Improvement by Thiazolidinediones of Vascular Endothelial Cell Dysfunction in Diabetic Patients: A Possible New Physiological Role of PPARγ

This study was aimed to evaluate the significance and mechanism of vascular endothelial dysfunction in diabetic patients. Thirty-eight patients with type 2 diabetes mellitus were categorized to 3 groups according to the grade of retinopathy and treated for 4 weeks randomly with glibenclamide (n = 14) or troglitazone (n = 24). While plasma tissue plasminogen activator (tPA) (23.9 vs. 8.9 ng/ml; P< 0.05) and plasminogen activator inhibitor-1 (PAI-1) (23.6 vs. 11.8 pg/ml; P< 0.05) levels were significantly elevated in type 2 diabetes patients compared to the control subjects, the PAI-1 titer, but not tPA, was correlated with the severity of retinopathy. Four weeks-treatment by troglitazone was associated with significant reduction of PAI-1 level (20.1 from 26.8 pg/ml, P< 0.05), but not that of tPA, which was correlated with reduction of the steady state plasma glucose (SSPG) titer, but not with that of fasting plasma glucose. Immunoreactive PAI-1 or endothelin-1 (ET-1) were measured by ELISA in culture medium of human umbilical vein endothelial cells (HuVEC) or bovine vascular endothelial cells (bVEC), respectively, in the presence or absence of test agents (insulin, thiazolidinediones, 15-deoxy-delta 12, 14-prostaglandin J2 (15d-PGJ2), bezafibrate). Thiazolidinediones inhibited tumor necrosis factor α (TNF- α )-stimulated PAI-1 secretion and mRNA expression in a dosedependent fashion. Thiazolidinediones and 15d-PGJ2, but not bezafibrate, inhibited basal and insulin-stimulated ET-1 secretion and mRNA expression in a dose-dependent fashion.