According to the “tubulo-centric” hypothesis of the glomerular hyperfiltration of diabetes mellitus (DM), tubuloglomerular feedback (TGF) is the critical determinant of the related renal hemodynamic dysfunction. To examine the role of TGF in human type-1 DM, 12 salt-repleted healthy (C) and 11 uncomplicated DM individuals underwent measurements of glomerular filtration rate (GFR), renal blood flow (RBF) and lithium-derived absolute “distal” sodium delivery (DDNa). Measurements were made during two 3-hour infusions of 0.012 mmolxkgxmin-1 L-arginine (ARG) buffered with either equimolar HCl or citric acid (CITR). Our hypothesis was that changes in TGF signalling would be directionally opposite with ARG.HCl versus ARG.CITR according to the effects of ARG buffering anion on DDNa. Similar changes in C and DM followed ARG.CITR, with declines in DDNa (-0.26±0.07 mmolxmin-1 C versus -0.31±0.07 DM) and increases in RBF [+299±25 mLxmin-1x(1.73 m2)-1 versus +319±29] and GFR [+6.6±0.8 mLxmin-1x(1.73 m2)-1 versus +11.6±1.2]. In contrast, with ARG.HCl, DDNa rose in both groups (p=0.001), but the response was 73% greater in DM (+1.50 ±0.15 mmolxmin-1 C versus +2.59±0.22 DM, p=0.001). RBF also increased [p=0.001, +219±20 mLxmin-1x(1.73 m2)-1 C, +105±14 DM], but ΔRBF after ARG.HCl was lower versus ARG.CITR in both groups (p=0.001). After ARG.HCl, ΔRBF also was 50% lower in DM versus C (p=0.001) and GFR, unchanged in C, declined in DM [-7.4 ± 0.9 mLxmin-1x(1.73 m2)-1, p=0.02 versus C]. After ARG.HCl, unlike ARG.CITR, DDNa increases in C and DM, associated with less ΔRBF and ΔGFR versus ARG.CITR. This suggests that the renal hemodynamic response to ARG is influenced substantially by the opposite actions of HCl versus CITR on DDNa and TGF. In DM, the association of ARG.HCl-induced exaggerated ΔDDNa, blunted ΔRBF and decline in GFR versus C show an enhanced TGF-dependence of renal vasodilatation to ARG, in agreement with a critical role of TGF in DM-related renal hemodynamic dysfunction.