Osteocalcin: An Endocrine Link Between Bone and Glucose Metabolism

Bu B Yeap

Disclosures

Expert Rev Endocrinol Metab. 2011;6(2):177-185. 

In This Article

Potential Issues with the Osteocalcin Paradigm in Humans

Warfarin is an anticoagulant in common clinical usage which antagonizes vitamin K-dependent γ-carboxylation of clotting factors to achieve its therapeutic effect.[37,38] However, warfarin also inhibits vitamin K-dependent γ-carboxylation of osteocalcin[19,20] and as such was used as a positive control to increase ucOC levels in the experiments by Karsenty et al.[17] If patients receiving warfarin therapy have increased ucOC levels, the expectation is that their insulin sensitivity would be enhanced and diabetes risk reduced. However, warfarin therapy is not commonly associated with hypoglycemia, even when given in conjunction with glucose-lowering therapy such as sulfonylureas.[39] These are areas of uncertainty that need to be resolved. Conversely, increased oral intake of vitamin K facilitates γ-carboxylation of coagulation factors and of osteocalcin.[40–42] There are reports indicating a generally positive effect of vitamin K on bone mineral density and fracture risk (for a review, see[43]). Several studies have examined the association of vitamin K intake and glycemic status. In a cross-sectional study of 2719 adults 26–81 years of age, Yoshida et al. reported that those with a higher intake of vitamin K had better insulin sensitivity and lower postchallenge glucose levels.[44] A cross-sectional analysis of adults 20–45 years of age from the National Health and Nutrition Examination Survey (NHANES) 1999–2004 reported that vitamin K intake in the highest, compared with the lowest, quintile was associated with lower prevalence of hyperglycemia as a component of metabolic syndrome.[45] A large prospective cohort study of Dutch men and women aged 20–70 years by Beulens et al. found that higher intakes of vitamin K were associated with reduced risk of Type 2 diabetes.[46] In addition, a 36-month randomized trial of vitamin K supplementation in nondiabetic adults 60–80 years of age found that vitamin K reduced insulin resistance in men but not in women.[47] As vitamin K supplementation lowers ucOC levels but is not associated with adverse metabolic outcomes, these studies in humans do not offer support for ucOC as a mediator of improved insulin sensitivity.

The second issue that needs to be addressed is to what extent associations of ucOC with glucose metabolism and insulin sensitivity in humans are a reflection of bone turnover in general rather than in ucOC particularly. TOC is a marker of bone turnover.[19] One explanation for an association between lower TOC and abnormal glucose metabolism may be that diabetes or higher glucose levels are associated with reduced bone turnover and as a result with lower TOC, which might partly explain the higher risk of hip fractures seen in adults with Type 2 diabetes.[48,49] However, if the model proposed by Karsenty et al. is relevant to humans, then lower ucOC (or ratio of ucOC/TOC) should be more strongly associated with adverse metabolic outcomes than lower TOC or another marker of bone turnover. In the study by Kindblom et al., plasma TOC was negatively associated with plasma glucose and fat mass, but a different marker of bone turnover N-terminal propeptide of type 1 procollagen (P1NP) was not.[25] In a regression model including both TOC and P1NP, TOC independently predicted plasma glucose and fat mass.[25] Similarly, in the study by Pittas et al., the bone turnover marker urine N-telopeptide was not associated with metabolic phenotype.[28] Nevertheless, additional studies are needed to clarify that lower ucOC levels are more strongly associated with adverse metabolic phenotypes than lower TOC, and that ucOC levels are independent predictors of metabolic outcomes in multivariate models, including other markers of bone turnover such as P1NP.

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