Acute effects of GIP and GLP-1 receptor antagonism in totally pancreatectomized individuals: A randomized double-blind, placebo-controlled crossover study

Liva S L Krogh; Mads M Helsted; Anders Englund; Natasha C Bergmann; Kirsa Skov-Jeppesen; Casper K Nielsen; Carsten P Hansen; Mette M Rosenkilde; Bolette Hartmann; Jens J Holst; Filip K Knop; Asger B Lund; Lærke S Gasbjerg

doi:10.1111/dom.70186

Acute effects of GIP and GLP-1 receptor antagonism in totally pancreatectomized individuals: A randomized double-blind, placebo-controlled crossover study

Liva S L Krogh, Mads M Helsted, Anders Englund, Natasha C Bergmann, Kirsa Skov-Jeppesen, Casper K Nielsen, Carsten P Hansen, Mette M Rosenkilde, Bolette Hartmann, Jens J Holst, Filip K Knop, Asger B Lund, Lærke S Gasbjerg^*

^*Corresponding author for this work

2 Citations (Scopus)

Abstract

Aims: The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) influence metabolism through strong effects on pancreatic hormone secretion but also in a pancreas-independent manner. Here, we investigated the isolated extrapancreatic effects of endogenous GIP and GLP-1 by applying hormone receptor antagonists in totally pancreatectomized individuals. Methods: Twelve totally pancreatectomized individuals each underwent four 270-min liquid mixed meal tests (480 kcal) in a randomized study design with infusions of the GIP receptor antagonist GIP(3-30)NH ₂ (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9-39)NH ₂ (450 pmol/kg/min), GIP(3-30)NH ₂ + exendin(9-39)NH ₂, and saline (placebo), respectively. Blood samples, appetite-related measures, heart rate, blood pressure, and ad libitum food intake data were collected. Participants continued their basal insulin but omitted bolus insulin in the morning of the experiment. Results: Infusions of GIP(3-30)NH ₂ and GIP(3-30)NH ₂ + exendin(9-39)NH ₂ attenuated meal-induced inhibition of bone resorption (carboxy-terminal collagen crosslinks) (nadir [mean ± SD] to 84 ± 9% and to 85 ± 8% of baseline, compared to placebo (64 ± 15%) (ps <0.05)). During exendin(9-39)NH ₂ and exendin(9-39)NH ₂ + GIP(3-30)NH ₂ co-infusion, GLP-1 plasma responses increased (ps <0.05). Infusion of GIP(3-30)NH ₂ or exendin(9-39)NH ₂ did not affect other measurements. Conclusion: Endogenous GIP contributes to the regulation of postprandial bone resorption independently of pancreatic factors. In contrast, GIP receptor and/or GLP-1 receptor antagonism had no measurable effects on glucose metabolism, gastric emptying, appetite, food intake, triglycerides, or haemodynamics, supporting a pancreatic contribution to some of these effects of the endogenous hormones, although the surgical reconstruction may have influenced the sensitivity of the targets.

Original language	English
Journal	Diabetes, Obesity and Metabolism
Volume	28
Issue number	1
Pages (from-to)	275-286
Number of pages	12
ISSN	1462-8902
DOIs	https://doi.org/10.1111/dom.70186
Publication status	Published - Jan 2026

Keywords

GIP receptor antagonist
GLP-1 receptor antagonist
incretin hormones
pancreatogenic diabetes
total pancreatectomy
Glucagon-Like Peptide 1
Double-Blind Method
Peptide Fragments/pharmacology
Humans
Middle Aged
Blood Glucose/metabolism
Gastric Inhibitory Polypeptide/pharmacology
Pancreatectomy
Male
Receptors, Gastrointestinal Hormone/antagonists & inhibitors
Insulin
Cross-Over Studies
Heart Rate/drug effects
Appetite/drug effects
Female
Adult
Eating/drug effects
Postprandial Period/drug effects
Glucagon-Like Peptide-1 Receptor/antagonists & inhibitors

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10.1111/dom.70186

Cite this

Krogh, L. S. L., Helsted, M. M., Englund, A., Bergmann, N. C., Skov-Jeppesen, K., Nielsen, C. K., Hansen, C. P., Rosenkilde, M. M., Hartmann, B., Holst, J. J., Knop, F. K., Lund, A. B., & Gasbjerg, L. S. (2026). Acute effects of GIP and GLP-1 receptor antagonism in totally pancreatectomized individuals: A randomized double-blind, placebo-controlled crossover study. Diabetes, Obesity and Metabolism, 28(1), 275-286. https://doi.org/10.1111/dom.70186

Acute effects of GIP and GLP-1 receptor antagonism in totally pancreatectomized individuals: A randomized double-blind, placebo-controlled crossover study. / Krogh, Liva S L ; Helsted, Mads M ; Englund, Anders et al.
In: Diabetes, Obesity and Metabolism, Vol. 28, No. 1, 01.2026, p. 275-286.

