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We aimed to systematically characterise the time-resolved proteomic response to glucose ingestion in humans, and to assess its robustness following prolonged complete caloric restriction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted oral glucose tolerance tests (OGTTs) in 11 healthy volunteers before and after 7 days of complete caloric restriction and measured the response of &gt;2900 targets through high-resolution plasma protein profiling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified a signature of 44 proteins that changed significantly following glucose ingestion, which was reproducible after 7 days without food, and was strongly (20-fold) enriched for \u2018stomach-specific\u2019 proteins. We report that annexin A10 (ANXA10) shows the most significant post-glucose change observed, similar to the trajectories of secreted hormones. We present observational human evidence from multiple sources suggesting that ANXA10 is secreted upon sensing an increase in gastric pH, with the stomach as the major contributing tissue. Despite a profound metabolic shift after 7 days of complete caloric restriction, characterised by delayed insulin secretion and postprandial hyperglycaemia, only four proteins showed robust evidence for a differential trajectory during both OGTTs. This included plasma levels of tryptophanyl-tRNA synthetase\u00a01 (WARS), for which we found a genetic association with glucose homeostasis and coronary artery disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>Our exploratory study identifies the proteomic response to glucose ingestion and demonstrates its reproducibility despite major shifts in glucose homeostasis. We characterise the gastrointestinal origin of these changes, and hypothesise a hitherto under-recognised role for sensing of changes in gastric pH on the plasma proteome.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06800-8","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T11:07:14Z","timestamp":1784286434000},"page":"2970-2982","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tissue origins of the plasma proteomic response to glucose ingestion in 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Valde (Norwegian School of Sport Sciences, Oslo, Norway) for excellent technical assistance and organising blood sampling. The authors acknowledge the Scientific Computing Department of the IT Division at the Charit\u00e9, Universit\u00e4tsmedizin Berlin (\n                      \n                      ) for providing computational resources that contributed to the research results reported in this paper. We also thank the study participants for their time and effort.","order":1,"name":"Ethics","label":"Acknowledgements","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"This work uses data provided by patients and collected by the NHS as part of their care and support. Individual-level data from UK Biobank are publicly available to bona fide researchers upon application (\n                      \n                      ).","order":2,"name":"Ethics","label":"Data availability","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The code used to generate the results and figures in this study is available at\n                      \n                      .","order":3,"name":"Ethics","label":"Code availability","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"This work was supported by the Norwegian School of Sport Sciences, the German Centre for Cardiovascular Research (DZHK), the German Ministry of Education and Research (BMBF), the Friede Springer Cardiovascular Prevention Center at Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Germany, and Prot4CVD (81X2100281) DZHK. The Genes & Health study is\/has recently been core-funded by Wellcome (WT102627 and WT210561), the UK Medical Research Council (M009017, MR\/X009777\/1 and MR\/X009920\/1), the Higher Education Funding Council for England Catalyst, Barts Charity (845\/1796), Health Data Research UK (for the London substantive site), and has received research delivery support from the NHS National Institute for Health Research Clinical Research Network (North Thames). We acknowledge the support from the National Institute for Health and Care Research Barts Biomedical Research Centre (NIHR203330), which is a delivery partnership of Barts Health NHS Trust, Queen Mary University of London, St George\u2019s University Hospitals NHS Foundation Trust and St George\u2019s University of London. The Genes & Health study is\/has recently been funded by Alnylam Pharmaceuticals and Genomics plc, and a Life Sciences Industry Consortium of AstraZeneca plc, Bristol-Myers Squibb Co., GlaxoSmithKline Research and Development Ltd, Maze Therapeutics Inc, Merck Sharp & Dohme LLC, Novo Nordisk A\/S, Pfizer Inc and Takeda Development Center Americas Inc.","order":4,"name":"Ethics","label":"Funding","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":5,"name":"Ethics","label":"Authors\u2019 relationships and activities","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"BU, MP and CL contributed to the conception and design of the study. DAvH, JJ and CL contributed to the acquisition of data. BU, AW, KJK, PBJ, AJK, MK, MZ, CB, SY, CM, JS and MP contributed to the analysis of data. BU, AW, KJK, PBJ, AJK, YB, MR, SO, SB, JCZ, JJ, MP and CL contributed to interpretation of the data. BU, MP and CL drafted the manuscript. All authors critically revised the manuscript for important intellectual content and approved the final version for publication. CL and MP are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.","order":6,"name":"Ethics","label":"Contribution statement","group":{"name":"EthicsHeading","label":"Ethics"}}]}}