Troglitazone treatment increases plasma vascular endothelial growth factorin diabetic patients and its mRNA in 3T3-L1 adipocytes

Troglitazone is one of the thiazolidinediones, a new class of oral antidiab etic compounds that are ligands of peroxisome proliferator-activated recept or-gamma. This study on vascular endothelial growth factor (VEGF), also kno wn as vascular permeability factor, was prompted by our clinical observatio n that the characteristics of troglitazone-induced edema were very similar to those caused by vascular hyperpermeability. when Japanese diabetic patie nts mere screened for plasma VEGF, me found levels to be significantly (P < 0.001) increased in troglitazone-treated subjects (120.1 +/- 135.0 pg/ml, n = 30) compared with those treated with diet alone (29.2 +/- 36.1 pg/ml, n = 10), sulfonylurea (25.8 +/- 22.2 pg/ml, n = 10), or insulin (24.6 +/- 19 .0 pg/ml, n = 10). Involvement of troglitazone in increased VEGF levels was further supported by the plasma VEGF levels in five patients before treatm ent (20.2 +/- 7.0 pg/ml), after 3 months of troglitazone treatment (83.6 +/ - 65.9 pg/ml), and 3 months after discontinuation (28.0 +/- 11.6 pg/ml). we further demonstrated that troglitazone, as well as rosiglitazone, at the p lasma concentrations observed in patients, increased VEGF mRNA levels in 3T 3-L1 adipocytes. VEGF is an angiogenic and mitogenic factor and is currentl y considered the most likely cause of neovascularization and hyperpermeabil ity in diabetic proliferative retinopathy. Although increased VEGF may be b eneficial for subjects with macroangiopathy and troglitazone is currently n ot available for clinical use, vascular complications, especially diabetic retinopathy, must be followed with great caution in subjects treated with t hiazolidinediones.