The role of endogenous GIP and GLP-1 in postprandial bone homeostasis

Abstract

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are well known for their insulinotropic effects and they are thought to affect bone homeostasis as mediators in the so-called entero-osseous axis. We examined the contributions of endogenous GIP and GLP-1, respectively, to postprandial bone homeostasis, in healthy subjects in two randomized and double-blind crossover studies. We included healthy men who received either four oral glucose tolerance tests (OGTTs) (n = 18, median age 27 (range 20-70), BMI 27.2 (22.4-37.0) kg/m²) or liquid mixed meal tests (MMTs) (n = 12, age 23 (19-65), BMI 23.7 (20.3-25.5) kg/m²) with infusions of 1) the GIP receptor antagonist GIP(3-30)NH₂, 2) the GLP-1 receptor antagonist exendin(9-39)NH₂, 3) both GIP(3-30)NH₂ and exendin(9-39)NH₂, or 4) placebo infusions (saline) on four separate visits. Bone resorption was evaluated from levels of circulating carboxy-terminal collagen crosslinks (CTX) and bone formation from levels of procollagen type 1 amino-terminal propeptide (P1NP). During placebo infusions, baseline-subtracted area under the curve values for CTX were -39 ± 5.0 (OGTT) and -57 ± 4.3 ng/ml × min (MMT). When GIP(3-30)NH₂ was administered, CTX suppression was significantly diminished compared to placebo (-30 ± 4.8 (OGTT) and -45 ± 4.6 ng/ml × min (MMT), P = 0.0104 and P = 0.0288, respectively, compared to placebo. During exendin(9-39)NH₂ infusion, CTX suppression after OGTT/MMT was similar to placebo (P = 0.28 (OGTT) and P = 0.93 (MMT)). The relative contribution of endogenous GIP to postprandial suppression of bone resorption during both OGTT and MMT was similar and reached 22-25%. There were no differences in P1NP concentrations between interventions. In conclusion, endogenous GIP contributes by up to 25% to postprandial suppression of bone resorption in humans whereas an effect of endogenous GLP-1 could not be demonstrated.

Trial registration: ClinicalTrials.gov NCT03133741 NCT03013296.

Keywords: Bone metabolism; Bone resorption; CTX; Exendin(9–39)NH(2); GIP(3–30)NH(2); Glucagon-like peptide 1; Glucose-dependent insulinotropic polypeptide; Gut-bone axis; Incretin hormones.