Tubular Na handling and tubuloglomerular feedback (TGF) activity were assessed using micropuncture techniques during the hyperfiltration phase of streptozotocin-induced diabetes mellitus in Sprague-Dawley rats. Three animal groups were studied, designated as having severe diabetes [blood sugar level (BSL) 18-25 mmol/l], moderate diabetes (BSL 13-18 mmol/l) and control (BSL less than 10 mmol/l). Single-nephron glomerular filtration rate (SNGFR) measured at both late proximal (LP) and early distal (ED) sites was elevated in severe diabetes compared with both other groups. TGF activity, determined as the difference between LP and ED measurements of SNGFR, was significantly increased in severe diabetes (46.4 +/- 6.6 vs. 30.1 +/- 6.5 vs. 14.8 +/- 1.9 nl/min). Tubular Na transport was higher in severe diabetes compared with control, as demonstrated by a decrease in fractional delivery of Na to the LP (42.9 +/- 3.0 vs. 52.9 +/- 1.9%), as well as to the ED site (4.5 +/- 0.4 vs. 12.3 +/- 0.9%). Administration of phlorizin to severely diabetic animals resulted in a BSL comparable to that observed in moderate diabetes, and whole animal GFR, as well as SNGFR, TGF activity, and tubular Na handling were also similar to those found in moderate diabetes. Studies performed during mannitol infusion demonstrated that osmotic diuresis alone was not associated with the changes in TGF and tubular Na handling observed in the diabetic state. These data suggest that the hyperfiltration occurring in early diabetes is associated with enhanced proximal and loop resorption of Na independent of Na-glucose cotransport and osmotic diuresis. Activation of TGF serves to limit the rise in GFR, which results from factors as yet unrecognized in the diabetic state.