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This study aimed to explore the function of human K cells at the molecular and cellular levels.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>CRISPR-Cas9 homology-directed repair was used to insert transgenes encoding a yellow fluorescent protein (Venus) or an Epac-based cAMP sensor (Epac-S-H187) in the GIP locus in human duodenal-derived organoids. Fluorescently labelled K cells were purified by FACS for RNA-seq and peptidomic analysis. GIP reporter organoids were employed for GIP secretion assays, live-cell imaging of Ca<jats:sup>2+<\/jats:sup> using Fura-2 and cAMP using Epac-S-H187, and basic electrophysiological characterisation. The G protein-coupled receptor genes <jats:italic>GPR142<\/jats:italic> and <jats:italic>CASR<\/jats:italic> were knocked out to evaluate roles in amino acid sensing.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>RNA-seq of human duodenal K cells revealed enrichment of several G protein-coupled receptors involved in nutrient sensing, including <jats:italic>FFAR1<\/jats:italic>, <jats:italic>GPBAR1<\/jats:italic>, <jats:italic>GPR119<\/jats:italic>, <jats:italic>CASR<\/jats:italic> and <jats:italic>GPR142<\/jats:italic>. Glucose induced action potential firing and cytosolic Ca<jats:sup>2+<\/jats:sup> elevation and caused a 1.8-fold increase in GIP secretion, which was inhibited by the sodium glucose co-transporter 1\/2 (SGLT1\/2) blocker sotagliflozin. Activation of the long-chain fatty acid receptor free fatty acid receptor 1 (FFAR1) induced a 2.7-fold increase in GIP secretion, while tryptophan and phenylalanine stimulated secretion by 2.8- and 2.1-fold, respectively. While <jats:italic>CASR<\/jats:italic> knockout blunted intracellular Ca<jats:sup>2+<\/jats:sup> responses, a <jats:italic>CASR<\/jats:italic>\/<jats:italic>GPR142<\/jats:italic> double knockout was needed to reduce GIP secretory responses to aromatic amino acids.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions\/interpretation<\/jats:title>\n                <jats:p>The newly generated human organoid K cell model enables transcriptomic and functional characterisation of nutrient-sensing pathways involved in human GIP secretion. Both calcium-sensing receptor (CASR) and G protein-coupled receptor 142 (GPR142) contribute to protein-stimulated GIP secretion. This model will be further used to identify potential targets for modulation of native GIP secretion in diabetes and obesity.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical Abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1007\/s00125-024-06293-3","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T06:02:59Z","timestamp":1729663379000},"page":"217-230","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Molecular mechanisms underlying glucose-dependent insulinotropic polypeptide secretion in human duodenal organoids"],"prefix":"10.1007","volume":"68","author":[{"given":"Nunzio","family":"Guccio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constanza","family":"Alcaino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily L.","family":"Miedzybrodzka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Santos-Hern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Davison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rula","family":"Bany Bakar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard G.","family":"Kay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Reimann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona M.","family":"Gribble","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,23]]},"reference":[{"key":"6293_CR1","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1146\/annurev-nutr-062320-113625","volume":"42","author":"N Guccio","year":"2022","unstructured":"Guccio N, Gribble FM, Reimann F (2022) Glucose-dependent insulinotropic polypeptide-a postprandial hormone with unharnessed metabolic potential. 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Some of the data were presented as an abstract at the 58th EASD Annual Meeting of the EASD in 2022 and the 5th European Incretin Study Group meeting in 2024.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"RNA-seq data are deposited in the National Center for Biotechnology Information\u2013Gene Expression Omnibus (NCBI GEO) repository (GSE271017). Mass spectrometry proteomics data are deposited to the ProteomeXchange Consortium via the PRIDE partner repository (PXD052659).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This research was funded by a Wellcome joint investigator award to FR\/FMG (220271\/Z\/20\/Z) and the MRC-Metabolic Diseases Unit (MRC_MC_UU_12012\/3). NG was funded by an MRC studentship. Core support was provided by the MRC (MRC_MC_UU_00014\/5) and Wellcome (100574\/Z\/12\/Z). The LC-MS\/MS instrument was funded by the MRC (MR\/M009041\/1).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"FMG and FR received funding from AstraZeneca and Eli Lilly for non-overlapping research on other projects. They received sponsorship from AstraZeneca, Eli Lilly, Sun Pharma and Mercodia to run the 5th European Incretin Study Group conference in Cambridge (April 2024). The authors declare that there are no other 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":"NG generated the majority of the results and wrote the first draft of the manuscript. CA and AD did the electrophysiology. ELM, MS-H and RBB provided training and support, including for organoid maintenance, CRISPR and live-cell imaging, helping with initial data collection and analysis. RGK performed and analysed LC-MS\/MS. CAS performed bioinformatics analysis of RNA-seq. FR and FMG designed and oversaw the study, revised the manuscript and are guarantors of the work. All authors contributed to manuscript revision and approved the published version.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}