Early diabetes mellitus is characterized by an increase in glomerular filtration rate and effective renal plasma flow which may initiate and potentiate glomerular injury which ultimately results in diabetic nephropathy. To investigate the role of hyperglycemia per se in mediating these hemodynamic changes, eight healthy adults had inulin clearance, creatinine clearance, and para-aminohippurate (PAH) clearance after steady state conditions of hyperglycemia were achieved (549 +/- 86). Clearances were repeated during equivalent osmotic diuresis with Mannitol. Euvolemia was maintained by quantitative fluid and electrolyte replacement of urinary losses. Mean inulin clearances were 87 +/- 6, 87 +/- 5, and 81 +/- 4 ml/min during control, glucose, and mannitol periods (p = ns). Creatinine clearance overestimated inulin clearance by 15-32% but there were no differences between control glucose and mannitol periods. PAH clearance fell from control values of 595 +/- 29 to 340 +/- 22 ml/min during hyperglycemia (p less than .05). During osmotic diuresis with mannitol PAH, clearance rose to control values. In vitro studies excluded the possibility that conjugation between glucose and PAH can explain the clearance results. These results in normal subjects documenting renal vasoconstriction with hyperglycemia are of particular interest in view of recent experimental data suggesting that failure to vasoconstrict characterizes the hemodynamics of early diabetes.