GIP and GLP-1 receptor antagonism during a meal in healthy individuals
Open accessAbstract
Context: The actions of both endogenous incretin hormones during a meal have not previously been characterized. Objective: Using specific receptor antagonists, we investigated the individual and combined contributions of endogenous glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) to postprandial glucose metabolism, energy expenditure, and gallbladder motility. Design: Randomized, double-blinded, placebo-controlled, crossover design. Setting: On four separate days, four liquid mixed meal tests (1894 kJ) over 270 minutes (min). Patients or Other Participants: Twelve healthy male volunteers. Interventions: Infusions of the GIP receptor antagonist GIP(3–30)NH2 (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9–39)NH2 (0–20 min: 1000 pmol/kg/min; 20–270 min: 450 pmol/kg/min), GIP(3–30)NH2+exendin(9–39)NH2, or placebo/saline. Main Outcome Measure: Baseline-subtracted area under the curve (bsAUC) of C-peptide. Results: Infusion of GIP(3–30)NH2+exendin(9–39)NH2 significantly increased plasma glucose excursions (bsAUC: 261 ± 142 mmol/L × min) during the liquid mixed meals compared with GIP(3–30)NH2 (180 ± 141 mmol/L × min; P = 0.048), exendin(9–39)NH2 (171 ± 114 mmol/L × min; P = 0.046), and placebo (116 ± 154 mmol/L × min; P = 0.015). Correspondingly, C-peptide:glucose ratios during GIP(3–30)NH2+exendin(9–39)NH2 infusion were significantly lower than during GIP(3–30)NH2 (P = 0.0057), exendin(9–39)NH2 (P = 0.0038), and placebo infusion (P = 0.014). GIP(3–30)NH2 resulted in significantly lower AUCs for glucagon than exendin(9–39)NH2 (P = 0.0417). Gallbladder ejection fraction was higher during GIP(3–30)NH2 compared with placebo (P = 0.004). For all interventions, energy expenditure and respiratory quotient were similar. Conclusions: Endogenous GIP and GLP-1 lower postprandial plasma glucose excursions and stimulate insulin secretion but only endogenous GIP affects gallbladder motility. The two incretin hormones potentiate each other’s effects in the control of postprandial glycemia in healthy men.
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GIP plays a role in gallbladder relaxation.
“In addition, GIP has recently been reported to play a role in gallbladder relaxation (41).”
From Safety issues of tirzepatide (pancreatitis and gallbladder or biliary disease) in type 2 diabetes and obesity: a systematic review and meta-analysis (2023) · cites this paper as [41]
Endogenous GIP, and not GLP-1, also induced gallbladder relaxation.
“Gasbjerg et al. showed that endogenous GIP, and not GLP-1, also induced gallbladder relaxation.”
From The real-world safety profile of tirzepatide: pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database (2024) · cites this paper as [24]
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Proglucagon-derived peptides: human physiology and therapeutic potential
Gasbjerg, L. S., Nielsen, C. K., Suppli, M. P., Grøndahl, M. F. G., Holst, J. J., Knop, F. K., Jeppesen, P. B., & Lund, A. (2025) · Physiological Reviews · doi:10.1152/physrev.00057.2024 · Cited by 18 · see citing works
Self-citationAssociation of a glucagon‐like peptide‐1 receptor gene variant with glucose response to a mixed meal
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In Vitro and In Vivo Effects of Palmaria palmata Derived Peptides on Glucose Metabolism
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What is the evidence regarding the safety of new obesity pharmacotherapies
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GIP(3-30)NH2 – a tool for the study of GIP physiology
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Gabe, M. B. N., Gasbjerg, L. S., Gadgaard, S., Lindquist, P., Holst, J. J., & ROSENKILDE, M. M. (2022) · British Journal of Pharmacology · doi:10.1111/bph.15866 · Cited by 14 · see citing works
Self-citationThe naturally occurring GIP(1-30)NH2 is a GIP receptor agonist in humans
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Self-citationAdvances in small-molecule insulin secretagogues for diabetes treatment
Su, J., Xu, J., Hu, S., Ye, H., Xie, L. N., & Ouyang, S. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117179 · Cited by 13 · see citing works
Islet hormones at the intersection of glucose and amino acid metabolism
White, P. J., Albrechtsen, N. J. W., & Campbell, J. E. (2025) · Nature Reviews Endocrinology · doi:10.1038/s41574-025-01100-4 · Cited by 14 · see citing works
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Self-citationThe Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection
Lindquist, P., Gasbjerg, L. S., Mokrosiński, J., Holst, J. J., Hauser, A. S., & ROSENKILDE, M. M. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.891586 · Cited by 10 · see citing works
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The evolution of the therapeutic concept ‘GIP receptor antagonism’
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Self-citationPharmacotherapy for chronic obesity management: a look into the future
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Aging-Related Obesity: Unveiling Mitochondrial and Metabolic Dysfunction
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Self-citationSustained Action of Imapextide, A Glucagon-Like Peptide-1 Receptor Antagonist, in Healthy Volunteers
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Secretion and Impact of Gut Hormones in Obesity and Diabetes
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Agonists and Antagonists of the Human GIP Receptor
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- Authors
- Gasbjerg, L. S., Helsted, M. M., Hartmann, B., Sparre-Ulrich, A. H., Veedfald, S., Stensen, S., Lanng, A. R., Bergmann, N. C., Christensen, M. B., Vilsbøll, T., Holst, J. J., Rosenkilde, M. M., & Knop, F. K.
- Affiliations
- University of Copenhagen (DK)
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Corresponding author
- Rosenkilde, Mette M
- Knop, Filip K
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2020-02-20
- Volume
- 105
- Issue
- 3
- Pages
- e725-e738
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W3007650583
- Cited by
- 68
- References
- 52
- Citations by year
- 2026: 6 · 2025: 17 · 2024: 7 · 2023: 10 · 2022: 12 · 2021: 7 · 2020: 8 · 2019: 1
- FWCI
- 6.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Amgen
- Eli Lilly and Company
- AstraZeneca
- Sanofi
- Steno Diabetes Center Copenhagen (SDCC 3.F CMP)
- European Foundation for the Study of Diabetes
- Gentofte Hospital
- Novo Nordisk
- Copenhagen Graduate School for Nanoscience and Nanotechnology
- Novo Nordisk Fonden (NNF16OC0022598)
- Norgine
- Det Sundhedsvidenskabelige Fakultet, Københavns Universitet
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, incretins, GIP receptor antagonist, GLP-1 receptor antagonists, exendin-9-39, postprandial blood glucose, C-peptide, insulin secretion, energy expenditure, gallbladder motility, mixed meal
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Adult, Aged, Blood Glucose, Double-Blind Method, Energy Metabolism, Gallbladder, Gastric Inhibitory Polypeptide, Gastrointestinal Motility, Humans, Male, Middle Aged, Peptide Fragments, Receptors, Gastrointestinal Hormone, Cross-Over Studies, Postprandial Period, Incretins, Young Adult, Meals, Healthy Volunteers
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