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±4.3ng/ml×min (MMT). When GIP(3-30)NH2 was administered, CTX suppression was significantly diminished compared to placebo (-30±4.8 (OGTT) and -45±4.6ng/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.