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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-2130
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 7 2574-2580
Copyright © 2007 by The Endocrine Society

Rosiglitazone Prevents Free Fatty Acid-Induced Vascular Endothelial Dysfunction

Friedrich Mittermayer, Georg Schaller, Johannes Pleiner, Katarzyna Krzyzanowska, Stylianos Kapiotis, Michael Roden and Michael Wolzt

Department of Clinical Pharmacology (F.M., G.S., J.P., M.W.), and Clinical Institute for Medical and Chemical Laboratory Diagnostics (S.K.), Medical University Vienna, A-1090 Vienna, Austria; Department of Internal Medicine I (K.K.), Rudolfstiftung Hospital, A-1030 Vienna, Austria; and 1st Medical Department (M.R.), Hanusch Hospital, A-1140 Vienna, Austria

Address all correspondence and requests for reprints to: Michael Wolzt, Medical University Vienna, Department of Clinical Pharmacology, AKH-Wien, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail: michael.wolzt{at}meduniwien.ac.at.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ELEVATED FREE FATTY ACID (FFA) plasma concentrations play an important role in the pathogenesis of insulin resistance (1, 2). Insulin resistance is characterized by reduced skeletal muscle (3) and hepatic glucose disposal, and can be provoked in healthy subjects by prolonged exposure to FFA (4). Thiazolidinediones (TZD) act as agonists of the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), improve insulin resistance, and reduce FFA plasma levels in patients with type 2 diabetes mellitus (5). The TZD rosiglitazone enhances endothelial function (6) and increases nitric oxide (NO) release in patients with type 2 diabetes (7). In addition, PPAR{gamma} agonists might be vasoprotective (8) by exerting antiinflammatory (9) and antioxidative effects (10).

Experimental elevation of FFA by infusion of triglyceride/heparin causes endothelial dysfunction in healthy humans (11, 12). Therefore, a reduction of FFA by activation of PPAR{gamma} should improve triglyceride/heparin-induced endothelial dysfunction. Furthermore, insulin resistance was associated with endothelial dysfunction (13). Thus, improved insulin sensitivity by TZD treatment could ameliorate endothelial dysfunction during exogenously elevated FFA plasma concentrations. Third, TZD reduces plasma levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) in insulin-resistant subjects (14) and increase the expression of the ADMA degrading enzyme dimethylamino dimethylarginine hydrolase (15). ADMA reduction by TZD treatment could also beneficially affect endothelial function.

We have measured vascular function of the forearm resistance vessels in healthy subjects receiving rosiglitazone or placebo to evaluate the role of PPAR{gamma} activation in FFA-induced endothelial dysfunction in the absence of confounding factors that could also affect vascular function, like preexisting insulin resistance or subclinical inflammation, as seen in patients with the metabolic syndrome or type 2 diabetes. A low-dose short insulin tolerance test (16) was performed to monitor the effect of rosiglitazone on FFA-induced insulin resistance. To assess whether endothelial function is related to changes of ADMA or the substrate for NO synthesis, L-arginine, plasma concentrations of the amino acids were quantified. Furthermore, high-sensitivity C-reactive protein (CRP) was determined as a marker of subclinical inflammation.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The study was approved by the Ethics Committee of the Medical University Vienna and conforms to the principles outlined in the Declaration of Helsinki, including current revisions and the Good Clinical Practice guidelines.

Subjects

There were 16 healthy volunteers from whom informed consent was obtained before enrollment included in the study. The clinical and metabolic parameters are presented in Table 1Go. A complete health examination, including physical examination, electrocardiogram, and laboratory screening, was performed in all subjects before the first study day. No participant was a smoker, or had a history or signs of arterial hypertension, hypercholesterolemia, or other cardiovascular risk factors. All study participants had normal glucose tolerance according to guidelines of the American Diabetes Association (17). Subjects were drug-free, including "over-the-counter" medications from 3 wk before screening until the study was complete. Studies were conducted in a quiet room with an ambient temperature of 22 C and complete resuscitation facilities after an overnight fast.


