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 (Glu13) is γ-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 γ-carboxylation of human OCN on its first Glu residue (Glu17) 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 γ-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
γ-carboxylation of OCN on Glu17 residue correlates with insulin resistance and subclinical inflammation, suggesting that γ-carboxylation of OCN negatively regulates its endocrine action in humans.
['Bonneau|Jessica|J|', 'Ferland|Guylaine|G|', 'Karelis|Antony D|AD|', 'Doucet|Éric|É|', 'Faraj|May|M|', 'Rabasa-Lhoret|Rémi|R|', 'Ferron|Mathieu|M|']
D001786:Blood Glucose D002245:Carbon Dioxide D005260:Female D018149:Glucose Intolerance D005951:Glucose Tolerance Test D006801:Humans D007333:Insulin Resistance D008297:Male D008875:Middle Aged D009765:Obesity D015675:Osteocalcin D050177:Overweight D017698:Postmenopause D011236:Prediabetic State D011499:Protein Processing, Post-Translational D012189:Retrospective Studies D012307:Risk Factors
Osteocalcin Insulin resistance γ-Carboxylation Inflammation Bone