Although we could not explain the discrepancy between the studies, the different levels of insulin resistance between the study subjects and different measurements assessing insulin sensitivity may be casual. In the current study, no difference in the osteocalcin level was noted between the NGT and pre-diabetes groups, and the level of the pre-diabetes group was somewhat higher compared with the NGT group, although it did

not reach statistical significance. Therefore, it is not until diabetes Alpelisib manufacturer develops that plasma osteocalcin levels are decreased. YM155 manufacturer As a plausible explanation for this finding, it is possible that osteoblasts may secrete more osteocalcin to overcome a given amount of insulin resistance,

and more insulin is initially secreted in pancreatic β-cells (pre-diabetes state). However, as insulin resistance becomes more severe, the osteoblast fails to secrete sufficient osteocalcin, insulin secretion is decreased, and diabetes finally develops. In partial agreement with our speculation, Winhofer et al. [10] reported that women with gestational diabetes have higher osteocalcin levels compared with women EVP4593 solubility dmso with NGT during pregnancy while no difference was observed between the two groups 12 weeks postpartum, and therefore, they hypothesized that osteocalcin can enhance insulin secretion in insulin-resistant states. This study had several limitations. First, this study was based on a cross-sectional analysis, and thus, we do not know whether or not our findings are merely correlations or if osteocalcin has direct glucose-lowering Florfenicol effects in human subjects, as in animal- and cell-based studies. Second, we did not differentiate plasma osteocalcin with respect to the gamma-carboxylation status, and only measured the total form of osteocalcin, instead

of directly measuring carboxylated and uncarboxylated osteocalcin. Therefore, we do not know the differential mechanism of both types of osteocalcin to regulate insulin secretion and insulin sensitivity. Third, it is known that the levels of bone turnover markers, including plasma osteocalcin, are different according to age, gender, and race or ethnicity [18]. In this study, although we adjusted for age and gender, we could not entirely exclude the effects of age and gender on the associations between plasma osteocalcin levels and glucose metabolism. Lastly, it has been suggested that bone resorption at low pH is necessary to decarboxylate osteocalcin, and thus, osteoclasts determine the carboxylation status and function of osteocalcin in mice [19] and possibly in humans [20]. Therefore, the additional measurement of bone resorption markers may further clarify the potential association between bone resorption, osteocalcin, and glucose homeostasis in humans.