{"doi":"10.2337/db19-1106","title":"Role of Proinsulin Self-Association in Mutant <i>INS</i> Gene–Induced Diabetes of Youth","abstract":"gene-induced diabetes of youth (MIDY). How these abnormal interactions are initiated remains unknown. Normally, PI-WT dimerizes in the ER. Here, we suggest that the normal PI-PI contact surface, involving the B-chain, contributes to dominant-negative effects of misfolded MIDY mutants. Specifically, we find that PI B-chain tyrosine-16 (Tyr-B16), which is a key residue in normal PI dimerization, helps confer dominant-negative behavior of MIDY mutant PI-C(A7)Y. Substitutions of Tyr-B16 with either Ala, Asp, or Pro in PI-C(A7)Y decrease the abnormal interactions between the MIDY mutant and PI-WT, rescuing PI-WT export, limiting ER stress, and increasing insulin production in β-cells and human islets. This study reveals the first evidence indicating that noncovalent PI-PI contact initiates dominant-negative behavior of misfolded PI, pointing to a novel therapeutic target to enhance PI-WT export and increase insulin production.","journal":"Diabetes","year":2020,"id":98333,"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":31,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"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":485139,"name":"Yi Xiong","orcid":"0000-0001-5064-4320","position":1,"is_corresponding":false},{"id":485140,"name":"Xin Li","orcid":"0000-0002-8898-9938","position":2,"is_corresponding":false},{"id":33712,"name":"Leena Haataja","orcid":"0000-0003-3701-4679","position":3,"is_corresponding":false},{"id":485141,"name":"Wei Chen","orcid":"0000-0002-6267-169X","position":4,"is_corresponding":false},{"id":485142,"name":"Saiful A. Mir","orcid":"0000-0003-1179-3774","position":5,"is_corresponding":false},{"id":485892,"name":"Li Lv","orcid":null,"position":6,"is_corresponding":false},{"id":184323,"name":"Rachel Madley","orcid":null,"position":7,"is_corresponding":false},{"id":485893,"name":"Dennis Larkin","orcid":null,"position":8,"is_corresponding":false},{"id":485143,"name":"Arfah Anjum","orcid":"0000-0003-0602-3206","position":9,"is_corresponding":false},{"id":338985,"name":"Balamurugan Dhayalan","orcid":"0000-0001-6002-1207","position":10,"is_corresponding":false},{"id":338983,"name":"Nischay Rege","orcid":"0000-0002-3858-9530","position":11,"is_corresponding":false},{"id":338986,"name":"Nalinda P. Wickramasinghe","orcid":"0000-0002-8700-2775","position":12,"is_corresponding":false},{"id":338990,"name":"Michael A. Weiss","orcid":"0000-0003-1325-1610","position":13,"is_corresponding":false},{"id":485144,"name":"Pamela Itkin‐Ansari","orcid":"0000-0002-8759-3034","position":14,"is_corresponding":false},{"id":250288,"name":"Randal J. Kaufman","orcid":"0000-0003-4277-316X","position":15,"is_corresponding":false},{"id":34148,"name":"David A. Ostrov","orcid":"0000-0002-4696-875X","position":16,"is_corresponding":false},{"id":33730,"name":"Peter Arvan","orcid":"0000-0002-4007-8799","position":17,"is_corresponding":false},{"id":289733,"name":"Ming Liu","orcid":"0000-0003-2665-4072","position":18,"is_corresponding":false},{"id":184322,"name":"Jinhong Sun","orcid":null,"position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-18T22:36:34.157932Z","pmid":"32139596","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":[]}