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Polymorphisms that increase islet\n KNCK17<\/jats:italic>\n expression or result in TALK-2 gain-of-function are associated with a predisposition for developing type 2 diabetes. However, there is a gap in knowledge of the beta cell function(s) of TALK-2. As K\n +<\/jats:sup>\n channels typically control beta cell Ca\n 2+<\/jats:sup>\n handling, we aimed to examine the TALK-2 channel control of beta cell Ca\n 2+<\/jats:sup>\n homeostasis and the resulting impact on insulin secretion.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Localisation of TALK-2 was evaluated with immunofluorescent staining as well as TALK-2-GFP construct co-expressed with intracellular markers. TALK-2 function was evaluated by measuring changes in cytoplasmic Ca\n 2+<\/jats:sup>\n (Ca\n 2+<\/jats:sup>\n C<\/jats:sub>\n ), endoplasmic reticulum Ca\n 2+<\/jats:sup>\n (Ca\n 2+<\/jats:sup>\n ER<\/jats:sub>\n ), ER membrane potential (\n V<\/jats:italic>\n m<\/jats:sub>\n ), K\n +<\/jats:sup>\n currents and insulin secretion in a TALK-2 inducible cell line and\/or primary human beta cells with adenoviral-mediated shRNA knockdown (KD) of TALK-2 or scramble shRNA.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n TALK-2 protein localised to the plasma membrane and ER membrane, and formed functional channels on the ER membrane. Ca\n 2+<\/jats:sup>\n ER<\/jats:sub>\n release was accelerated by TALK-2 (slope for TALK-2-expressing cells vs controls: 14.8\u00a0\u00b1\u00a00.7 vs 8.9\u00a0\u00b1\u00a01.3, respectively, shown as mean\u00a0\u00b1\u00a0SE), which reduced Ca\n 2+<\/jats:sup>\n ER<\/jats:sub>\n storage (\u0394Ca\n 2+<\/jats:sup>\n ER<\/jats:sub>\n amplitude: TALK-2-expressing cells reduced by 25\u00a0\u00b1\u00a05%) and increased basal relative Ca\n 2+<\/jats:sup>\n C<\/jats:sub>\n (fold increase by 12\u00a0\u00b1\u00a02%). Furthermore, TALK-2 diminished ER membrane hyperpolarisation following Ca\n 2+<\/jats:sup>\n ER<\/jats:sub>\n release (Accelerated Sensor of Action Potentials [ASAP3\n ER<\/jats:sub>\n ] amplitude decreased by 20\u00a0\u00b1\u00a00.8% in TALK-2-expressing cells), suggesting that TALK-2 strengthens the electrical driving force for Ca\n 2+<\/jats:sup>\n ER<\/jats:sub>\n leak. In human beta cells, TALK-2-KD increased Ca\n 2+<\/jats:sup>\n ER<\/jats:sub>\n stores by reducing Ca\n 2+<\/jats:sup>\n ER<\/jats:sub>\n leak (2.30\u00a0\u00b1\u00a00.12 vs controls 2.65\u00a0\u00b1\u00a00.14). Moreover, TALK-2-KD reduced beta cell Ca\n 2+<\/jats:sup>\n C<\/jats:sub>\n at euglycaemic conditions (2.88\u00a0\u00b1\u00a00.36 vs controls 3.16\u00a0\u00b1\u00a00.36) and increased beta cell Ca\n 2+<\/jats:sup>\n C<\/jats:sub>\n influx in response to hyperglycaemic conditions (4.07\u00a0\u00b1\u00a00.55 vs controls 3.45\u00a0\u00b1\u00a00.48). Human pseudoislets with beta cell-specific TALK-2-KD displayed reduced basal insulin secretion (0.266\u00a0\u00b1\u00a00.065 vs controls 0.432\u00a0\u00b1\u00a00.073) and enhanced glucose-stimulated insulin secretion (GSIS; 85.01\u00a0\u00b1\u00a013.96 vs controls 42.53\u00a0\u00b1\u00a05.52).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions\/interpretation<\/jats:title>\n \n These data support the notion that TALK-2 functions on the human beta cell ER membrane to increase the electrical driving force for beta cell Ca\n 2+<\/jats:sup>\n ER<\/jats:sub>\n release, reduces glucose-stimulated Ca\n 2+<\/jats:sup>\n influx and limits GSIS. Furthermore, TALK-2-mediated amplification of Ca\n 2+<\/jats:sup>\n ER<\/jats:sub>\n leak likely enhances basal insulin secretion by increasing Ca\n 2+<\/jats:sup>\n C<\/jats:sub>\n . Therefore, polymorphisms in\n KCNK17<\/jats:italic>\n that increase TALK-2 activity or expression would be predicted to increase type 2 diabetes risk by blunting beta cell glucose-stimulated Ca\n 2+<\/jats:sup>\n influx, limiting GSIS, promoting Ca\n 2+<\/jats:sup>\n ER<\/jats:sub>\n leak and elevating basal insulin secretion.