Nuclear factor-kappaB suppressive and inhibitor-kappaB 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 anti-inflammatory effect, in vitro, and in experimental animals. To test these properties in humans, we investigated the effect of troglitazone on the proinflammatory transcription factor nuclear factor-kappaB and its inhibitory protein IkappaB 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-HODE, 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 be inhibited up to week 4. On the other hand, IkappaB 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.