胰岛素通过涉及内皮依赖性血管舒张和雷帕霉素哺乳动物靶蛋白复合物 1 信号转导的间接机制刺激人体骨骼肌蛋白质合成。

Insulin stimulates human skeletal muscle protein synthesis via an indirect mechanism involving endothelial-dependent vasodilation and mammalian target of rapamycin complex 1 signaling.

机构信息

Sealy Center on Aging, Department of Internal Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-0460, USA.

出版信息

J Clin Endocrinol Metab. 2010 Aug;95(8):3848-57. doi: 10.1210/jc.2009-2696. Epub 2010 May 19.

DOI:10.1210/jc.2009-2696

PMID:20484484

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2913031/

Abstract

OBJECTIVE

Our objective was to determine whether endothelial-dependent vasodilation is an essential mechanism by which insulin stimulates human skeletal muscle protein synthesis and anabolism.

SUBJECTS

Subjects were healthy young adults (n=14) aged 31+/-2 yr.

DESIGN

Subjects were studied at baseline and during local leg infusion of insulin alone (control, n=7) or insulin plus the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, n=7) to prevent insulin-induced vasodilation.

METHODS

We measured skeletal muscle protein metabolism with stable isotope tracers, blood flow with indocyanine green, capillary recruitment with contrast enhanced ultrasound, glucose metabolism with stable isotope tracers, and phosphorylation of proteins associated with insulin (Akt) and amino acid-induced mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling (mTOR, S6 kinase 1, and eukaryotic initiation factor 4E-binding protein 1) with Western blot analysis.

RESULTS

No basal differences between groups were detected. During insulin infusion, blood flow and capillary recruitment increased in the control (P<0.05) group only; Akt phosphorylation and glucose uptake increased in both groups (P<0.05), with no group differences; and mTORC1 signaling increased more in control (P<0.05) than in L-NMMA. Phenylalanine net balance increased (P<0.05) in both groups, but with opposite mechanisms: increased protein synthesis (basal, 0.051+/-0.006 %/h; insulin, 0.077+/-0.008 %/h; P<0.05) with no change in proteolysis in control and decreased proteolysis (P<0.05) with no change in synthesis (basal, 0.061+/-0.004 %/h; insulin, 0.050+/-0.006 %/h; P value not significant) in L-NMMA.

CONCLUSIONS

Endothelial-dependent vasodilation and the consequent increase in nutritive flow and mTORC1 signaling, rather than Akt signaling, are fundamental mechanisms by which insulin stimulates muscle protein synthesis in humans. Additionally, these data underscore that insulin modulates skeletal muscle proteolysis according to its effects on nutritive flow.

摘要

目的

我们的目的是确定内皮依赖性血管舒张是否是胰岛素刺激人体骨骼肌蛋白质合成和合成代谢的关键机制。

受试者

受试者为健康的年轻成年人（n=14），年龄 31+/-2 岁。

设计

受试者在基础状态和局部腿部输注胰岛素（对照组，n=7）或胰岛素加一氧化氮合酶抑制剂 NG-单甲基-L-精氨酸（L-NMMA，n=7）时进行研究，以防止胰岛素引起的血管舒张。

方法

我们使用稳定同位素示踪剂测量骨骼肌蛋白质代谢，使用吲哚菁绿测量血流，使用对比增强超声测量毛细血管募集，使用稳定同位素示踪剂测量葡萄糖代谢，使用 Western blot 分析测量与胰岛素（Akt）和氨基酸诱导的哺乳动物雷帕霉素靶蛋白（mTOR）复合物 1（mTORC1）信号相关的蛋白质的磷酸化（mTOR、S6 激酶 1 和真核起始因子 4E 结合蛋白 1）。

结果

两组之间没有发现基础差异。在胰岛素输注期间，仅在对照组中血流和毛细血管募集增加（P<0.05）；Akt 磷酸化和葡萄糖摄取在两组中均增加（P<0.05），但无组间差异；并且 mTORC1 信号在对照组中增加更多（P<0.05）。苯丙氨酸净平衡增加（P<0.05），但两组的机制相反：对照组蛋白质合成增加（基础，0.051+/-0.006%/h；胰岛素，0.077+/-0.008%/h；P<0.05），而蛋白酶解无变化，L-NMMA 组蛋白酶解减少（P<0.05），合成无变化（基础，0.061+/-0.004%/h；胰岛素，0.050+/-0.006%/h；P 值无意义）。