• The concept of renal functional reserve has recently been introduced. To test this ability of the kidneys to increase the glomerular filtration rate (GFR) above the baseline level, the GFR response to short-term protein load was measured. Recent studies have provided conflicting data concerning the GFR response to a protein load in insulin-dependent diabetics who are known to have increased baseline GFRs. Thus, we studied nine insulin-dependent diabetics with a disease of at least a ten-year duration (none were hypertensive or proteinuric) and compared their data with those of five nondiabetic controls with normal renal function. All the diabetics, except one, showed a significant increase in GFR (mean ± SEM, 60±9 to 74±14 mL/min/sq m); the controls also had increased GFRs (mean± SEM, 53±6 to 69±6 mL/min/sq m). The one patient who demonstrated no rise in the GFR had the lowest GFR measured, 33 mL/min/sq m. To explore the mechanism of this response, we measured the plasma levels of putative mediators glucagon and human growth hormone. Although glucagon showed the expected rise after the protein meal, the variability was so large that no statistically significant relationship could be identified. Human growth hormone remained constant and low in the controls and showed more variability and was higher in the diabetics; again, no relationship to the GFR could be demonstrated. Thus, our data demonstrated a normal response to a short-term protein load by a group of well-defined diabetic subjects who would be at risk to show subtle renal abnormalities.