Stimulation of Urinary TGF- and Isoprostanes in Response to Hyperglycemia in Humans

TGF- and oxidant stress have been considered to play key roles in the pathogenesis of diabetic vascular complications; however, the stimulus for these factors in humans is not clear. The purpose of this in vivo study was to determine whether transient hyperglycemia in humans is sufficient to increase renal production of TGF-1 and urinary isoprostanes in normal humans. A hyperglycemic clamp procedure was performed on 13 healthy volunteers. An infusion of glucose was delivered to maintain the plasma glucose between 200 and 250 mg/dl for 120 min. Timed urine samples, collected on an overnight period before the study, at each void on completion of the procedure, and the following overnight, were assayed for TGF-1, F2-isoprostanes, and creatinine. Plasma samples were assayed for TGF-1 before and at timed intervals throughout hyper-glycemia. Mean baseline TGF-1 in plasma was 4.57 0.22 ng/ml, and no change in plasma TGF-1 levels was detected throughout the hyperglycemia period. Baseline urine TGF-1 was 4.14 1.16 pg/mg creatinine. The fractional urine samples showed a sharp increase in TGF-1 excretion in the 12-h period after exposure to hyperglycemia, with a mean peak TGF-1 of 30.43 8.05 pg/mg (P 0.002). TGF-1 excretion in the subsequent overnight urine sample was not different from baseline (4.62 1.21 pg/mg). Urinary isoprostanes increased from a baseline of 4.92 0.74 to 13.8 3.37 ng/mg creatinine. It is concluded that 120 min of hyperglycemia in normal humans is sufficient to induce an increase in renal TGF-1 and isoprostane production. Clin J Am Soc Nephrol 1: 263–268, 2006. doi: 10.2215/CJN.0099090