Introduction: The gastro-intestinal hormone glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-induced insulin secretion, with bone anabolic effects through GIP receptor (GIPR) in animal models. We explore its potential in humans by analyzing association between polymorphisms (SNPs) in the GIP and GIPR genes with bone phenotypes in young and elderly women. Methods: Association between GIP (rs2291725) and GIPR (rs10423928) and BMD, bone mineral content (BMC), bone microarchitecture, fracture and body composition was analyzed in the OPRA (75y, n. =. 1044) and PEAK-25 (25y; n. =. 1061) cohorts and serum-GIP in OPRA. Results: The GIP receptor AA-genotype was associated with lower ultrasound values in young women (BUA p=0.011; SI p=0.030), with no association to bone phenotypes in the elderly. In the elderly, the GIP was associated with lower ultrasound (GG vs. AA; SOS padj=0.021) and lower femoral neck BMD and BMC after adjusting for fat mass (padj=0.016 and padj=0.03). In young women, neither GIPR nor GIP associated with other bone phenotypes including spine trabecular bone score. In the elderly, neither SNP associated with fracture. GIP was associated with body composition only in Peak-25; GIPR was not associated with body composition in either cohort. Serum-GIP levels (in elderly) were not associated with bone phenotypes, however lower levels were associated with the GIPR A-allele (β=-6.93; padj=0.03). Conclusions: This first exploratory association study between polymorphisms in GIP and GIPR in relation to bone phenotypes and serum-GIP in women at different ages indicates a possible, albeit complex link between glucose metabolism genes and bone, while recognizing that further studies are warranted.
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