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

Diabetes Obes Metab. 2026 Jan;28(1):275-286. doi: 10.1111/dom.70186. Epub 2025 Oct 10.

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)NH2 (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9-39)NH2 (450 pmol/kg/min), GIP(3-30)NH2 + exendin(9-39)NH2, 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)NH2 and GIP(3-30)NH2 + exendin(9-39)NH2 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)NH2 and exendin(9-39)NH2 + GIP(3-30)NH2 co-infusion, GLP-1 plasma responses increased (ps <0.05). Infusion of GIP(3-30)NH2 or exendin(9-39)NH2 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.

Trial registration: ClinicalTrials.gov NCT05177653.

Keywords: GIP receptor antagonist; GLP‐1 receptor antagonist; incretin hormones; pancreatogenic diabetes; total pancreatectomy.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Appetite / drug effects
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Cross-Over Studies
  • Double-Blind Method
  • Eating / drug effects
  • Female
  • Gastric Inhibitory Polypeptide* / administration & dosage
  • Gastric Inhibitory Polypeptide* / pharmacology
  • Glucagon-Like Peptide 1
  • Glucagon-Like Peptide-1 Receptor* / antagonists & inhibitors
  • Heart Rate / drug effects
  • Humans
  • Insulin
  • Male
  • Middle Aged
  • Pancreatectomy*
  • Peptide Fragments* / administration & dosage
  • Peptide Fragments* / pharmacology
  • Postprandial Period / drug effects
  • Receptors, Gastrointestinal Hormone* / antagonists & inhibitors

Substances

  • Gastric Inhibitory Polypeptide
  • Receptors, Gastrointestinal Hormone
  • Peptide Fragments
  • Glucagon-Like Peptide-1 Receptor
  • exendin (9-39)
  • gastric inhibitory polypeptide receptor
  • Blood Glucose
  • Glucagon-Like Peptide 1
  • gastric inhibitory polypeptide (3-30)-amide
  • Insulin

Associated data

  • ClinicalTrials.gov/NCT05177653