Undercarboxylated Osteocalcin Improves Insulin‐Stimulated Glucose Uptake in Muscles of Corticosterone‐Treated Mice

Abstract

Short‐term administration of glucocorticoids (GCs) impairs muscle insulin sensitivity at least in part via the reduction of undercarboxylated osteocalcin (ucOC). However, whether ucOC treatment reverses the GC‐induced muscle insulin resistance remains unclear. To test the hypothesis that ucOC directly ameliorates impaired insulin‐stimulated glucose uptake (ISGU) induced by short‐term GC administration in mice muscle and to identify the molecular mechanisms, mice were implanted with placebo or corticosterone (CS) slow‐release pellets. Two days post‐surgery, insulin‐tolerance tests (ITTs) were performed. On day 3, serum was collected and extensor digitorum longus (EDL) and soleus muscles were isolated and treated ex vivo with vehicle, ucOC (30\u2009ng/mL), insulin (60 µU/mL), or both. Circulating hormone levels, muscle glucose uptake, and muscle signaling proteins were assessed. CS administration reduced both serum osteocalcin and ucOC levels, whole‐body insulin sensitivity, and muscle ISGU in EDL. Ex vivo ucOC treatment restored ISGU in CS‐affected muscle, without increasing non‐insulin‐stimulated glucose uptake. In CS‐affected EDL muscle, ucOC enhanced insulin action on phosphorylated (p‐)protein kinase B (Akt)Ser473and the p‐extracellular signal‐regulated kinase isoform 2 (ERK2)Thr202/Tyr204/total (t)ERK2 ratio, which correlated with ISGU. In CS‐affected soleus muscle, ucOC enhanced insulin action on p‐mammalian target of rapamycin (mTOR)Ser2481, the p‐mTORSer2481/tmTOR ratio, p‐Akt substrate of 160kD (AS160)Thr642, and p‐protein kinase C (PKC) (pan)Thr410, which correlated with ISGU. Furthermore, p‐PKC (pan)Thr410 correlated with p‐AktSer473 and p‐AS160Thr642. ucOC exerts direct insulin‐sensitizing effects on CS‐affected mouse muscle, likely through an enhancement in activity of key proteins involved in both insulin and ucOC signaling pathways. Furthermore, these effects are muscle type‐dependent. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.