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  		TABLE 1. Clinical and metabolic characteristics at baseline

 
Study design

This study followed a double-blind, randomized, placebo-controlled parallel-group design. Baseline measurements of forearm blood flow (FBF), insulin sensitivity, and other outcome parameters were done on d 1 before first drug administration. A fine-needle (27-G needle Sterican, B; Braun, Melsungen, Germany) was inserted into the brachial artery of the nondominant arm. After a 20-min resting period, FBF responses to acetylcholine and nitroglycerine were measured. After rosiglitazone/placebo treatment for 21 d, a plastic cannula was placed in each forearm for monitoring of plasma concentrations of the outcome parameters and administration of the lipid solution, respectively. FBF measurement and insulin sensitivity were reassessed, and triglyceride/heparin infused iv for 6 h. After 5 h of infusion, measurement of FBF, acetylcholine- and nitroglycerine-induced vasodilation, and insulin sensitivity was repeated.

Study drugs

Eight milligrams of rosiglitazone (Avandia; Smith Kline Beecham Laboratoires, Mayenne, France) or placebo were administered as an oral daily dose for 21 d. Twice a week, subjects had to attend the research institution for tablet distribution. Compliance was assessed by observing drug intake at the study visits and pill count. The triglyceride emulsion (Intralipid 20%, 1.5 ml/min; Fresenius Kabi AB, Uppsala, Sweden) plus heparin (bolus: 200 IU; constant infusion rate: 0.2 IU/kg·min; Ebewe Pharma Ges.m.b.H. NFG. KG, Unterach, Austria) was infused iv to achieve systemic FFA levels known to induce endothelial dysfunction and insulin resistance (11, 18, 19). Heparin was added to enhance breakdown of triglycerides to FFA in plasma (11). To assess endothelium-dependent vasodilation of the human forearm resistance vasculature, increasing doses of acetylcholine (25, 50, and 100 nmol/min; Clinalfa, Läufelfingen, Switzerland) were infused into the brachial artery. Endothelium-independent vasodilation was assessed by intraarterial infusion of nitroglycerine (4, 8, and 16 nmol/min; Perlinganit, Schwarz Pharma AG, Monheim, Germany). Both vasodilators were infused for 3 min per dose level, with a 15-min washout period between the drugs (20). On d 21, the lipid infusion was started 25 min after the end of the nitroglycerine infusion for baseline FBF measurements.

FBF measurements

FBF was measured in both arms, as described previously (20, 21). Strain gauges, placed on the forearms, were connected to plethysmographs (EC-6; D.E. Hokanson, Inc., Bellevue, WA) to measure changes in forearm volume in response to inflation of venous congesting cuffs. Drug effects were expressed as the ratio of blood flow in the intervention to the control arm (22), where predose ratio was defined as 100%. Wrist cuffs were inflated to suprasystolic pressures during each measurement to exclude circulation to the hands. Flow measurements were recorded for 9 sec at 30-sec intervals during drug infusions, and the early linear increase of the flow curves was used for calculation of FBF.

Low-dose short insulin tolerance test

Plasma glucose was measured before and at each minute from 3–15 min after iv administration of 0.05 IU/kg insulin (Insulin Actrapid; Novo-Nordisk A/S, Bagsvaerd, Denmark). Thereafter, subjects received 100-ml 10% glucose iv to prevent hypoglycemia. Insulin sensitivity was derived from the slope of blood glucose concentrations. This method correlates with the euglycemic hyperinsulinemic clamp and is validated for the evaluation of insulin sensitivity in healthy subjects (16). A low-dose short insulin tolerance test was performed after each FBF measurement.

Laboratory analysis

Total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, CRP, glucose, and insulin were determined by routine laboratory methods of the Clinical Institute for Medical and Chemical Laboratory Diagnostics of the Medical University Vienna. Plasma concentrations of FFA were measured using enzymatic methods, as described previously (23, 24). For measurement of L-arginine, ADMA, and symmetrical dimethylarginine (SDMA), plasma was subjected to cation exchange solid-phase extraction and analyzed by HPLC. The coefficients of variation for intersample and intrasample variations tested with a pooled plasma sample were less than 3% for all analytes. The detection limit for dimethylarginines was 0.04 µmol/liter (25, 26).

Statistics

Outcome parameters were compared using two-way ANOVA for repeated measurements and the Fisher least significant difference post hoc test after log transformation applying the Statistica software package (Release 6; StatSoft, Inc., Tulsa, OK). Comparisons of baseline parameters were assessed with the Mann-Whitney U test. A two-tailed P value < 0.05 was considered significant. A power calculation based on a priori assumption of {alpha} = 0.05 and ß = 0.20, assuming a within group {varsigma} of 0.1 and a between groups {varsigma} of 0.2, revealed that a study in 16 subjects (eight in each group) has a power of 80% to detect a minimum of 7.5% and 20% difference in FBF ratio, respectively. Values are expressed as means and SD unless indicated otherwise.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
No differences in metabolic and baseline outcome parameters were detectable between groups of subjects randomized to placebo or rosiglitazone (Tables 1Go and 2Go). After the first volunteer developed symptomatic hypoglycemia during the low-dose short insulin tolerance test, an infusion of 100-ml 10% glucose iv was started after each insulin tolerance test. With this approach, no hypoglycemia was observed. All other drugs and infusions were well tolerated, and no adverse reactions were reported. All subjects completed the study according to the protocol.


