Association between osteocalcin gamma-carboxylation and insulin resistance in overweight and obese postmenopausal women

Aim: In mice, osteocalcin (OCN) acts as a bone-derived hormone promoting insulin sensitivity and glucose tolerance. In that species, OCN endocrine action is inhibited when its first glutamic acid residue (G1u13) is gamma-carboxylated (Gla). The importance of this posttranslational modification for OCN function in human is still unclear. Our objectives were to identify an assay to assess gamma-carboxylation of human OCN on its first Glu residue (G1u17) and to test its association with insulin resistance and inflammation profile in overweight women. Methods: Several ELISAs were tested to determine their specificity toward various forms of human OCN. Associations between OCN gamma-carboxylation and determinants of glucose tolerance, insulin sensitivity, liver function and subclinical inflammation were then investigated in 129 non-diabetic overweight and obese postmenopausal women. Results: We identified assays allowing the measurement of total OCN (tOCN) and the ratio of Gla17/tOCN. Circulating Gla17/tOCN levels correlated negatively with insulin sensitivity assessed by hyperinsulinemic-euglyceamic clamp (P = 0.02) or insulin sensitivity index derived from oral glucose tolerance test (P = 0.00003), and positively with insulin resistance assessed by HOMA-IR (P = 0.0005) and with markers of subclinical inflammation and liver enzymes, including C-reactive protein (CRP; P = 0.007) and aspartate aminotransferase (AST; P = 0.009). Conclusions: gamma-carboxylation of OCN on Glu17 residue correlates with insulin resistance and subclinical inflammation, suggesting that gamma-carboxylation of OCN negatively regulates its endocrine action in humans. (C) 2017 Elsevier Inc. All rights reserved.