Neuronal nitric oxide synthase mediates insulin- and oxidative stress-induced glucose uptake in skeletal muscle myotubes

Dean L Kellogg Jr, Karen M. McCammon, Kathryn S. Hinchee-Rodriguez, Martin L Adamo, Linda J. Roman

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Previously published studies strongly suggested that insulin- and exercise-induced skeletal muscle glucose uptake require nitric oxide (NO) production. However, the signal transduction mechanisms by which insulin and contraction regulated NO production and subsequent glucose transport are not known. In the present study, we utilized the myotube cell lines treated with insulin or hydrogen peroxide, the latter to mimic contraction-induced oxidative stress, to characterize these mechanisms. We found that insulin stimulation of neuronal nitric oxide synthase (nNOS) phosphorylation, NO production, and GLUT4 translocation were all significantly reduced by inhibition of either nNOS or Akt2. Hydrogen peroxide (H2O2) induced phosphorylation of nNOS at the same residue as did insulin, and also stimulated NO production and GLUT4 translocation. nNOS inhibition prevented H2O2-induced GLUT4 translocation. AMP activated protein kinase (AMPK) inhibition prevented H2O2 activation and phosphorylation of nNOS, leading to reduced NO production and significantly attenuated GLUT4 translocation. We conclude that nNOS phosphorylation and subsequently increased NO production are required for both insulin- and H2O2-stimulated glucose transport. Although the two stimuli result in phosphorylation of the same residue on nNOS, they do so through distinct protein kinases. Thus, insulin and H2O2-activated signaling pathways converge on nNOS, which is a common mediator of glucose uptake in both pathways. However, the fact that different kinases are utilized provides a basis for the use of exercise to activate glucose transport in the face of insulin resistance.

Original languageEnglish (US)
Pages (from-to)261-269
Number of pages9
JournalFree Radical Biology and Medicine
Volume110
DOIs
StatePublished - Sep 1 2017

Keywords

  • Exercise
  • GLUT4
  • Insulin
  • Myotubes
  • Nitric oxide
  • Nitric oxide synthase
  • Oxidative stress
  • Skeletal muscle

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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