Tissue origins of the plasma proteomic response to glucose ingestion in humans

AIMS/HYPOTHESIS: Circulating proteins act as important hormonal signals of nutrient intake. 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. METHODS: 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 >2900 targets through high-resolution plasma protein profiling. RESULTS: 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 'stomach-specific' 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 1 (WARS), for which we found a genetic association with glucose homeostasis and coronary artery disease. CONCLUSIONS/INTERPRETATION: 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.

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Publication Details

Journal
Diabetologia
Published
2026-07-17
DOI
https://doi.org/10.1007/s00125-026-06800-8
Primary Topic
S100 Proteins and Annexins
Type
article
Field-Weighted Citation Impact
0.00

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article

Tissue origins of the plasma proteomic response to glucose ingestion in humans

Maik Pietzner, Anders J. Kolnes, Kristoffer Jensen Kolnes, Stephen O’Rahilly et al.
Diabetologia
S100 Proteins and Annexins
article

Tissue origins of the plasma proteomic response to glucose ingestion in humans

Maik Pietzner, Anders J. Kolnes, Kristoffer Jensen Kolnes, Stephen O’Rahilly, Martijn Zoodsma, Carl Beuchel, David A. van Heel, Carlo Maj, Summaira Yasmeen, Mine Koprulu, Julia Carrasco-Zanini, Claudia Langenberg, Alice Williamson, Burulça Uluvar, Mar Reinés, Per Bendix Jeppesen, Johannes Schumacher, Jørgen Jensen, Sina Bartfeld, Yanki Bambal
article en

Abstract

AIMS/HYPOTHESIS: Circulating proteins act as important hormonal signals of nutrient intake. 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. METHODS: 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 >2900 targets through high-resolution plasma protein profiling. RESULTS: 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 'stomach-specific' 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 1 (WARS), for which we found a genetic association with glucose homeostasis and coronary artery disease. CONCLUSIONS/INTERPRETATION: 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.

Diabetologia
Steno Diabetes Centers (DK), Philipps University of Marburg (DE), Queen Mary University of London (GB), University of Oslo (NO), Aarhus University (DK), University of Cambridge (GB), Odense University Hospital (DK), Wellcome/MRC Institute of Metabolic Science (GB), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Max Planck Institute for Molecular Genetics (DE), Technische Universität Berlin (DE), Norwegian School of Sport Sciences (NO), Charité - Universitätsmedizin Berlin (DE)
Deutsches Zentrum für Herz-Kreislaufforschung, Bundesministerium für Bildung und Forschung, Norges Idrettshøgskole
Zero hunger
Openalex Percentile: Top 14%
S100 Proteins and Annexins
DOIOpen Access PDFOpenAlex
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