Bone marrow responses to GLP-1 and GIP infusion under hyperglycaemic conditions

Abstract Objective Food intake stimulates secretion of incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which acutely suppress systemic markers of bone resorption in humans. Whether incretins exert parallel effects on bone turnover within the bone marrow (BM) microenvironment during hyperglycaemia is unknown. We investigated the acute effects of GLP-1, GIP, and their combination on bone turnover in BM under hyperglycaemic conditions, alongside BM metabolomics and stromal cell characteristics. Design Crossover study in healthy men. Methods Twelve men completed three study days with two-hour intravenous infusions of GLP-1, GIP, or combined GLP-1+GIP during a hyperglycaemic clamp targeting postprandial plasma glucose. Bone resorption (C-terminal telopeptide of type I collagen, CTX) and formation (procollagen type I N-terminal propeptide, P1NP) markers were measured in peripheral plasma during infusions and in BM plasma before and after infusions. Untargeted metabolomic profiling by liquid chromatography-mass spectrometry was performed on BM plasma, and BM stromal cells (BMSCs) were assessed ex vivo for clonogenic capacity and osteogenic and adipogenic differentiation. Results All infusions suppressed BM plasma CTX to a similar extent. P1NP increased transiently in peripheral plasma during GIP and GLP-1+GIP infusions and was elevated in BM plasma after GIP infusion. Metabolomics revealed changes consistent with altered glucose and insulin levels, without a bone-specific signature. BMSC differentiation was unchanged, although clonogenic capacity was reduced after GLP-1+GIP infusion. Conclusions Under hyperglycaemic conditions, both incretins acutely suppressed bone resorption in healthy men without detectable bone-specific metabolic signatures. GIP was additionally associated with increased BM P1NP at 2 hours, in contrast to only a short-lived rise in peripheral plasma, suggesting a possible transient uncoupling of bone turnover.