Urotensin II (UII) is the most potent vasoconstrictor peptide, whereas it acts as a vasodilator on some arteries. We studied plasma levels of UII in diabetic patients with normal serum creatinine levels (<90 micromol/l) and the expression of UII and its receptor in cultured human vascular endothelial cells. Plasma UII levels were significantly elevated by 1.8-fold in diabetic patients without proteinuria (7.8+/-0.6 fmol/ml; P <0.0001) and 1.7-fold in those with overt proteinuria (7.3+/-0.9 fmol/ml; P =0.0018) when compared with healthy subjects (4.4+/-0.2 fmol/ml). No significant correlation was obtained between plasma UII levels and fasting blood sugar (P =0.631 and P =0.853 in non-proteinuric and proteinuric diabetic patients respectively), glycated haemoglobin levels (P =0.376 and P =0.888 respectively) or serum creatinine levels (P =0.301 and P =0.568 respectively). Reverse transcriptase-PCR analysis showed the expression of mRNAs encoding UII precursor and UII-receptor precursors in cultured human coronary artery endothelial cells and umbilical vein endothelial cells, suggesting that vascular endothelial cells are one of the sources of UII in blood. These findings suggest that elevation of plasma UII levels may be an important background factor in diabetic cardiovascular and organ complications in diabetic subjects without renal failure.