The Steno hypothesis suggests that albuminuria reflects widespread vascular 
damage (proliferative retinopathy and severe macroangiopathy) due to a 
generalized vascular (endothelial) dysfunction. We assessed this concept in 
NIDDM (non-insulin-dependent diabetic) patients with (13 female/ 39 male, age 60 
+/- 7 years, group 1) and without (12 female /41 male, age 61 +/- 7 years, group 
2) diabetic nephropathy compared to matched non-diabetic subjects (7 female/15 
male, age 58 +/- 8 years, group 3). A 12-lead ECG was recorded and coded blindly 
using the Minnesota Rating Scale; the World Health Organization cardiovascular 
questionnaire was used to assess past and present evidence of myocardial 
infarction, angina pectoris, stroke, and peripheral vascular disease (digital 
systolic blood pressure determination). The degree of diabetic retinopathy was 
scored from fundus photography. The following variables were measured: 
transcapillary escape rate of albumin (initial disappearance of intravenously 
injected 125I-labelled human serum albumin), plasma concentrations of prorenin 
(radioimmunoassay) and serum concentrations of von Willebrand factor 
(enzyme-linked immunoadsorbent assay). Prevalence of ischaemic heart disease 
(ECG reading) (49/20/5)% and peripheral vascular disease as indicated by reduced 
systolic blood pressure on big toe (69/30/ 14)% was significantly higher in 
group 1 vs group 2 (p < 0.01) and in group 2 vs group 3 (p < 0.01), 
respectively. The prevalence and severity of retinopathy was higher in group 1 
vs 2 (p < 0.01). Transcapillary escape rate of albumin (%/h) was elevated in 
group 1 and 2 as compared to control subjects: 7.9 (4.3-13.7); 7.4 (3.7-16.4) vs 
6.0 (3.4-8.7), (p < 0.005), respectively. Plasma prorenin activity (IU/ml) was 
raised in group 1 and group 2 as compared to group 3: 272 (59-2405); 192 
(18-813), and 85 (28-246), p < 0.001, respectively. Serum von Willebrand factor 
(IU/ ml) was elevated in group 1 as compared to group 2 and 3: 2.07 (0.83-4.34); 
1.60 (0.30-2.99) and 1.50 (1.00-2.38), p < 0.001, respectively. Our study 
demonstrated that NIDDM patients with and without albuminuria had increased 
transcapillary escape of albumin and raised prorenin activity, whereas only 
those with albuminuria had increased von Willebrand factor. Patients with NIDDM 
may have abnormal endothelial function in the absence of albuminuria.