GLP-2 and GIP exert separate effects on bone turnover: A randomized, placebo-controlled, crossover study in healthy young men

Kirsa Skov-Jeppesen; Maria S Svane; Christoffer Martinussen; Maria B N Gabe; Lærke S Gasbjerg; Simon Veedfald; Kirstine N Bojsen-Møller; Sten Madsbad; Jens J Holst; Mette M Rosenkilde; Bolette Hartmann

doi:10.1016/j.bone.2019.05.014

GLP-2 and GIP exert separate effects on bone turnover: A randomized, placebo-controlled, crossover study in healthy young men

Bone. 2019 Aug:125:178-185. doi: 10.1016/j.bone.2019.05.014. Epub 2019 May 15.

Affiliations

¹ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
² Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Department of Endocrinology, Hvidovre University Hospital, Hvidovre, Denmark.
³ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁴ Department of Endocrinology, Hvidovre University Hospital, Hvidovre, Denmark.
⁵ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. Electronic address: [email protected].

PMID: 31100534
DOI: 10.1016/j.bone.2019.05.014

Abstract

Background: Glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) both inhibit bone resorption in humans but the underlying mechanisms are poorly understood. In vitro, GLP-2 activates the GIP-receptor (GIPR).

Objective: Based on in vitro studies, we hypothesized that the antiresorptive effect of GLP-2 was mediated through the GIPR. This was tested using the selective GIPR-antagonist GIP(3-30)NH₂.

Methods: The study was a randomized, single-blinded, placebo-controlled, crossover study conducted at Hvidovre University Hospital, Denmark. Eight healthy young men were included and studied on four study days: GIP (200 μg), GLP-2 (800 μg), GIP(3-30)NH₂ (800 pmol/kg/min) + GLP-2 (800 μg), and placebo. The main outcomes were bone resorption measured as collagen type 1 C-terminal telopeptide (CTX) and bone formation measured as procollagen type 1 N-terminal propeptide (P1NP).

Results: CTX (mean ± SEM) significantly decreased after both GIP (to 55.3 ± 6.3% of baseline at t = 90 min) and GLP-2 (to 60.5 ± 5.0% of baseline at t = 180 min). The maximal reduction in CTX after GIP(3-30)NH₂ + GLP-2 (to 63.2 ± 3.1% of baseline) did not differ from GLP-2 alone (p = 0.95) nor did net AUC_0-240 (-6801 ± 879%*min vs -6027 ± 648%*min, p = 0.56). At t = 30 min, GIP significantly (p < 0.0001) increased P1NP to 115.1 ± 2.2% of baseline compared with 103.1 ± 1.5% after placebo. Both GLP-2 and GIP(3-30)NH₂ + GLP-2 significantly (p < 0.0001) decreased P1NP to 91.3 ± 1.1% and 88.1 ± 3.0% of baseline, respectively (at t = 45 min) compared with placebo.

Conclusions: GIPR antagonism did not inhibit the GLP-2-induced reduction in bone resorption (CTX) in healthy young men. In contrast to GLP-2, GIP increased P1NP despite decreasing CTX indicating an uncoupling of bone resorption from formation. Thus, GLP-2 and GIP seem to exert separate effects on bone turnover in humans.

Clinical trials information: ClinicalTrials.gov (NCT03159741).

Keywords: Bone formation; Bone resorption; CTX; P1NP; PTH.

Publication types

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

MeSH terms

Adult
Animals
Blood Glucose / drug effects
Bone Remodeling / drug effects*
COS Cells
Chlorocebus aethiops
Cross-Over Studies
Cyclic AMP / metabolism
Gastric Inhibitory Polypeptide / pharmacology*
Glucagon-Like Peptide 2 / pharmacology*
Humans
Male
Receptors, Gastrointestinal Hormone / metabolism
Young Adult

Substances

Blood Glucose
Glucagon-Like Peptide 2
Receptors, Gastrointestinal Hormone
Gastric Inhibitory Polypeptide
gastric inhibitory polypeptide receptor
Cyclic AMP

Associated data

ClinicalTrials.gov/NCT03159741