Elevated plasma levels of immunoreactive urotensin II and its increased urinary excretion in patients with Type 2 diabetes mellitus: association with progress of diabetic nephropathy

Urotensin II (UII) is the most potent vasoconstrictor peptide ever identified. In order to clarify the pathophysiological role of UII in diabetes mellitus, we examined plasma immunoreactive UII levels and urinary excretion of immunoreactive UII in 10 control subjects and 48 patients with Type 2 diabetes mellitus. The patients were divided into three groups according to the renal function: Group I with Ccr ≥ 70 ml/min, group II with 30 ≤ Ccr < 70 ml/min and group III with Ccr < 30 ml/min. Plasma immunoreactive UII levels were elevated in the three diabetic groups compared with normal controls ( P < 0.05). Group III patients had significantly higher plasma immunoreactive UII levels (15.9 ± 2.2 fmol/ml, mean ± S.E.M., n = 6) by approximately 1.6-fold than did group I (10.9 ± 0.9 fmol/ml, n = 17) and group II (10.8 ± 0.8 fmol/ml, n = 25) ( P < 0.05). Urinary excretion of immunoreactive UII was significantly increased in group III patients (52.4 ± 14.8 pmol/day) by more than 1.8-fold compared with control subjects, groups I and II ( P < 0.005). Fractional excretion of immunoreactive UII significantly increased as renal function decreased. Presence of diabetic retinopathy or neuropathy had negligible effects on plasma immunoreactive UII levels and urinary immunoreactive UII excretion. Reverse phase HPLC analyses showed three immunoreactive peaks in normal plasma extracts and multiple immunoreactive peaks in normal urine extracts. Thus, Type 2 diabetes mellitus itself is a factor to elevate plasma immunoreactive UII levels, and accompanying renal failure is another independent factor for the increased plasma immunoreactive UII levels in Type 2 diabetic patients. Increased urinary immunoreactive UII excretion in Type 2 diabetic patients with advanced diabetic nephropathy may be due not only to the elevated plasma immunoreactive UII levels but also to increased UII production and/or decreased UII degradation in the diseased kidney.