Osteocalcin (OCN) is a bone-derived
hormone involved in the regulation of
glucose metabolism. In serum, OCN exists in carboxylated and uncarboxylated forms (ucOCN), and studies in rodents suggest that ucOCN is the bioactive form of this
hormone. Whether this is also the case in humans is unclear, because a reliable assay to measure ucOCN is not available. Here, we established and validated a new immunoassay (ELISA) measuring human ucOCN and used it to determine the level of bioactive OCN in two cohorts of
overweight or obese subjects, with or without
type 2 diabetes (T2D). The ELISA could specifically detect ucOCN concentrations ranging from 0.037 to 1.8 ng/mL. In a first cohort of
overweight or obese postmenopausal women without diabetes (n = 132), ucOCN correlated negatively with fasting
glucose (r = -0.18, P = 0.042) and
insulin resistance assessed by the homeostatic model assessment of
insulin resistance (r = -0.18, P = 0.038) and positively with
insulin sensitivity assessed by a hyperinsulinemic-euglycemic clamp (r = 0.18, P = 0.043) or
insulin sensitivity index derived from an oral
glucose tolerance test (r = 0.26, P = 0.003). In a second cohort of subjects with
severe obesity (n = 16), ucOCN was found to be lower in subjects with T2D compared with those without T2D (2.76 ± 0.38 versus 4.52 ± 0.06 ng/mL, P = 0.009) and to negatively correlate with fasting
glucose (r = -0.50, P = 0.046) and
glycated hemoglobin (r = -0.57, P = 0.021). Moreover, the subjects with ucOCN levels below 3 ng/mL had a reduced insulin secretion rate during a hyperglycemic clamp (P = 0.03). In conclusion, ucOCN measured with this novel and specific assay is inversely associated with
insulin resistance and β-cell dysfunction in humans.