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  		TABLE 2. Outcome parameters at baseline (d 1), after 21 d of treatment with placebo (n = 8) or rosiglitazone (n = 8, d 21), and after 5 h of triglyceride/heparin infusion (d 21 FFA)

 
Endothelium-dependent and -independent vasodilation

Basal FBF as well as acetylcholine- and nitroglycerine-induced increase in FBF were comparable between the two groups before and after 21 d of placebo/rosiglitazone intake. After 5 h of continuous triglyceride/heparin administration, basal FBF increased in both study groups (P = 0.003 placebo and P = 0.013 rosiglitazone vs. before triglyceride/heparin on d 21, P = 0.596 between groups; Table 2Go), and a reduced reactivity to acetylcholine was seen in subjects receiving triglyceride/heparin and placebo (P = 0.010 vs. d 1, P = 0.024 vs. d 21 before triglyceride/heparin), but not in subjects receiving rosiglitazone (P = 0.542 vs. d 1, P = 0.790 vs. d 21 before triglyceride/heparin, P = 0.016 vs. placebo) (Fig. 1Go and Table 3Go). Endothelium-independent vasodilation to nitroglycerine was not affected by infusion of triglyceride/heparin in both groups (Fig. 2Go).


Figure 1
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  		FIG. 1. FBF ratio in response to intraarterial infusion of acetylcholine in subjects receiving rosiglitazone (open symbols, n = 8) or placebo (closed symbols, n = 8) before first drug administration (d 1), after 21 d of rosiglitazone/placebo treatment (d 21), and after 5 h of exogenously increased FFA concentrations (d 21 FFA). Significant differences between groups are indicated (*, P < 0.05 post hoc test Fisher least significant difference). Data represent means ± SD.

 

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  		TABLE 3. Absolute FBF values (intervention arm corrected by blood flow in the control arm in ml/min·100 ml) during acetylcholine (Ach) administration on d 1 and 21 before and during (d 21 FFA) elevated FFA plasma concentrations

 

Figure 2
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  		FIG. 2. FBF ratio in response to intraarterial infusion of nitroglycerine in subjects receiving rosiglitazone (open symbols, n = 8) or placebo (closed symbols, n = 8) treated subjects before first drug administration (d 1), after 21 d of rosiglitazone/placebo treatment (d 21), and after 5 h of exogenously increased FFA concentrations (d 21 FFA). No difference was detectable between groups. Data represent means ± SD.

 
Metabolic parameters, CRP, and methylarginines

Treatment with rosiglitazone for 21 d reduced FFA plasma concentrations (P = 0.001 vs. d 1), which was not detectable after placebo (P = 0.221 vs. d 1; P = 0.025 between groups). Administration of triglyceride/heparin resulted in a substantial increase of FFA and triglyceride plasma concentrations in both study groups (both P < 0.001). This elevation was attenuated in subjects receiving rosiglitazone (P = 0.047 and P = 0.008 vs. placebo, respectively). Plasma glucose concentrations were not affected by rosiglitazone or placebo and triglyceride/heparin infusion in both groups. Insulin concentrations did not change after 21 d of rosiglitazone or placebo but increased in the placebo group during triglyceride/heparin infusion (P = 0.022 vs. d 21 before triglyceride/heparin; P = 0.049 between groups). Insulin sensitivity was not influenced by rosiglitazone or placebo treatment and reduced by triglyceride/heparin infusion to a similar extent in both groups (P = 0.031 vs. d 21 before triglyceride/heparin for rosiglitazone and P = 0.006 vs. d 21 before triglyceride/heparin for placebo, respectively; P = 0.425 between groups). L-arginine, ADMA, and SDMA were not affected by rosiglitazone or placebo, and similarly decreased during triglyceride/heparin infusion in both groups (both P < 0.05). CRP was not affected by rosiglitazone or placebo or triglyceride/heparin infusion (Table 2Go). None of the parameters correlated significantly with endothelium-dependent or -independent vasodilation.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Short-term administration of the PPAR{gamma} agonist rosiglitazone prevents FFA-induced endothelial dysfunction of resistance arteries in vivo. This effect was observed in the absence of changes in insulin sensitivity, endogenous methylarginines, or subclinical inflammation, as indicated by unchanged CRP in healthy subjects.

