Improved vascular function upon pioglitazone treatment in type 2 diabetes is not associated with changes in mononuclear NF-kappaB binding activity.
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.
Rudofsky
G
G
Department Medicine I and Clinical Chemistry, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany.
Reismann
P
P
Grafe
I A
IA
Konrade
I
I
Djuric
Z
Z
Tafel
J
J
Buchbinder
S
S
Zorn
M
M
Humpert
P M
PM
Hamann
A
A
Morcos
M
M
Nawroth
P P
PP
Bierhaus
A
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001916:Brachial Artery / Q000187:drug effects / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D000077205:Pioglitazone; D010919:Placebos; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D007004:Hypoglycemic Agents; D016328:NF-kappa B; D010919:Placebos; D045162:Thiazolidinediones; D000077205:Pioglitazone