Rosiglitazone Prevents Free Fatty Acid-Induced Vascular Endothelial Dysfunction

Abstract

Elevated plasma free fatty acid (FFA) levels contribute significantly to insulin resistance, while thiazolidinediones (TZDs) improve insulin resistance and lower plasma FFA levels in diabetic patients by acting as agonists of the peroxisome proliferator-activated receptor-γ (PPARγ). In particular, the TZD rosiglitazone improves endothelial function and increases nitric oxide release in patients with type 2 diabetes. It would be expected that reducing FFA by activating PPARγ would improve triglyceride/heparin-induced endothelial dysfunction. This randomized, double blind, placebo-controlled study examined the effects of 8 mg of rosiglitazone daily or placebo, given orally for 3 weeks to 16 healthy males. All subjects received 20% Intralipid, a triglyceride emulsion, and heparin by intravenous infusion to achieve FFA levels known to produce endothelial dysfunction and insulin resistance. Forearm blood flow (FBF) responses to acetylcholine, an endothelium-dependent vasodilator, and nitroglycerine, an endothelium-independent vasodilator, were measured in both arms by strain-gauge plethysmography. Circulating levels of C-reactive protein (CRP) and asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, also were measured. Rosiglitazone administration did not alter FBF reactivity. Infusing triglyceride and heparin substantially increased plasma FFA concentrations, increased FBF in both study groups, and lowered endothelium-dependent vasodilation by 38%. Reduced reactivity to acetylcholine was observed in placebo recipients but not in those given rosiglitazone. In neither group did infusion of triglyceride/heparin influence endothelium-independent vasodilation in response to nitroglycerine. Levels of CRP remained unchanged, but insulin sensitivity and plasma ADMA levels decreased in the presence of elevated FFA levels in both study groups. In this trial rosiglitazone mitigated the increase in FFA levels following triglyceride/heparin infusion and also prevented FFA-induced endothelial dysfunction. These effects were observed in healthy individuals before any change in insulin sensitivity or plasma ADMA concentration.