Glomerular hyperfiltration has been claimed to be a risk factor for the development of diabetic nephropathy. Protein intake and hyperglycemia can both increase GFR in diabetic and normal subjects. Our study was designed to explore the relative importance of short-term changes in protein intake and glycemia on the modulation of renal hemodynamics in insulin-dependent diabetic (IDDM) patients with and without glomerular hyperfiltration. The renal hemodynamic response to a protein challenge was studied in eight hyperfiltering (HF) and eight normofiltering (NF) patients after a three week period of low or normal protein diet (LPD, NPD), each study being conducted twice, in random order, under conditions of prevailing hyperglycemia (H) and euglycemia (E). In HF patients GFR failed to increase significantly in response to protein challenge during NPD under conditions of either H or E (Baseline vs. 2 hr H: 151 +/- 4 vs. 155 +/- 6, NS; E 147 +/- 4 vs. 157 +/- 7 ml/min/1.73 m2, NS). A more normal response was restored following LPD with GFR increasing in all but one patient after challenge during H and in all patients during E (Baseline vs. 2 hr H: 130 +/- 7 vs. 145 +/- 8, P less than 0.07; E: 127 +/- 7 vs. 143 +/- 7 ml/min/1.73 m2, P less than 0.01). Changes in RPF paralleled the changes in GFR and filtration fraction remained stable under all study conditions.(ABSTRACT TRUNCATED AT 250 WORDS)