title: Association between osteocalcin gamma-carboxylation and insulin resistance in overweight and obese postmenopausal women.
abstract: OBJECTIVE
  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.
authors.affiliation: Unité de recherche en physiologie intégrative et moléculaire, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada; Programme de biologie moléculaire, Université de Montréal, Québec H3T 3J7, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Bonneau
authors.affiliation: Département de Nutrition, Université de Montréal, Québec H3T 3J7, Canada.
authors.forename: Guylaine
authors.initials: G
authors.lastname: Ferland
authors.affiliation: Department of Exercise Science, Université du Québec à Montréal, Québec, Canada.
authors.forename: Antony D
authors.initials: AD
authors.lastname: Karelis
authors.affiliation: School of Human Kinetics, University of Ottawa, Ottawa, Canada.
authors.forename: Éric
authors.initials: É
authors.lastname: Doucet
authors.affiliation: Département de Nutrition, Université de Montréal, Québec H3T 3J7, Canada; Unité de recherche en nutrition, lipoprotéines et maladies cardiométaboliques, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors.forename: May
authors.initials: M
authors.lastname: Faraj
authors.affiliation: Département de Nutrition, Université de Montréal, Québec H3T 3J7, Canada; Unité de recherche en maladies métaboliques, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors.forename: Rémi
authors.initials: R
authors.lastname: Rabasa-Lhoret
authors.affiliation: Unité de recherche en physiologie intégrative et moléculaire, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada; Programme de biologie moléculaire, Université de Montréal, Québec H3T 3J7, Canada; Départements de Médecine et de Biochimie et Médecine Moléculaire, Université de Montréal, Québec H3T 3J7, Canada; Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada, Institut de recherches cliniques de Montréal. Electronic address: mathieu.ferron@ircm.qc.ca.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Ferron
mesh_terms: D001786:Blood Glucose / Q000378:metabolism; D002245:Carbon Dioxide / Q000378:metabolism*; D005260:Female; D018149:Glucose Intolerance / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D015675:Osteocalcin / Q000378:metabolism*; D050177:Overweight / Q000378:metabolism*; D017698:Postmenopause / Q000378:metabolism*; D011236:Prediabetic State / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D001786:Blood Glucose; D015675:Osteocalcin; D002245:Carbon Dioxide; C041069:carboxyl radical
keywords: Bone; Inflammation; Insulin resistance; Osteocalcin; γ-Carboxylation