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Submitted on December 2, 2004
Accepted on March 24, 2005
B Activation and Leads to GLUT4 Downregulation in Skeletal Muscle Cells
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Spain
* To whom correspondence should be addressed. E-mail: mvazquezcarrera{at}ub.edu.
The mechanisms by which elevated levels of free fatty acids cause insulin resistance are not well understood. In addition, accumulating evidence suggests a link between inflammation and type 2 diabetes. Here, we report that exposure of C2C12 skeletal muscle cells to 0.5 mM palmitate results in increased mRNA levels (3.5-fold induction, P<0.05) and secretion (control 375±57 vs. palmitate 1129±177 pg/ml, P<0.001) of the proinflammatory cytokine IL-6. Palmitate increased Nuclear Factor (NF)-
B activation and coincubation of the cells with palmitate and the NF-B inhibitor pyrrolidine dithiocarbamate prevented both IL-6 expression and secretion. Further, incubation of palmitate-treated cells with calphostin C, a strong and specific inhibitor of protein kinase C (PKC), and PMA, that downregulates PKC in long-term incubations, abolished induction of IL-6 production. Finally, exposure of skeletal muscle cells to palmitate caused a fall in the mRNA levels of GLUT4 and insulin-stimulated glucose uptake, whereas in the presence of anti-IL-6 antibody, that neutralizes the biological activity of mouse IL-6 in cell culture, these reductions were prevented. These findings suggest that IL-6 may mediate several of the prodiabetic effects of palmitate.
B •
PKC •
Calphostin C
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