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MARGARITA LORENZO Y COLS. ANAL. REAL ACAD. NAC. FARM.

Furthermore, the residue Ser307 of IRS-1 seems to be one of the
residues phosphorylated by TNF-a via p38MAPK, although other
residues in either IRS-1 or IRS-2 or IR can not be discarding. The
role of p38MAPK in inflamatory diseases, including obesity and
cardiovascular dysfunction, is well recognized since this kinase
regulated the biosynthesis of pro-inflamatory cytokines as well as is
involved in the signaling transduction pathways activated by
cytokines, as elegantly reviewed (2).

Several reports have also implicated IKK activation by TNF-a on
serine phosphorylation of IRS-1, and aspirin rescues insulin-induced
glucose uptake in 3T3-L1 adipocytes treated with TNF-a (15, 26). In
this regard, activation of IKK dependent on the functionality of
p38MAPK was observed during chronic treatment with TNF-a in
neonatal myotubes. Moreover, inhibition of IKK activation with
salicylate completely restores insulin signaling to normal levels,
despite the presence of TNF-a (24) but salicylate does not affect
p38MAPK activation by TNF-a. Then, IKK could act downstream of
p38MAPK and could mediate TNF-a-induced insulin resistance on
skeletal muscle, as summarized in Figure 3.

FIGURE 3.- Treatment with TNF-a impairs insulin-stimulated glucose uptake
in myocytes at the level of the IRS-1 by a double mechanism that involves 1)
serine phosphorylation by IKK and p38MAPK and 2) tyrosine dephosphorylation

by the phosphatase PTP1B. Inhibition of IKK activation with salicylate, and
ablation of PTP1B restores insulin sensitivity in the presence of the cytokine.

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