Bonneau Jessica, Ferland Guylaine, Karelis Antony D, Doucet Éric, Faraj May, Rabasa-Lhoret Rémi, Ferron Mathieu
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.
Département de Nutrition, Université de Montréal, Québec H3T 3J7, Canada.
J Diabetes Complications. 2017 Jun;31(6):1027-1034. doi: 10.1016/j.jdiacomp.2017.01.023. Epub 2017 Feb 13.
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.
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.
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).
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.
在小鼠中，骨钙素（OCN）作为一种骨源性激素，可促进胰岛素敏感性和葡萄糖耐量。在该物种中，当其首个谷氨酸残基（Glu13）发生γ-羧化（Gla）时，OCN的内分泌作用受到抑制。这种翻译后修饰对人类OCN功能的重要性仍不清楚。我们的目标是确定一种检测方法，以评估人类OCN首个Glu残基（Glu17）的γ-羧化情况，并测试其与超重女性胰岛素抵抗和炎症指标的相关性。
测试了几种酶联免疫吸附测定（ELISA）方法，以确定它们对各种形式人类OCN的特异性。然后在129名非糖尿病超重和肥胖绝经后女性中，研究了OCNγ-羧化与葡萄糖耐量、胰岛素敏感性、肝功能和亚临床炎症指标之间的相关性。
我们确定了可测量总OCN（tOCN）以及Gla17/tOCN比值的检测方法。循环中的Gla17/tOCN水平与通过高胰岛素正常血糖钳夹评估的胰岛素敏感性呈负相关（P = 0.02），或与口服葡萄糖耐量试验得出的胰岛素敏感性指数呈负相关（P = 0.00003），与通过稳态模型评估的胰岛素抵抗（HOMA-IR）呈正相关（P = 0.0005），并与亚临床炎症标志物和肝酶呈正相关，包括C反应蛋白（CRP；P = 0.007）和天冬氨酸转氨酶（AST；P = 0.009）。
OCN在Glu17残基上的γ-羧化与胰岛素抵抗和亚临床炎症相关，提示OCN的γ-羧化在人类中对其内分泌作用起负调节作用。