Research output: Contribution to journal › Journal article › Research › peer-review

Krogh, LSL , Helsted, MM , Englund, A, Bergmann, NC, Skov-Jeppesen, K, Nielsen, CK , Hansen, CP, Rosenkilde, MM, Hartmann, B, Holst, JJ, Knop, FK, Lund, AB & Gasbjerg, LS 2026, 'Acute effects of GIP and GLP-1 receptor antagonism in totally pancreatectomized individuals: A randomized double-blind, placebo-controlled crossover study', Diabetes, Obesity and Metabolism, vol. 28, no. 1, pp. 275-286. https://doi.org/10.1111/dom.70186

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title = "Acute effects of GIP and GLP-1 receptor antagonism in totally pancreatectomized individuals: A randomized double-blind, placebo-controlled crossover study",

abstract = "Aims: The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) influence metabolism through strong effects on pancreatic hormone secretion but also in a pancreas-independent manner. Here, we investigated the isolated extrapancreatic effects of endogenous GIP and GLP-1 by applying hormone receptor antagonists in totally pancreatectomized individuals. Methods: Twelve totally pancreatectomized individuals each underwent four 270-min liquid mixed meal tests (480 kcal) in a randomized study design with infusions of the GIP receptor antagonist GIP(3-30)NH 2 (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9-39)NH 2 (450 pmol/kg/min), GIP(3-30)NH 2 + exendin(9-39)NH 2, and saline (placebo), respectively. Blood samples, appetite-related measures, heart rate, blood pressure, and ad libitum food intake data were collected. Participants continued their basal insulin but omitted bolus insulin in the morning of the experiment. Results: Infusions of GIP(3-30)NH 2 and GIP(3-30)NH 2 + exendin(9-39)NH 2 attenuated meal-induced inhibition of bone resorption (carboxy-terminal collagen crosslinks) (nadir [mean ± SD] to 84 ± 9\% and to 85 ± 8\% of baseline, compared to placebo (64 ± 15\%) (ps <0.05)). During exendin(9-39)NH 2 and exendin(9-39)NH 2 + GIP(3-30)NH 2 co-infusion, GLP-1 plasma responses increased (ps <0.05). Infusion of GIP(3-30)NH 2 or exendin(9-39)NH 2 did not affect other measurements. Conclusion: Endogenous GIP contributes to the regulation of postprandial bone resorption independently of pancreatic factors. In contrast, GIP receptor and/or GLP-1 receptor antagonism had no measurable effects on glucose metabolism, gastric emptying, appetite, food intake, triglycerides, or haemodynamics, supporting a pancreatic contribution to some of these effects of the endogenous hormones, although the surgical reconstruction may have influenced the sensitivity of the targets.",

keywords = "GIP receptor antagonist, GLP-1 receptor antagonist, incretin hormones, pancreatogenic diabetes, total pancreatectomy, Glucagon-Like Peptide 1, Double-Blind Method, Peptide Fragments/pharmacology, Humans, Middle Aged, Blood Glucose/metabolism, Gastric Inhibitory Polypeptide/pharmacology, Pancreatectomy, Male, Receptors, Gastrointestinal Hormone/antagonists \& inhibitors, Insulin, Cross-Over Studies, Heart Rate/drug effects, Appetite/drug effects, Female, Adult, Eating/drug effects, Postprandial Period/drug effects, Glucagon-Like Peptide-1 Receptor/antagonists \& inhibitors",

author = "Krogh, \{Liva S L\} and Helsted, \{Mads M\} and Anders Englund and Bergmann, \{Natasha C\} and Kirsa Skov-Jeppesen and Nielsen, \{Casper K\} and Hansen, \{Carsten P\} and Rosenkilde, \{Mette M\} and Bolette Hartmann and Holst, \{Jens J\} and Knop, \{Filip K\} and Lund, \{Asger B\} and Gasbjerg, \{L{\ae}rke S\}",

note = "{\textcopyright} 2025 John Wiley \& Sons Ltd.",

year = "2026",

month = jan,

doi = "10.1111/dom.70186",

language = "English",

volume = "28",

pages = "275--286",

journal = "Diabetes, Obesity and Metabolism",

issn = "1462-8902",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "1",

}

TY - JOUR

T1 - Acute effects of GIP and GLP-1 receptor antagonism in totally pancreatectomized individuals

