Pioglitazone Decreases Asymmetric Dimethylarginine Levels in Patients with Impaired Glucose Tolerance or Type 2 Diabetes

Background and Aims: Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is a biomarker and mediator of cardiovascular disease in patients with impaired glucose tolerance (IGT) or diabetes mellitus (DM). Advanced glycation end products (AGEs) and their receptor (RAGE) axis is involved in ADMA generation as well. However, it remains unclear whether pioglitazone could decrease ADMA levels by reducing RAGE expression in humans. Design and Methods: Forty-eight IGT or type 2 DM (T2DM) patients were assigned to receive either pioglitazone (n = 29) or glimepiride (n = 19) and evaluated at baseline and 16 weeks of follow-up. We compared the effects of pioglitazone and glimepride on ADMA and soluble form of RAGE (sRAGE) levels and then studied whether the changes in serum ADMA level (Delta ADMA) after treatment with pioglitazone were correlated with Delta sRAGE. We further examined which Delta clinical variables were independently associated with Delta ADMA. Results: After 16-week treatments, fasting plasma glucose and glycated hemoglobin (HbA1c) values were comparably reduced in both groups. Compared with glimepiride, pioglitazone treatment significantly decreased ADMA levels and improved insulin sensitivity, while it elevated high-density lipoprotein cholesterol (HDL-C) and sRAGE values and increased body weight and waist circumference. In multiple stepwise regression analysis, log-transformed Delta fibronectin were a sole independent determinant of log-transformed Delta ADMA (r=-0.551, R-2 = 0.303). Conclusions: This study demonstrated that pioglitazone decreased serum ADMA levels in a glucose-lowering independent manner. Elevation of fibronectin by pioglitazone may contribute to the reduction of serum levels of ADMA in IGT or T2DM subjects, thus playing a protective role against cardiovascular disease.