Kirsa Skov-Jeppesen1, Maria S Svane2, Christoffer Martinussen2, Maria B N Gabe3, Lærke S Gasbjerg1, Simon Veedfald1, Kirstine N Bojsen-Møller4, Sten Madsbad4, Jens J Holst1, Mette M Rosenkilde1, Bolette Hartmann5. 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: bhartmann@sund.ku.dk.
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 AUC0-240 (-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).
RCT Entities:
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 AUC0-240 (-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).
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