Changes in the composition and assembly of extracellular matrix (ECM) are the most prominent structure abnormalities of the vascular system encountered in early diabetes. Hyaluronan (HA) is a key biologically active element of ECM that plays a crucial role in vascular remodelling in atherosclerosis and restenosis following percutaneous coronary intervention. Hyperglycaemia led to significant increase in HA secretion by vascular smooth muscle cells. Hyperglycaemia also strongly induced HA synthase mRNA levels, notably HAS1-HAS3 mRNA. Remarkably, peroxisome proliferator-activated receptor (PPAR-γ) agonists pioglitazone (Pio) and rosiglitazone (Rosi), a class of anti-diabetic drugs, attenuated hyperglycaemia-induced HA secretion and reduced HAS2 mRNA expression. In vitro experiment with siRNA specific to PPAR-γ demonstrated that the attenuation of hyperglycaemia-induced HA secretion by Pio and Rosi was independent of PPAR-γ activity. Furthermore, hyperglycaemia-induced increase in HA secretion and HAS2 mRNA expression involved protein kinase Cβ2 (PKCβ2) activation, while Pio and Rosi exerted their attenuating effect on HA secretion by inhibiting PKCβ2.