All study participants received the same amount of triglyceride and weight adapted heparin to increase FFA plasma concentrations. However, FFA and triglyceride levels increased significantly less in rosiglitazone-treated subjects compared with those receiving placebo. This effect of rosiglitazone is consistent with animal and other human models (27, 28). TZD can enhance FFA uptake into cells by increasing plasma triglyceride lipolysis and transendothelial FFA transport (29, 30, 31). The increase in plasma FFA was paralleled by the development of endothelial dysfunction in the forearm resistance vasculature, which is compatible with previous studies (11, 12). Surprisingly, FFA concentrations were not associated with endothelium-dependent vasodilation in our study. However, this study was not designed to assess such correlations and might have been underpowered to detect a negative relationship, which has been demonstrated previously in a cohort of 76 healthy subjects (32). Steinberg et al. (11) described a dose dependency of triglyceride/heparin-induced impairment of endothelial function. Due to the prolonged infusion of triglyceride/heparin, FFA concentrations obtained in subjects receiving rosiglitazone were higher than FFA concentrations that induced endothelial dysfunction in our previous experiments (12). Thus, FFA reduction by rosiglitazone per se is unlikely to improve vascular function. Nevertheless, rosiglitazone maintained integrity of pharmacological reactivity to acetylcholine in the forearm vasculature, which suggests additional PPAR{gamma} mediated effects on the vasculature during FFA elevation. Tripathy et al. (33) have shown that acute elevation of FFA increases reactive oxygen species and nuclear factor-{kappa}B expression along with deterioration of flow-mediated vasodilation of the brachial artery in humans. Antioxidative and antiinflammatory properties have been described for rosiglitazone and troglitazone (9, 10, 34, 35). These mechanisms could contribute to the improvement of FFA-induced endothelial dysfunction by rosiglitazone. However, CRP concentrations were not affected by triglyceride/heparin infusion in our study, suggesting that antiinflammatory effects of rosiglitazone are of little if any impact in our study. In contrast to our results, a CRP-lowering effect of rosiglitazone has been described in healthy subjects recently (36). However, CRP concentrations reported in this uncontrolled study were twice as high as in the present cohort, indicating subtle subclinical inflammation. This might explain the discrepancy between the studies and the lack of antiinflammatory actions of rosiglitazone in the healthy subjects under study. FFA plasma concentrations were reduced after 21 d of rosiglitazone, which was also previously reported from other studies (5, 27).

The finding that FFAs increase basal FBF is consistent with previous studies (11, 12, 37, 38). The augmentation of FBF was not affected by rosiglitazone, which suggests that it is independent of PPAR{gamma} activation. Increased NO production or elevated insulin concentrations are unlikely to have enhanced blood flow because basal NO synthesis is reduced and insulin-mediated vasodilation diminished during experimental elevation of FFA plasma concentrations (39). Mechanisms like increased cardiac output or vasoconstriction in other vascular beds than the forearm have been discussed to account for increased blood flow and blood pressure during elevated FFA plasma concentrations (37). However, the reasons for enhanced blood flow during lipid infusion remain unclear. Absolute FBF during acetylcholine infusion in rosiglitazone-treated subjects was even higher during FFA elevation than without FFA. This higher increase could be due to the greater basal FBF during FFA, which is reflected by comparable relative acetylcholine effects before and during FFA in rosiglitazone-treated subjects (Fig. 1Go).

As expected, experimental elevation of FFA decreased insulin sensitivity. Interestingly, no difference in the reduction of insulin sensitivity by infusion of triglyceride/heparin could be observed between the study groups. This is in accordance with a recent study by Dhindsa et al. (27), showing that FFA-induced insulin resistance as assessed by a euglycemic clamp is not improved by pretreatment with rosiglitazone, despite a smaller increase in FFA plasma concentrations in rosiglitazone-treated subjects, as seen in this study. Our findings and those from Dhindsa et al. (27) suggest that the insulin sensitizing effect of rosiglitazone is distinct from the site of action of FFA on insulin sensitivity. Thus, altered insulin resistance is unlikely to contribute to the positive effect of rosiglitazone on FFA-induced endothelial dysfunction. This is further supported by the fact that endothelial function is already reduced after 2 h of FFA elevation (12), when insulin resistance is not present yet (4). However, the lack of effect of rosiglitazone on FFA-induced insulin resistance is, therefore, limited to this experimental setting.

