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
N1 - © 2025 John Wiley & Sons Ltd.
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 -