TNF-alpha induces endothelial dysfunction in diabetic adults, an effect reversible by the PPAR-gamma agonist pioglitazone.
OBJECTIVE
Inflammation contributes to the pathogenesis of cardiovascular disease. Tumour necrosis factor (TNF)-alpha, in particular, is a key mediator of inflammation and vascular dysfunction and progression of atherosclerotic disease. Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, not only improves insulin sensitivity, but may also have anti-inflammatory effects. The aims of this study were to investigate the acute effects of local intra-arterial infusion with low-dose TNF-alpha on resistance vessel endothelial function in type 2 diabetes and to determine whether short-term pioglitazone treatment protects against vascular dysfunction induced by this inflammatory stimulus.


RESULTS
A randomized, parallel, placebo-controlled, double blind trial with 30 mg pioglitazone once daily for 4 weeks was performed in 16 male patients with recently diagnosed type 2 diabetes. Forearm plethysmography (FBF) was used to evaluate the effect on resistance vessel responses of intra-arterial administration of serotonin (NO-dependent vasodilation) and nitroprusside (endothelium-independent vasodilation) followed by another FBF-measurement during the second hour of intra-arterial infusion with TNF-alpha (10 ng/100 mL forearm volume/min for 2 h). Endothelial-dependent FBF of type 2 diabetic patients was significantly impaired (25.4%) by intra-arterial TNF-alpha infusion (P = 0.01), whereas nitroprusside-induced vasodilation did not change. Treatment with pioglitazone for 4 weeks completely blocked TNF-alpha-induced impairment of endothelial-dependent FBF compared with placebo. No significant changes in plasma concentrations of TNF-alpha, interleukin-6, soluble TNF-alpha-receptors, or CD40L were observed.


CONCLUSIONS
Pioglitazone treatment can convey direct protection against cytokine (TNF-alpha)-induced endothelial dysfunction in humans with an increased cardiovascular risk due to type 2 diabetes.
Martens
Fabrice M A C
FM
Department of Internal Medicine, Section of Vascular Medicine, University Medical Center Utrecht, F02.126, Heidelberglaan 100, PO Box 85500, 3508 GA Utrecht, The Netherlands.
Rabelink
Ton J
TJ
op 't Roodt
Jos
J
de Koning
Eelco J P
EJ
Visseren
Frank L J
FL
D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D011446:Prospective Studies; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects*; D014655:Vascular Resistance / Q000187:drug effects
D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077205:Pioglitazone