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Articles in PresS, published online ahead of print November 26, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00345.2002
Submitted on August 5, 2002
Accepted on November 21, 2002
1 Department of Physiology and Biophysics, University of Campinas, Campinas, SP, Brazil
2 Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil
3 Department of Physiology and Biophysics, University of Sao Paulo, Sao Paulo, SP, Brazil
* To whom correspondence should be addressed. E-mail: boschero{at}unicamp.com.br.
Short-term muscle denervation is a reproducible model of tissue specific insulin resistance. To investigate the molecular basis of insulin resistance in denervated muscle the downstream signaling molecules of the insulin-signaling pathway were examined in intact and denervated soleus muscle of rats. Short-term denervation induced a significant fall in glucose clearance rates (62% of control, p<0.05) as detected by euglycemic-hyperinsulinemic clamp, and was associated with significant decrease in insulin-stimulated tyrosine phosphorylation of IR (73% of control, p<0.05), IRS1 (69% of control, p<0.05) and IRS2 (82% of control, p<0.05) and serine phosphorylation of Akt (39% of control, p<0.05). Moreover, denervation reduced insulin-induced association between IRS1/IRS2 and p85/PI3-kinase. Notwithstanding, denervation caused an increase in IRS1 (275%, p<0.05) and IRS2 (180%, p<0.05) associated PI3-kinase activity, but the contents of phosphorylated phosphoinositides detected by HPLC were significantly reduced in lipid fractions. In face of the apparent discrepancy we evaluated the expression and activity of the 5-inositol, lipid phosphatase SHIP2 and the serine phosphorylation of p85/PI3-kinase. No major differences in SHIP2 expression were detected between intact and denervated muscle. However, serine phosphorylation of p85/PI3-kinase was reduced in denervated muscle, while the blockade of SHIP2 expression by antisense oligonucleotide treatment led to partial restoration of phosphorylated phosphoinositide contents and to improved glucose uptake. Thus, modulation of the functional status of SHIP2 may be a major mechanism of insulin resistance induced by denervation.
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