Inhibition of insulin signaling and glycogen synthesis by phorbol dibutyrate in rat skeletal muscle

Yenshou Lin, Samar I. Itani, Theodore G. Kurowski, David J. Dean, Zhijun Lou, Gordon C. Yaney, Neil B. Ruderman

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22 Citations (Scopus)

Abstract

Numerous studies have shown a correlation between changes in protein kinase C (PKC) distribution and/or activity and insulin resistance in skeletal muscle. To investigate which PKC isoforms might be involved and how they affect insulin action and signaling, studies were carried out in rat soleus muscle incubated with phorbol esters. Muscles preincubated for 1 h with I μM phorbol 12,13-dibutyrate (PDBu) showed an impaired ability of insulin to stimulate glucose incorporation into glycogen and a translocation of PKC-α, -βI, -θ, and -ε, and probably -βII, from the cytosol to membranes. Preincubation with 1 μM PDBu decreased activation of the insulin receptor tyrosine kinase by insulin and to an even greater extent the phosphorylation of Akt/protein kinase B and glycogen synthase kinase-3. However, it failed to diminish the activation of phosphatidylinositol 3′-kinase by insulin. Despite these changes in signaling, the stimulation by insulin of glucose transport (2-deoxyglucose uptake) and glucose incorporation into lipid and oxidation to CO2 was unaffected. The results indicate that preincubation of skeletal muscle with phorbol ester leads to a translocation of multiple conventional and novel PKC isoforms and to an impairment of several, but not all, events in the insulin-signaling cascade. They also demonstrate that these changes are associated with an inhibition of insulin-stimulated glycogen synthesis but that, at the concentration of PDBu used here, glucose transport, its incorporation into lipid, and its oxidation to CO2 are unaffected.

Original languageEnglish
Pages (from-to)E8-E15
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume281
Issue number1 44-1
Publication statusPublished - 2001 Oct 10

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Keywords

  • Akt/protein kinase B
  • Glycogen synthase kinase-3
  • Phorbol dibutyrate
  • Protein kinase C
  • Soleus muscle

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Lin, Y., Itani, S. I., Kurowski, T. G., Dean, D. J., Lou, Z., Yaney, G. C., & Ruderman, N. B. (2001). Inhibition of insulin signaling and glycogen synthesis by phorbol dibutyrate in rat skeletal muscle. American Journal of Physiology - Endocrinology and Metabolism, 281(1 44-1), E8-E15.