{"doi":"10.2337/db21-0170","title":"Syntaxin 4 Enrichment in β-Cells Prevents Conversion to Autoimmune Diabetes in Non-Obese Diabetic (NOD) Mice","abstract":"Syntaxin 4 (STX4), a plasma membrane–localized SNARE protein, regulates human islet β-cell insulin secretion and preservation of β-cell mass. We found that human type 1 diabetes (T1D) and NOD mouse islets show reduced β-cell STX4 expression, consistent with decreased STX4 expression, as a potential driver of T1D phenotypes. To test this hypothesis, we generated inducible β-cell–specific STX4-expressing NOD mice (NOD-iβSTX4). Of NOD-iβSTX4 mice, 73% had sustained normoglycemia vs. <20% of control NOD (NOD-Ctrl) mice by 25 weeks of age. At 12 weeks of age, before diabetes conversion, NOD-iβSTX4 mice demonstrated superior whole-body glucose tolerance and β-cell glucose responsiveness than NOD-Ctrl mice. Higher β-cell mass and reduced β-cell apoptosis were also detected in NOD-iβSTX4 pancreata compared with pancreata of NOD-Ctrl mice. Single-cell RNA sequencing revealed that islets from NOD-iβSTX4 had markedly reduced interferon-γ signaling and tumor necrosis factor-α signaling via nuclear factor-κB in islet β-cells, including reduced expression of the chemokine CCL5; CD4+ regulatory T cells were also enriched in NOD-iβSTX4 islets. These results provide a deeper mechanistic understanding of STX4 function in β-cell protection and warrant further investigation of STX4 enrichment as a strategy to reverse or prevent T1D in humans or protect β-cell grafts.","journal":"Diabetes","year":2021,"id":199404,"datarank":0.4273224966334212,"base_score":2.302585092994046,"endowment":2.302585092994046,"self_citation_contribution":0.3453877639491069,"citation_network_contribution":0.0819347326843143,"self_endowment_contribution":0.3453877639491069,"citer_contribution":0.0819347326843143,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":4,"citers_with_citation_signal":3,"citers_with_endowment":3,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9569,"is_data_producer":true,"deposit_databanks":{"figshare":["10.2337/figshare.16613851"]},"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":776519,"name":"Erika M. McCown","orcid":null,"position":1,"is_corresponding":false},{"id":754933,"name":"Miwon Ahn","orcid":"0009-0000-5723-4447","position":2,"is_corresponding":false},{"id":641873,"name":"Pablo Andrés García","orcid":"0000-0003-1900-1831","position":3,"is_corresponding":false},{"id":274022,"name":"Sergio Branciamore","orcid":"0000-0002-2556-8765","position":4,"is_corresponding":false},{"id":253787,"name":"Shanshan Tang","orcid":"0000-0002-1115-6479","position":5,"is_corresponding":false},{"id":474662,"name":"Defu Zeng","orcid":"0000-0001-9585-1411","position":6,"is_corresponding":false},{"id":369809,"name":"Bart O. Roep","orcid":"0000-0002-3110-7391","position":7,"is_corresponding":false},{"id":241714,"name":"Debbie C. Thurmond","orcid":"0000-0002-6303-4596","position":8,"is_corresponding":false},{"id":754934,"name":"Eunjin Oh","orcid":"0009-0003-9437-0570","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-18T23:50:40.558460Z","pmid":"34556496","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":[]}