysfunction in the progression of T1D.FUNDINGThis work was supported by grants from the NIH (3UC4DK112217-01S1, U01DK123594-02, UC4DK112217, UC4DK112232, U01DK123716, and P30 DK019525) and the Vanderbilt Diabetes Research and Training Center (DK20593).","journal":"Journal of Clinical Investigation","year":2022,"id":236726,"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":66,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9388,"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":858386,"name":"Andrea V. Rozo","orcid":null,"position":1,"is_corresponding":false},{"id":858387,"name":"Jeffrey Roman","orcid":null,"position":2,"is_corresponding":false},{"id":630425,"name":"Wei Qin","orcid":"0000-0001-8042-8784","position":3,"is_corresponding":false},{"id":625169,"name":"Daniel Traum","orcid":"0000-0002-0195-5525","position":4,"is_corresponding":false},{"id":503533,"name":"Long Gao","orcid":"0000-0002-2631-6914","position":5,"is_corresponding":false},{"id":857720,"name":"Jinping Liu","orcid":"0000-0002-4854-1610","position":6,"is_corresponding":false},{"id":14811,"name":"Elisabetta Manduchi","orcid":"0000-0002-4110-3714","position":7,"is_corresponding":false},{"id":109220,"name":"Chengyang Liu","orcid":"0000-0002-5802-1547","position":8,"is_corresponding":false},{"id":304327,"name":"Maria L. Golson","orcid":"0000-0002-2927-2013","position":9,"is_corresponding":false},{"id":250527,"name":"Golnaz Vahedi","orcid":"0000-0002-2249-8247","position":10,"is_corresponding":false},{"id":109221,"name":"Ali Naji","orcid":"0000-0002-6926-3306","position":11,"is_corresponding":false},{"id":152894,"name":"Franz M. Matschinsky","orcid":null,"position":12,"is_corresponding":false},{"id":23929,"name":"Mark A. Atkinson","orcid":"0000-0001-8489-4782","position":13,"is_corresponding":false},{"id":7379,"name":"Alvin C. Powers","orcid":"0000-0003-1941-5786","position":14,"is_corresponding":false},{"id":250528,"name":"Marcela Briššová","orcid":"0000-0002-4999-3280","position":15,"is_corresponding":false},{"id":250526,"name":"Klaus H. Kaestner","orcid":"0000-0002-1228-021X","position":16,"is_corresponding":false},{"id":304326,"name":"Doris A. Stoffers","orcid":"0000-0003-2626-2124","position":17,"is_corresponding":false},{"id":415494,"name":"Nicolai M. Doliba","orcid":"0000-0003-4598-9222","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T00:22:03.686498Z","pmid":"35642629","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":[]}