Insulin concentrations were increased by FFA in the placebo group only, which is at variance with previous studies using triglyceride/heparin infusion and cannot be explained on the basis of our results (11, 12). It has been demonstrated that excessively high FFA concentrations are capable of stimulating insulin secretion (40), arguing that higher or prolonged FFA exposure can induce a reactive insulin release. This observation could in turn influence the insulin sensitivity test applied in this study, where a bolus administration yields a point estimate rather than a continued glucose disposition index into other compartments, as during clamp studies. Higher FFA plasma concentrations lead to higher insulin levels during the low-dose short insulin tolerance test, which could result in a reduced requirement of exogenous insulin for glucose disposal. This could confound estimates of insulin sensitivity. However, the increase of insulin during elevated FFA in the placebo group was not significantly different from that in the rosiglitazone group. This renders a false result regarding the similar decrease of insulin sensitivity in subjects receiving placebo and rosiglitazone rather unlikely.

ADMA plasma concentrations were not influenced by treatment with rosiglitazone, which is in contrast to findings in insulin-resistant subjects (14). However, normal levels of ADMA in the insulin-sensitive subjects under study might not be influenced further by TZD treatment. Elevation of FFA plasma levels caused a significant decrease of L-arginine, ADMA, and SDMA. This may be due to regional vasodilation (24), which may also cause renal hyperperfusion, leading to augmented clearance of the amino acids. Although the detailed mechanism has not been addressed in this study, the results clearly argue against an influence of dimethylarginines on FFA-induced endothelial dysfunction.

Endothelial dysfunction is associated with insulin resistance (41, 42) and type 2 diabetes mellitus (43, 44). Elevated FFAs are considered important contributors of vascular dysfunction in insulin-resistant subjects that promote the development of cardiovascular disease (45). Endothelial dysfunction assessed by acetylcholine-induced vasodilation of resistance arteries is associated with an increased risk for cardiovascular events (46, 47, 48). Thus, improvement of endothelial function could positively influence the cardiovascular risk profile in patients with the metabolic syndrome independent of improvement of glucose metabolism or insulin resistance. The model of triglyceride/heparin infusion in healthy humans is widely used to study the effects of FFA elevation in the absence of confounding factors that are usually present in patients with chronically elevated FFA concentrations. This gives insight into the pathophysiological effects of FFA. However, the acute and excessive FFA increase in the model used might not be representative for clinical conditions. The relevance of endothelial dysfunction after high-dose lipid infusion is unclear, and there are no studies available to extrapolate our findings on acutely impaired vascular function to future cardiovascular events in subjects with preexisting endothelial dysfunction. Thus, our findings are limited to demonstrate that acute detrimental effects by FFA on the vasculature can be effectively prevented by treatment with rosiglitazone, at least in healthy subjects with normal insulin sensitivity and low cardiovascular risk. A large prospective trial already showed a positive effect of the TZD pioglitazone on a combined secondary endpoint of total mortality, nonfatal myocardial infarction, and stroke in patients with type 2 diabetes and macrovascular disease (49). Although a different TZD was studied, the effect on the cardiovascular system might represent a class effect (50).

The present study is limited by the relatively small sample size, the fact that only male patients were included, and the use of a model to increase FFA in healthy subjects, which is not directly transferable to patients with chronic disease.

In conclusion, treatment with rosiglitazone prevents FFA-induced endothelial dysfunction and reduces exogenously increased FFA plasma concentrations in vivo. These effects are independent of changes in insulin sensitivity and plasma concentrations of the endogenous NO synthase inhibitor ADMA in healthy subjects.


   Footnotes
 
Disclosure Statement: The authors have nothing to declare.

First Published Online May 1, 2007

Abbreviations: ADMA, Asymmetric dimethylarginine; CRP, C-reactive protein; FBF, forearm blood flow; FFA, free fatty acid; NO, nitric oxide; PPAR{gamma}, peroxisome proliferator-activated receptor {gamma}; SDMA, symmetric dimethylarginine; TZD, thiazolidinedione(s).

Received September 28, 2006.

Accepted April 24, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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