Mono- and Co-Activation of the GIP and GLP-1 Receptors Inhibits Bone Resorption

Abstract

We investigated the effect of mono- and co-administration of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) on bone resorption and formation. Seventeen overweight/obese men without diabetes were included in a randomized, double-blinded, placebo-controlled, cross-over study and subjected to a 50g oral glucose tolerance test (OGTT) and four isoglycemic intravenous glucose infusions (IIGI), mimicking the glucose excursions from the OGTT, with concomitant infusions of GIP (4 pmol/kg/min), GLP-1 (1 pmol/kg/min), GIP+GLP-1 (4 and 1 pmol/kg/min, respectively) or placebo. Bone resorption and formation were assessed by measurements of carboxy-terminal type 1 collagen crosslinks (CTX), and procollagen type 1 N-terminal propeptide (P1NP), respectively. Suppression of CTX is shown in Fig. 1. During OGTT the baseline subtracted area under the curve (bsAUC) was significantly lower than during IIGI+saline infusion (-9,117±566 (mean±SEM) vs. -4,333±583 %×min, P<0.0001). Infusion of GLP-1 and GIP significantly potentiated CTX suppression to -10,751±799 %×min and 13,714±440 %×min, respectively. Co-administration of GIP+GLP-1 suppressed CTX to -15,466±268 %×min. P1NP levels were unaffected. Our data suggest that GLP-1, like GIP, may be involved in bone homeostasis and that co-administration of GIP+GLP-1 inhibits bone resorption more than each hormone alone. Disclosure N.C. Bergmann: Employee; Self; Zealand Pharma A/S. A.B. Lund: Other Relationship; Self; Novo Nordisk A/S. S.M. Heimbürger: Research Support; Self; Novo Nordisk A/S. L. Jessen: Employee; Self; Zealand Pharma A/S. Stock/Shareholder; Self; Zealand Pharma A/S, Novo Nordisk A/S. M.B. Christensen: None. T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.