Korean Circ J KCJ Korean Circulation Journal 1738-5520 1738-5555 The Korean Society of Circulation 10.4070/kcj.2007.37.5.221 Original Article Peroxisome Proliferator-Activated Receptor Gamma(PPAR-γ) Agonist Improves Endothelial Function in Diabetic Patients with Metabolic Syndrome: Pivotal Role of NOx and Inflammation Kho Jin-Sin MD Park Sung-Ji MD Im Sung-Il MD Choi Bong-Ryong MD Kwak Choong-Hwan MD Hwang Jin-Yong MD Department of Internal Medicine, College of Medicine, Gyeong-Sang National University, Jinju, Korea. Corresponding author (sjpark223@yahoo.co.kr) 05 2007 31 05 2007 37 5 221 229 27 01 2007 12 04 2007 © 2007, The Korean Society of Circulation 2007 Background and Objectives

Nitric oxide (NO) is thought to have antiatherosclerotic properties. On the other hand, NO activity is reduced in patients with metabolic syndrome, and endothelial dysfunction is an important early sign of atherosclerosis in patients with metabolic syndrome. The aim of this study was to investigate the effect of pioglitazone on the endothelial function in terms of the plasma NOx (combined nitrate/nitrite), the circulating inflammatory markers and the autonomic nervous system.

 Subjects and Methods

We randomized 40 subjects with metabolic syndrome, and they were assigned to receive 15 mg of pioglitazone per day (the PIO group, n=21) during 12 weeks or they were placed in the placebo group (the PLA group, n=19). We estimate the endothelial function by performing vascular ultrasound. The plasma NOx levels, the levels of the inflammatory markers and the GRK2 levels were measured.

 Results

After 12 weeks of therapy, flow mediated dilation (FMD) was improved in the PIO group (from 6.7±6% to 11.7±5%, respectively: p<0.05), but not in the PLA group. The level of plasma NOx was increased in the PIO group (from 67.7±30 nmol/dL to 92.9±41 nmol/dL, respectively: p<0.001), but not in the PLA group. The plasma levels of hsCRP and IL-6 dropped significantly (from 2.6±2.3 mg/L to 1.2±1.3 mg/L and 1.7±2.1 pg/mL to 0.7±0.5 pg/mL, respectively: p<0.05) in the PIO group, but not in the PLA group. The levels of GRK2 (the PLA group from 0.0061±0.0023 ng to 0.0075±0.0031 ng, and the PIO group from 0.0024±0.002 ng to 0.0015±0.001 ng, p=ns) didn't dropped significantly.

 Conclusion

Administration of PPAR-γ agonist in patients suffering with metabolic syndrome improves their endothelial function, enhances the production of NOx and reduces the proinflammatory markers, but this is not related to sympathetic regulation. PPAR-γ agonist may be able to modulate the progression of atherosclerosis.

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Changes of lipid profiles. This bar Graphs showed the percent changes after treatment. Significant decrease in total cholesterol and triglyceride in pioglitazone group compared with placebo group. In contrast, no significant changes were observed in LDL-cholesterol, HDL-cholesterol and lipoprotein a. TG: triglyceride, HDL-C: high density lipoprotein cholesterol, LDL-C: low density lipoprotein cholesterol, Lp (a): lipoprotein a.

Changes of inflammatory markers. By inflammatory markers, hsCRP was reduced in pioglitazone group, but not in placebo group after 12 weeks of treatment. IL-6, another inflammatory markers, a regulator of CRP released from the hepatocytes, were also reduced significantly in pioglitazone group. hsCRP: high sensitivity C-reactive protein, IL-6: interleukin-6, NS: not significant.

Changes of nitric oxide. The plasma Nox (combined nitrate/nitrite) level were increased significantly in pioglitazone group, but not in placebo group after 12 weeks of treatment, NS: not significant.

Changes of GRK2 levels. No differences in the GRK2 levels of lymphocytes between the two groups of individuals. GRK2: G protein-coupled receptor kinases 2, NS: not significant.

ΔFMD after 12 weeks of treatment. The changes of FMD after 12 weeks treatment were enhanced in pioglitazone group not in placebo group. ΔFMD: delta changes of flow-mediated dilatation.

Changes of FMD. Looking at some results from vascular function in the two groups of patients on the two graphs here, the graph on the left side looks at endothelium-dependent vascular function and the graph on the right side shows the results from the endothelium-independent vascular function. Individuals in the pioglitazone group have significantly greater endothelium-dependent vascular dysfunction than individuals in the placebo group. There were no differences in endothelium-independent vascular function between the two groups of individuals. FMD: flow-mediated dilatation.

Baseline characteristics of metabolic syndrome patients

All patients are metabolic syndrome subjects. Values are expressed as the mean±SD. There were no differences among each baseline value. BP: blood pressure, BMI: body mass index

Changes of metabolic parameters

Values are expressed as the mean±SD. BMI: body mass index, FBS: fasting blood sugar, PP2: post-prandial 2 hour sugar, NS: not significant, HOMA: homeostatic model assessment

Multivariate logistic regression analysis with changes of FMD (ΔFMD≥2.1) dependent variables

CI: confidence interval, ΔHOMA: changes of homeostatic model assessment index, ΔhsCRP: changes of high-sensitivity C-reactive protein, ΔNO: changes of nitric oxide, ΔIL-6: changes of interleukin-6, ΔTC: changes of total cholesterol, ΔTG: changes of triglyceride, ΔLDL-C: changes of low density lipoprotein cholesterol, ΔHDLC: changes of high density lipoprotein cholesterol