Separate and Combined Effects of GIP and GLP-1 Infusions on Bone Metabolism in Overweight Men without Diabetes

CONTEXT: The gut-derived incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), have been suggested to play a role in bone metabolism. Exogenous administration of GIP inhibits bone resorption, while the effect of GLP-1 is less clear. Furthermore, the combined effect of exogenous GIP and GLP-1 on bone metabolism is unknown.

OBJECTIVE: To investigate the effect of separate and combined infusions of the incretin hormones GIP and GLP-1 on bone resorption and formation.

DESIGN: Randomized, double-blinded, placebo-controlled, crossover study including five study days.

PARTICIPANTS: Seventeen overweight/obese men.

INTERVENTIONS: On the first study day, a 50 g oral glucose tolerance test (OGTT) was performed. On the next four study days, isoglycemic IV glucose infusions (IIGI), mimicking the glucose excursions from the OGTT, were performed 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, respectively.

PRIMARY OUTCOMES: Changes in bone resorption assessed by measurements of carboxy-terminal type I collagen crosslinks (CTX), and in bone formation as assessed by procollagen type 1 N-terminal propeptide (P1NP) concentrations.

RESULTS: During the OGTT, CTX was significantly lowered by 54±13% from baseline (mean±SD) compared to 28±12% during IIGI+saline (P <0.0001). During IIGI+GLP-1 and IIGI+GIP, respectively, CTX was lowered by 65±16% and 74±9% from baseline, while IGII+GIP+GLP-1 lowered CTX by 84±4% from baseline. P1NP levels were unaffected by the interventions.

CONCLUSIONS: Our data suggest that GLP-1, like GIP, may be involved in regulation of bone resorption and that GIP and GLP-1 together have partially additive inhibitory effects.