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Context: Free fatty acids (FFAs) cause insulin resistance and vascular endothelial dysfunction. The peroxisome proliferator-activated receptor gamma agonist rosiglitazone acts as insulin sensitizer and could exert vasoprotective properties by preservation of endothelium-dependent vasodilation., Objective: We tested the effect of rosiglitazone on FFA-induced endothelial dysfunction of the forearm resistance vessels, insulin sensitivity, asymmetric dimethylarginine (ADMA), and high-sensitivity C-reactive protein concentrations in humans., Design and Setting: We conducted a double-blind, randomized, placebo-controlled parallel-group study at a university hospital., Patients and Interventions: Rosiglitazone 8 mg daily or placebo was administered to 16 healthy male subjects for 21 d. On the last day, triglycerides and heparin were infused iv to increase FFA plasma concentrations., Main Outcome Measures: Forearm blood flow responses to the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator nitroglycerine were assessed using strain-gauge plethysmography at baseline, and on d 21 before and after 5 h of triglyceride/heparin infusion., Results: Forearm blood flow reactivity was not affected by rosiglitazone or placebo. Infusion of triglyceride/heparin substantially increased FFA concentrations (P < 0.001) and reduced endothelium-dependent vasodilation by 38 +/- 17% (P = 0.024). In the face of lower FFA elevation (P = 0.047 vs. controls), endothelium-dependent vasodilation was preserved in subjects receiving rosiglitazone (P = 0.016 vs. placebo). Endothelium-independent vasodilation and C-reactive protein were unchanged, whereas insulin sensitivity and plasma ADMA similarly decreased in both study groups after FFA elevation (both P < 0.05 vs. baseline)., Conclusions: Rosiglitazone mitigates the increase in FFA after infusion of triglyceride/heparin and prevents FFA-induced endothelial dysfunction. These effects are independent and possibly occur before any changes in insulin sensitivity and ADMA plasma concentrations in healthy subjects.

Context: Exercise training exerts beneficial effects on metabolic and vascular risk factors in patients with type 1 diabetes mellitus (T1DM). It is unknown whether training also influences concentrations of visfatin, a novel insulin-mimetic adipocytokine., Objectives: In this study, we have investigated whether plasma visfatin concentrations are altered by training in patients with T1DM., Design and Patients: Fasting plasma visfatin concentrations and metabolic parameters were measured in 18 patients with T1DM who participated in a supervised aerobic exercise program for 4 months. Three subjects discontinued training prematurely after 2 months. Samples were obtained before and during training and 8 months after the end of regular exercise. Fourteen healthy young subjects served as controls., Results: At baseline, patients with T1DM had higher visfatin concentrations than controls (64.1 +/- 12.0 vs. 1.3 +/- 0.0 ng/ml, P < 0.01). Exercise reduced visfatin after 2 and 4 months to 27.8 +/- 2.6 (n = 18) and 17.5 +/- 3.4 ng/ml (n = 15), respectively (P < 0.001 for n = 15 subjects who participated in all visits, ANOVA). This effect was maintained 8 months after cessation of training, with visfatin concentrations of 19.7 +/- 5.0 ng/ml (n = 15). Metabolic parameters were not affected by the training program., Conclusion: Elevated visfatin concentrations in patients with T1DM can be lowered by regular physical exercise. It is unknown whether glucose tolerance is affected by changes in visfatin concentrations.

Insulin resistance is associated with an inappropriate elevation of plasma FFA and endothelial dysfunction. FFA could stimulate formation of reactive oxygen species, which could be responsible for vascular impairment. In this randomized, double-blind, cross-over study in 10 healthy volunteers (24 +/- 3 yr old), forearm blood flow (FBF) responses to intraarterial acetylcholine (ACh) and glyceryl trinitrate were assessed with coadministration of vitamin C (24 mg/ml) or placebo, respectively, in the presence of increased plasma FFA induced by Intralipid/heparin infusion. The rise in plasma FFA from 320 +/- 64 to 1852 +/- 232 micromol/liter was associated with a reduced response of FBF to ACh by 55% (P < 0.01). During coadministration of vitamin C, the impaired responsiveness of FBF to ACh was completely reversed and not different from that observed under baseline conditions. Vitamin C did not affect plasma FFA concentrations. Glyceryl trinitrate responsiveness was unchanged during FFA elevation, with or without vitamin C. These data suggest that FFA-induced vascular oxidative stress could contribute to endothelial dysfunction in insulin-resistant patients. High concentrations of antioxidants are able to reverse the local effects of FFA on endothelium-dependent vasodilation.