Nuclear factor-κB suppressive and inhibitor-κB stimulatory effects of troglitazone in obese patients with type 2 diabetes:: Evidence of an antiinflammatory action?

It has been shown recently that troglitazone:exerts an antiinflammatory effect, in vitro, and in experimental animals. To test these properties in humans, we investigated the effect pf troglitazone on the proinflammatory transcription factor nuclear factor-kappaB and its inhibitory protein I kappaB in mononuclear cells (MNC) and plasma soluble:intracellular adhesion molecule-1, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, and C-reactive protein. We also examined the effect of troglitazone on reactive oxygen species generation, p47(phox) subunit expression, 9-hydroxyoctadecadienoic acid (9-HODE), 13-MODE, o-tyrosine, and m-tyrosine in obese patients with type 2 diabetes. Seven obese patients with type 2 diabetes were treated with troglitazone (400 mg/day) for 4 weeks. Blood samples were obtained at weekly intervals. Nuclear factor-kappaB binding activity in MNC nuclear extracts was significantly inhibited after troglitazone treatment at week 1 and continued to he inhibited up to week 4. On the other hand, I kappaB protein levels increased significantly after troglitazone treatment at week 1, and this increase persisted throughout the study. Plasma monocyte chemoattractant protein-1 and soluble intracellular adhesion molecule-1 concentrations did-not decrease significantly after troglitazone treatment,:although there was a trend toward inhibition. Reactive oxygen species generation by polymorphonuclear cells and MNC, p47(phox) subunit protein quantities, plasminogen activator inhibitor-1, and C-reactive protein levels decreased significantly after troglitazone intake, 13-HODE/linoleic acid and 9-HODE/linoleic acid ratios also decreased, after troglitazone intake. However, o-tyrosine/phenylalanine and m-tyrosine/phenylalanine ratios did not change significantly. These data show that troglitazone has profound antiinflammatory effects in addition to antioxidant effects in obese type 2 diabetics; these effects may be relevant to the recently described beneficial antiatherosclerotic effects of troglitazone at the vascular level.