{"doi":"10.1101/2021.04.08.435504","title":"Heterogenous impairment of α-cell function in type 2 diabetes is linked to cell maturation state","abstract":"Abstract In diabetes, glucagon secretion from pancreatic α-cells is dysregulated. We examined α-cells from human donors and mice using combined electrophysiological, transcriptomic, and computational approaches. Rising glucose suppresses α-cell exocytosis by reducing P/Q-type Ca 2+ channel activity, and this is disrupted in type 2 diabetes (T2D). Upon high-fat-feeding of mice, α-cells shift towards a ‘β-cell-like’ electrophysiologic profile in concert with an up-regulation of the β-cell Na + channel isoform Scn9a and indications of impaired α-cell identity. In human α-cells we identify links between cell membrane properties and cell surface signalling receptors, mitochondrial respiratory complex assembly, and cell maturation. Cell type classification using machine learning of electrophysiology data demonstrates a heterogenous loss of ‘electrophysiologic identity’ in α-cells from donors with T2D. Indeed, a sub-set of α-cells with impaired exocytosis is defined by an enrichment in progenitor markers suggesting important links between α-cell maturation state and dysfunction in T2D. Key findings α-cell exocytosis is suppressed by glucose-dependent inhibition of P/Q-type Ca 2+ currents Dysfunction of α-cells in type 2 diabetes is associated with a ‘β-cell-like’ electrophysiologic signature Patch-seq links maturation state, the mitochondrial respiratory chain, and cell surface receptor expression to α-cell function α-cell dysfunction occurs preferentially in cells enriched in endocrine lineage markers","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":214755,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9629,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":235295,"name":"Joan Camuñas-Soler","orcid":"0000-0001-6148-8132","position":1,"is_corresponding":false},{"id":483207,"name":"Linford J.B. Briant","orcid":"0000-0003-3619-3177","position":2,"is_corresponding":false},{"id":808775,"name":"Theodore dos Santos","orcid":"0000-0002-9761-3609","position":3,"is_corresponding":false},{"id":727425,"name":"Aliya F Spigelman","orcid":"0000-0001-6188-2041","position":4,"is_corresponding":false},{"id":320873,"name":"Emily M. Walker","orcid":"0000-0001-8394-1567","position":5,"is_corresponding":false},{"id":361506,"name":"Rafael Arrojo e Drigo","orcid":"0000-0001-7712-013X","position":6,"is_corresponding":false},{"id":238645,"name":"Austin Bautista","orcid":null,"position":7,"is_corresponding":false},{"id":73982,"name":"Robert C. Jones","orcid":"0000-0001-7235-9854","position":8,"is_corresponding":false},{"id":235296,"name":"James Lyon","orcid":"0000-0001-7737-5183","position":9,"is_corresponding":false},{"id":809516,"name":"Aifang Nie","orcid":null,"position":10,"is_corresponding":false},{"id":727424,"name":"Nancy Smith","orcid":"0000-0001-6317-7207","position":11,"is_corresponding":false},{"id":255373,"name":"Jocelyn E. Manning Fox","orcid":"0000-0002-4157-2094","position":12,"is_corresponding":false},{"id":44518,"name":"Seung K. Kim","orcid":"0000-0001-6135-7810","position":13,"is_corresponding":false},{"id":281315,"name":"Patrik Rorsman","orcid":"0000-0001-7578-0767","position":14,"is_corresponding":false},{"id":488598,"name":"Roland Stein","orcid":"0000-0002-7577-0013","position":15,"is_corresponding":false},{"id":11049,"name":"Stephen R. Quake","orcid":"0000-0002-1613-0809","position":16,"is_corresponding":false},{"id":7384,"name":"Patrick E. MacDonald","orcid":"0000-0002-5439-6288","position":17,"is_corresponding":false},{"id":808774,"name":"Xiaoqing Dai","orcid":"0000-0002-1957-1060","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T23:52:51.201033Z","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":[]}