<i>Introduction:</i> The aim of our study was to clarify the hypothesis that proximal tubule (PT) dysfunction may be responsible for early diabetic nephropathy (DN), independently of preceding glomerular endothelial dysfunction. The pattern of endothelial dysfunction and its potential variability was evaluated in two vascular beds, the kidney and the brain. <i>Methods:</i> A total of 68 normoalbuminuric type 2 diabetes mellitus (DM) patients were enrolled in a cross-sectional study and the following parameters were assessed: urinary albumin:creatinine ratio (UACR), urinary α₁-microglobulin, urinary β₂-microglobulin, plasma asymmetric dimethyl-arginine (ADMA), serum creatinine, glomerular filtration rate (GFR), C-reactive protein (CRP), fibrinogen, HbA_1c; pulsatility and resistance indices in the internal carotid artery and middle cerebral artery and intima-media thickness (IMT) in the common carotid artery; cerebrovascular reactivity was evaluated through the breath-holding test. <i>Results:</i> Plasma ADMA was increased in 12 patients (17.5%), urinary α₁-microglobulin in 19 patients (27.9%) and urinary β₂-microglobulin in 16 patients (23.5%). Cerebral hemodynamic indices correlated with plasma ADMA, CRP, fibrinogen, duration of DM, HbA_1c and GFR. ADMA correlated with fibrinogen, CRP, HbA_1c, duration of DM and GFR. There were no correlations between ADMA and UACR, and urinary α₁-/β₂-microglobulin. Also, no correlations were found between urinary α₁-/β₂-microglobulin and UACR, HbA_1c, duration of DM and GFR. <i>Conclusion:</i> The increase in urinary α₁-/β₂-microglobulin precedes the stage of albuminuria. It may be assumed that early DN is related to PT dysfunction. Endothelial dysfunction plays a pivotal role in the brain vasculature, while its involvement in the development of early DN is not conditional on the occurrence of albuminuria.