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The role of osteocalcin in human glucose metabolism: marker or mediator?

Nature Reviews Endocrinology volume 9, pages 43–55 (2013)Cite this article

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Abstract

Increasing evidence supports an association between the skeleton and energy metabolism. These interactions are mediated by a variety of hormones, cytokines and nutrients. Here, the evidence for a role of osteocalcin in the regulation of glucose metabolism in humans is reviewed. Osteocalcin is a bone matrix protein that regulates hydroxyapatite size and shape through its vitamin-K-dependent, γ-carboxylated form. The concentration of osteocalcin in the circulation is a measure of bone formation. The undercarboxylated form of osteocalcin is active in glucose metabolism in mice. Total serum osteocalcin concentrations in humans are inversely associated with measures of glucose metabolism; however, human data are inconclusive with regard to the role of uncarboxylated osteocalcin in glucose metabolism because most studies do not account for the influence of vitamin K on the proportion of undercarboxylated osteocalcin or differentiate between the total and uncarboxylated forms of osteocalcin. Furthermore, most human studies do not concomitantly measure other bone turnover markers to isolate the role of osteocalcin as a measure of bone formation from its effect on glucose metabolism. Carefully designed studies are required to define the role of osteocalcin and its carboxylated or undercarboxylated forms in the regulation of glucose metabolism in humans.

Key Points

  • Osteocalcin is a calcium-binding bone matrix protein that contains the vitamin-K-dependent amino acid, γ-carboxyglutamic acid; circulating osteocalcin concentrations are a measure of bone formation

  • Studies in mice show that osteocalcin acts as a hormone to affect insulin sensitivity and energy expenditure; only the undercarboxylated form of osteocalcin is active

  • Human dietary intake of vitamin K is suboptimal, in contrast to that in mice—and, as a consequence, both bone and serum osteocalcin are undercarboxylated in humans

  • Most human studies examining the association between serum osteocalcin and measures of glucose metabolism do not differentiate between the total and undercarboxylated forms or take into account vitamin K intake

  • Most human studies also do not measure other bone turnover markers to distinguish circulating osteocalcin as a measure of bone turnover from its effect on glucose metabolism

  • In mice, the uncarboxylated form of osteocalcin is linked to glucose homeostasis, whereas in humans the data are inconclusive

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Figure 1: Vitamin K is required for the formation of γ-carboxyglutamic acid.
Figure 2: Direct structural analysis of osteocalcin by NMR imaging and X-ray crystallography predicts a tight globular structure comprised of three α-helices, a C-terminal hydrophobic core and an unstructured N-terminus.
Figure 3: Response of all forms of osteocalcin to vitamin K supplementation in humans.
Figure 4: Correlations among osteocalcin measures.
Figure 5: Speculative model of the role of osteocalcin in glucose metabolism.

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Change history

  • 23 November 2012

    In the version of this article initially published online there was a mistake saying that binding of osteocalcin in vitro to a G-protein-coupled receptor (Gprc6a) in isolated mouse Leydig cells was associated with a reduction in the biosynthesis of testosterone. The sentence should have read "Furthermore, the researchers showed that binding of osteocalcin in vitro to a G-protein-coupled receptor (Gprc6a) in isolated mouse Leydig cells was associated with an increase in the biosynthesis of testosterone.79" The error has been corrected for the HTML and PDF versions of the article.

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Acknowledgements

The authors' research is supported by the US Department of Agriculture (USDA), Agricultural Research Service, under Cooperative Agreement No. 58-1950-7-707, and NIH grants DK69341, AG14759, AR38460 and P30 DK04735. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the USDA.

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Authors and Affiliations

  1. Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, 02111, MA, USA

    Sarah L. Booth & Amanda Centi

  2.  Translational Research Institute of Metabolism and Diabetes, Florida Hospital, Sanford Burnham Institute, 301 E. Princeton Street, Orlando, 32804, FL, USA

    Steven R. Smith

  3.  Orthopedics and Rehabilitation, Yale School of Medicine, 333 Cedar Street, New Haven, 06520-8071, CT, USA

    Caren Gundberg

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  1. Sarah L. Booth
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Contributions

S. L. Booth, A. Centi and C. Gundberg researched data for the article, provided a substantial contribution to discussions of its content, wrote the article and reviewed and/or edited the manuscript before submission. S. R. Smith provided a substantial contribution to discussions of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Sarah L. Booth.

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Supplementary information

Supplementary Table 1

Cross-sectional Associations between Bone Turnover Markers and Glucose Metabolism and Adiposity in Non-Diabetic Children and Adults (DOC 175 kb)

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Booth, S., Centi, A., Smith, S. et al. The role of osteocalcin in human glucose metabolism: marker or mediator?. Nat Rev Endocrinol 9, 43–55 (2013). https://doi.org/10.1038/nrendo.2012.201

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