{"doi":"10.7554/elife.89967.1.sa0","title":"Reviewer #3 (Public Review): The MODY-associated TALK-1 L114P mutation causes islet α-cell overactivity and β-cell inactivity resulting in transient neonatal diabetes and glucose dyshomeostasis in adults","abstract":"A gain-of-function mutation in the TALK-1 K+ channel (p.L114P) associated with maturity-onset diabetes of the young (MODY) was recently reported in two distinct families. TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion (GSIS). KCNK16, the gene that encodes TALK-1, is the most abundant and β-cell– restricted K+ channel transcript; polymorphisms in the KCNK16 locus are also associated with an increased risk of type-2 diabetes. To investigate the impact of TALK-1-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 mixed C57BL/6J: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 GSIS and can be reduced with insulin treatment. TALK-1-L114P drastically increased whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and loss of glucose-induced Ca2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced GSIS and plasma insulin levels, which significantly impaired glucose homeostasis. Taken together, this study determined that the MODY-associated TALK-1-L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by altering islet hormone secretion during development. These data strongly suggest that TALK-1 is an islet-restricted target for the treatment of diabetes.","journal":null,"year":2023,"id":411623,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9564,"is_data_producer":false,"deposit_databanks":null,"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":1192321,"name":"Shrestha Shristi","orcid":null,"position":3,"is_corresponding":false},{"id":1192322,"name":"Cartailler Jean-Philippe","orcid":null,"position":4,"is_corresponding":false},{"id":699524,"name":"Leesa Sampson","orcid":"0000-0002-2523-7616","position":5,"is_corresponding":false},{"id":289722,"name":"Mark A. Magnuson","orcid":"0000-0002-8824-6499","position":6,"is_corresponding":false},{"id":345680,"name":"David A. Jacobson","orcid":"0000-0003-1816-5375","position":7,"is_corresponding":false},{"id":1192320,"name":"Nakhe Arya Y.","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T01:21:42.971455Z","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":[]}