Institute of Health and Sport (IHES), Victoria University, Melbourne, Australia.
Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong, VIC, Australia.
J Bone Miner Res. 2019 Aug;34(8):1517-1530. doi: 10.1002/jbmr.3731. Epub 2019 Jun 12.
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 ng/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) and the p-extracellular signal-regulated kinase isoform 2 (ERK2) /total (t)ERK2 ratio, which correlated with ISGU. In CS-affected soleus muscle, ucOC enhanced insulin action on p-mammalian target of rapamycin (mTOR) , the p-mTOR /tmTOR ratio, p-Akt substrate of 160kD (AS160) , and p-protein kinase C (PKC) (pan) , which correlated with ISGU. Furthermore, p-PKC (pan) correlated with p-Akt and p-AS160 . 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 American Society for Bone and Mineral Research.
短期给予糖皮质激素（GCs）至少部分通过减少非羧化骨钙素（ucOC）来损害肌肉胰岛素敏感性。然而，ucOC 治疗是否能逆转 GC 诱导的肌肉胰岛素抵抗尚不清楚。为了检验 ucOC 是否能直接改善短期 GC 给药引起的小鼠肌肉胰岛素刺激葡萄糖摄取（ISGU）受损的假说，并确定其分子机制，将小鼠植入安慰剂或皮质酮（CS）缓释微球。手术后 2 天进行胰岛素耐量试验（ITT）。第 3 天，采集血清，分离并离体处理伸趾长肌（EDL）和比目鱼肌，用载体、ucOC（30ng/ml）、胰岛素（60uU/ml）或两者联合处理。检测循环激素水平、肌肉葡萄糖摄取和肌肉信号蛋白。CS 给药降低了血清骨钙素和 ucOC 水平、全身胰岛素敏感性和 EDL 肌肉 ISGU。离体 ucOC 处理恢复了 CS 影响的肌肉中的 ISGU，而不增加非胰岛素刺激的葡萄糖摄取。在 CS 影响的 EDL 肌肉中，ucOC 增强了胰岛素对磷酸化（p）蛋白激酶 B（Akt）和 p-细胞外信号调节激酶同工型 2（ERK2）/总（t）ERK2 比值的作用，与 ISGU 相关。在 CS 影响的比目鱼肌中，ucOC 增强了胰岛素对哺乳动物雷帕霉素靶蛋白（mTOR）的作用，p-mTOR/tmTOR 比值、p-Akt 底物 160kD（AS160）和 p-蛋白激酶 C（PKC）（泛），与 ISGU 相关。此外，p-PKC（泛）与 p-Akt 和 p-AS160 相关。ucOC 对 CS 影响的小鼠肌肉具有直接的胰岛素增敏作用，可能是通过增强参与胰岛素和 ucOC 信号通路的关键蛋白的活性。此外，这些作用依赖于肌肉类型。2019 年美国骨矿盐研究学会。
