Thiazolidinediones such as
pioglitazone have been shown to exert anti-inflammatory effects independent of their
insulin sensitizing effects by reducing activation of the proinflammatory
transcription factor NF-kappaB in animal models of experimental diabetes. Furthermore, short-term
pioglitazone treatment ameliorates endothelial dysfunction in conduit arteries of patients with
type 2 diabetes. Since
inflammation is supposed to impair flow-mediated vasodilatation, we studied the effects of an 8-week
pioglitazone intervention on endothelial function and mononuclear
NF-kappaB activation in patients with
type 2 diabetes. Twenty patients were included in a randomized, double-blind, placebo-controlled study receiving 30 mg
pioglitazone or placebo, respectively. Flow-mediated endothelium dependent vasodilatation (FMD) of the brachial artery,
NF-kappaB binding activity in peripheral blood mononuclear cells [pBMC, determined by electrophoretic mobility shift assay (EMSA)] and
interleukin-6 (IL-6)-transcription rates (determined by real-time PCR) were measured at study entry and after eight weeks of intervention.
Pioglitazone treatment resulted in a significant improvement of FMD (4.3%+/-3.3; p=0.003), while no effect was seen under placebo medication (2.0%+/-2.7; p=0.71). The correction of FMD was neither paralleled by a
pioglitazone-dependent reduction in mononuclear
NF-kappaB binding activity (DeltaNF-kappaB activity:
pioglitazone: 9.2%+/-6.7, p=0.24; placebo: 5.7%+/-19.6; p=0.82) nor in
NF-kappaB dependent gene transcription as determined for
IL-6 (DeltaIL-6
pioglitazone: +1.8%+/-12.0, p=0.93; placebo: -0.2%+/-9.7; p=0.92). These data demonstrate for the first time that
pioglitazone treatment improves endothelial dysfunction in patients with
type 2 diabetes without affecting
NF-kappaB binding activity and
NF-kappaB dependent proinflammatory gene expression in pBMC.