T2 - A randomized double-blind, placebo-controlled crossover study

AU - Krogh, Liva S L

AU - Helsted, Mads M

AU - Englund, Anders

AU - Bergmann, Natasha C

AU - Skov-Jeppesen, Kirsa

AU - Nielsen, Casper K

AU - Hansen, Carsten P

AU - Rosenkilde, Mette M

AU - Hartmann, Bolette

AU - Holst, Jens J

AU - Knop, Filip K

AU - Lund, Asger B

AU - Gasbjerg, Lærke S

PY - 2026/1

Y1 - 2026/1

N2 - Aims: The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) influence metabolism through strong effects on pancreatic hormone secretion but also in a pancreas-independent manner. Here, we investigated the isolated extrapancreatic effects of endogenous GIP and GLP-1 by applying hormone receptor antagonists in totally pancreatectomized individuals. Methods: Twelve totally pancreatectomized individuals each underwent four 270-min liquid mixed meal tests (480 kcal) in a randomized study design with infusions of the GIP receptor antagonist GIP(3-30)NH 2 (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9-39)NH 2 (450 pmol/kg/min), GIP(3-30)NH 2 + exendin(9-39)NH 2, and saline (placebo), respectively. Blood samples, appetite-related measures, heart rate, blood pressure, and ad libitum food intake data were collected. Participants continued their basal insulin but omitted bolus insulin in the morning of the experiment. Results: Infusions of GIP(3-30)NH 2 and GIP(3-30)NH 2 + exendin(9-39)NH 2 attenuated meal-induced inhibition of bone resorption (carboxy-terminal collagen crosslinks) (nadir [mean ± SD] to 84 ± 9% and to 85 ± 8% of baseline, compared to placebo (64 ± 15%) (ps <0.05)). During exendin(9-39)NH 2 and exendin(9-39)NH 2 + GIP(3-30)NH 2 co-infusion, GLP-1 plasma responses increased (ps <0.05). Infusion of GIP(3-30)NH 2 or exendin(9-39)NH 2 did not affect other measurements. Conclusion: Endogenous GIP contributes to the regulation of postprandial bone resorption independently of pancreatic factors. In contrast, GIP receptor and/or GLP-1 receptor antagonism had no measurable effects on glucose metabolism, gastric emptying, appetite, food intake, triglycerides, or haemodynamics, supporting a pancreatic contribution to some of these effects of the endogenous hormones, although the surgical reconstruction may have influenced the sensitivity of the targets.

AB - Aims: The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) influence metabolism through strong effects on pancreatic hormone secretion but also in a pancreas-independent manner. Here, we investigated the isolated extrapancreatic effects of endogenous GIP and GLP-1 by applying hormone receptor antagonists in totally pancreatectomized individuals. Methods: Twelve totally pancreatectomized individuals each underwent four 270-min liquid mixed meal tests (480 kcal) in a randomized study design with infusions of the GIP receptor antagonist GIP(3-30)NH 2 (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9-39)NH 2 (450 pmol/kg/min), GIP(3-30)NH 2 + exendin(9-39)NH 2, and saline (placebo), respectively. Blood samples, appetite-related measures, heart rate, blood pressure, and ad libitum food intake data were collected. Participants continued their basal insulin but omitted bolus insulin in the morning of the experiment. Results: Infusions of GIP(3-30)NH 2 and GIP(3-30)NH 2 + exendin(9-39)NH 2 attenuated meal-induced inhibition of bone resorption (carboxy-terminal collagen crosslinks) (nadir [mean ± SD] to 84 ± 9% and to 85 ± 8% of baseline, compared to placebo (64 ± 15%) (ps <0.05)). During exendin(9-39)NH 2 and exendin(9-39)NH 2 + GIP(3-30)NH 2 co-infusion, GLP-1 plasma responses increased (ps <0.05). Infusion of GIP(3-30)NH 2 or exendin(9-39)NH 2 did not affect other measurements. Conclusion: Endogenous GIP contributes to the regulation of postprandial bone resorption independently of pancreatic factors. In contrast, GIP receptor and/or GLP-1 receptor antagonism had no measurable effects on glucose metabolism, gastric emptying, appetite, food intake, triglycerides, or haemodynamics, supporting a pancreatic contribution to some of these effects of the endogenous hormones, although the surgical reconstruction may have influenced the sensitivity of the targets.

KW - GIP receptor antagonist

KW - GLP-1 receptor antagonist

KW - incretin hormones

KW - pancreatogenic diabetes

KW - total pancreatectomy

KW - Glucagon-Like Peptide 1

KW - Double-Blind Method

KW - Peptide Fragments/pharmacology

KW - Humans

KW - Middle Aged

KW - Blood Glucose/metabolism

KW - Gastric Inhibitory Polypeptide/pharmacology

KW - Pancreatectomy

KW - Male

KW - Receptors, Gastrointestinal Hormone/antagonists & inhibitors

KW - Insulin

KW - Cross-Over Studies

KW - Heart Rate/drug effects

KW - Appetite/drug effects

KW - Female

KW - Adult

KW - Eating/drug effects

KW - Postprandial Period/drug effects

KW - Glucagon-Like Peptide-1 Receptor/antagonists & inhibitors

UR - https://www.scopus.com/pages/publications/105018602823

U2 - 10.1111/dom.70186

DO - 10.1111/dom.70186

M3 - Journal article

C2 - 41069310

SN - 1462-8902

VL - 28

SP - 275

EP - 286

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

IS - 1

ER -

Acute effects of GIP and GLP-1 receptor antagonism in totally pancreatectomized individuals: A randomized double-blind, placebo-controlled crossover study

Abstract

Keywords

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