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J Clin Endocrinol Metab. 2014 Apr;99(4):E729-33. doi: 10.1210/jc.2013-3766. Epub 2014 Jan 21.

A functional amino acid substitution in the glucose-dependent insulinotropic polypeptide receptor (GIPR) gene is associated with lower bone mineral density and increased fracture risk.

Author information

  • 1Department of Biomedical Sciences and NNF Center for Basic Metabolic Research (S.S.T., T.Han., O.P., J.J.H.), Faculty of Health and Medical Sciences (P.E.), University of Copenhagen, DK-2200 Copenhagen, Denmark; Department of Endocrinology and Metabolism (T.Har., L.R., B.L.L.), Aarhus University Hospital, DK-8000 C Aarhus, Denmark; Department of Cardiology, Nephrology, and Endocrinology (P.E.), Hillerød Hospital, DK-3400 Hillerød, Denmark; Department of Endocrinology (J.B.J.), Hvidovre University Hospital, DK-2650 Hvidovre, Denmark; and Department of Endocrinology M (A.P.H.), Odense University Hospital, DK-5000 Odense, Denmark.

Abstract

CONTEXT:

Food ingestion decreases bone resorption, and glucose-dependent insulinotropic polypeptide (GIP) may mediate this effect. Mice overexpressing GIP have increased osteoblast activity and are rescued from age-related bone loss, whereas GIPR knockout mice have decreased cortical bone mass and compromised bone quality. Carriers of the functional variant GIPR Glu354Gln (rs1800437) have higher plasma glucose 2 hours after glucose ingestion, suggesting that the variant encoding GIPR 354Gln decreases the effect of GIP.

OBJECTIVE:

The objective of the study was to investigate the effect of GIPR Glu354Gln on bone mineral density (BMD) and fracture risk.

DESIGN:

This was a prospective, comprehensive, cohort study (number NCT00252408).

PARTICIPANTS:

A total of 1686 perimenopausal women were included.

MAIN OUTCOME MEASURES:

Dual-energy X-ray absorptiometry was performed at baseline and after 10 years. Incident fractures were recorded during the follow-up and were obtained from the Danish National Patient Registry, giving a total follow-up time of a minimum 16 years.

RESULTS:

After 10 years, women with the minor frequency C allele of rs1800437 (354Gln) had significantly lower BMD at the femoral neck compared with carriers of the major G-allele (CC: 0.755 ± 0.015 g/cm(2) vs CG: 747 ± 0.005 g/cm(2); GG: 0.766 ± 0.004 g/cm(2), P < .001). Correspondingly, total hip BMD was significantly lower among C allele carriers (CC: 0.881 ± 0.016 g/cm(2); CG: 0.884 ± 0.005 g/cm(2); and GG: 0.906 ± 0.004 g/cm(2), P < .001). Finally, women homozygous for the variant C allele had an increased risk (hazard ratio 1.6, confidence interval 1.0-2.6, P < .05) of nonvertebral fractures.

CONCLUSION:

This study demonstrates an association between a functional GIPR polymorphism Glu354Gln (rs1800437) and BMD and fracture risk. These findings further establish GIP to be involved in the regulation of bone density.

PMID:
24446656
DOI:
10.1210/jc.2013-3766
[PubMed - indexed for MEDLINE]
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