{"doi":"10.7554/elife.89967","title":"The MODY-associated KCNK16 L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults","abstract":"The gain-of-function mutation in the TALK-1 K + channel (p.L114P) is associated with maturity-onset diabetes of the young (MODY). TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion. The KCNK16 gene encoding TALK-1 is the most abundant and β-cell-restricted K + channel transcript. To investigate the impact of KCNK16 L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation was generated. Heterozygous and homozygous Kcnk16 L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1 (ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous Kcnk16 L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. Kcnk16 L114P increased whole-cell β-cell K + currents resulting in blunted glucose-stimulated Ca 2+ entry and loss of glucose-induced Ca 2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes.","journal":"eLife","year":2023,"id":366119,"datarank":0.3454968264995648,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.05361030414126777,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.05361030414126777,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":5,"citers_with_citation_signal":4,"citers_with_endowment":4,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE239566"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":369839,"name":"Prasanna K. Dadi","orcid":"0000-0001-5377-5991","position":1,"is_corresponding":false},{"id":1122346,"name":"Jin‐Sun Kim","orcid":"0000-0001-9382-7442","position":2,"is_corresponding":false},{"id":346921,"name":"Matthew T. Dickerson","orcid":"0000-0002-6187-3951","position":3,"is_corresponding":false},{"id":1122815,"name":"Soma Behera","orcid":null,"position":4,"is_corresponding":false},{"id":866320,"name":"Jordyn R Dobson","orcid":"0009-0007-1815-1279","position":5,"is_corresponding":false},{"id":250518,"name":"Shristi Shrestha","orcid":"0000-0003-4519-1712","position":6,"is_corresponding":false},{"id":250517,"name":"Jeeyeon Cha","orcid":"0000-0002-0312-2391","position":7,"is_corresponding":false},{"id":699524,"name":"Leesa Sampson","orcid":"0000-0002-2523-7616","position":8,"is_corresponding":false},{"id":289722,"name":"Mark A. Magnuson","orcid":"0000-0002-8824-6499","position":9,"is_corresponding":false},{"id":345680,"name":"David A. Jacobson","orcid":"0000-0003-1816-5375","position":10,"is_corresponding":false},{"id":1122345,"name":"Arya Y. Nakhe","orcid":"0000-0003-2192-5865","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T01:14:55.198227Z","pmid":"38700926","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":[]}