\n <\/jats:p>\n <\/jats:sec>\n \n Graphical Abstract<\/jats:title>\n <\/jats:sec>","DOI":"10.1007\/s00125-026-06683-9","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T14:43:42Z","timestamp":1772030622000},"page":"1581-1599","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The diabetes-associated K+ channel TALK-2 controls human beta cell endoplasmic reticulum Ca2+ handling, which promotes basal insulin release and limits glucose-stimulated insulin secretion"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1815-1279","authenticated-orcid":false,"given":"Jordyn R.","family":"Dobson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5377-5991","authenticated-orcid":false,"given":"Prasanna K.","family":"Dadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6187-3951","authenticated-orcid":false,"given":"Matthew T.","family":"Dickerson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2192-5865","authenticated-orcid":false,"given":"Arya Y.","family":"Nakhe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7171-3050","authenticated-orcid":false,"given":"Soma","family":"Behera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3596-469X","authenticated-orcid":false,"given":"Shannon E.","family":"Gibson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6147-0046","authenticated-orcid":false,"given":"Spencer J.","family":"Peachee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7931-3784","authenticated-orcid":false,"given":"Anthony","family":"Piron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5112-1692","authenticated-orcid":false,"given":"Miriam","family":"Cnop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1816-5375","authenticated-orcid":false,"given":"David A.","family":"Jacobson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"issue":"6","key":"6683_CR1","doi-asserted-by":"publisher","first-page":"379","DOI":"10.3390\/biology13060379","volume":"13","author":"JR Dobson","year":"2024","unstructured":"Dobson JR, Jacobson DA (2024) Disrupted endoplasmic reticulum Ca(2+) handling: a harbetainger of beta-cell failure. 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The IIDP (NIH grant no. 2UC4DK098085) supported this work by providing human islets. The Vanderbilt Cell Imaging Shared Resource allowed for confocal microscopy of live cells and tissue sections (DK020593). pCAG-ASAP3\n ER\n was a gift from B. Bloodgood (Addgene plasmid no. 195356;\n \n ; RRID: Addgene195356; Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA). GCEPIA1-SNAPER was a gift from P. Xu (Addgene plasmid no. 172659;\n \n ; RRID: Addgene_172659; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China). ER-RpHLuorin2 was a gift from G. van den Bogaart (Addgene plasmid no. 171717;\n \n ; RRID: Addgene_ 171717; Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands). HEK293 cells were kindly provided by R. Colbran (Molecular Physiology and Biophysics Department, Vanderbilt University). Figure schematics were created using BioRender.com. Some of the data were presented as an abstract at the 60\n th\n EASD Annual Meeting of the European Association for the Study of Diabetes meeting in 2024.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The authors declare that all data supporting the findings of this study are available and will be shared upon request. The eQTL dataset used in this study was obtained from Alonso et al [\n \n ], and the corresponding summary statistics are available through the TIGER portal,\n \n . The multi-ancestry GWAS dataset was derived from Suzuki et al [\n \n ], with summary statistics accessible from the DIAGRAM consortium website,\n \n .","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This research was funded by grants from the National Institutes of Health (NIH) (DK129340-S1, DK129340, DK136768 and DK097392), NIH training grants (1T32GM139800-01, 5T32DK07563), and the Leona M. and Harry B. Helmsley Charitable Trust (G-1912-03550). MC acknowledges support from the European Union\u2019s Horizon 2020 research and innovation program T2DSystems under grant agreement no. 667191 and the Walloon Region strategic axis Fonds de la Recherche Scientifique (FRFS)\u2013Walloon Excellence in Life Sciences and Biotechnology (WELBIO). AP is funded by Fonds de la Recherche Scientifique (FNRS).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"JRD and DAJ conceptualised the design of the project and wrote the manuscript. All authors performed experiments and data acquisition detailed here. JRD, SB and PKD assisted with human pseudoislet formation. JRD, MTD and SJP conducted electrophysiology recordings. JRD and SEG performed live cell imaging. AYN and PKD developed the TALK-2 inducible cell line. JRD performed dynamic insulin secretion and statistical analysis. MC and AP performed the co-localisation analysis of human islet eQTL and multi-ancestry GWAS. All authors critically reviewed the manuscript and approve the final version. DAJ is the guarantor of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}