The tissue concentration of UDP-N-acetylglucosamine modulates the stimulatory effect of insulin on skeletal muscle glucose uptake

Meredith Hawkins, Ivo Angelov, Rong Liu, Nir Barzilai, Luciano Rossetti

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

To delineate the biochemical mechanism by which increased availability of GlcN impairs insulin action on skeletal muscle glucose uptake, we replenished the uridine pool during GIcN administration. Co-infusion of uridine with GlcN prevented the GlcN-induced fall in skeletal muscle UDP- glucose levels (24.9 ± 5.3 versus 10.1 ± 2.9 nmol/g; p < 0.01) and further increased the skeletal muscle UDP-GlcNAc levels (198.4 ± 26.3 versus 96.0 ± 8.4 nmol/g; p < 0.01). Greater reductions in the rates of glucose infusion (~53%), glucose uptake (~43%), and glycogen synthesis (~60%) were observed with the addition of uridine. Similarly, the infusion of uridine alone markedly increased the skeletal muscle levels of both UDP-glucose (55.2 ± 14.2 versus 17.8 ± 6.1 nmol/g; p < 0.01) and UDP-GlcNAc (86.8 ± 8.8 versus 35.9 ± 8.4 nmol/g;p < 0.05) and induced marked insulin resistance. The decrease in insulin action on peripheral glucose uptake was highly correlated with the increase in skeletal muscle UDP-GlcNAc levels. Finally, immunoisolation of GLUT4-containing vesicles revealed that the rate of labeled GlcN incorporation was ~100-fold greater following GIcN compared with saline infusions (p < 0.01). We suggest that the marked reduction in insulin action induced by GlcN and uridine is mediated by increased accumulation of muscle UDP-N-acetylhexosamines, perhaps via altered glycosylation of protein(s) in GLUT4-containing vesicles.

Original languageEnglish (US)
Pages (from-to)4889-4895
Number of pages7
JournalJournal of Biological Chemistry
Volume272
Issue number8
DOIs
StatePublished - Feb 21 1997

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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