Although microvascular diabetic complications have been well-characterized there is still uncertainty regarding the mechanisms that lead to their development. In the past two main pathogenic hypotheses have been proposed: the metabolic hypothesis and the hypoxic hypothesis (11,12). According to the metabolic hypothesis, hyperglycemia is directly responsible of end-organ damage and development of complications through the activation of the polyol pathway. On the other hand, according to the hypoxic hypothesis, the structural alterations detected in kidney, eye, and nerve microvascu-lature, including basement membrane thickening and endothelial cell proliferation, were considered as the main factor contributing to reduced blood flow and tissue ischemia (13). It is now apparent that both the metabolic and vascular pathways are linked. More specifically, endothelial dysfunction has been suggested as the common denominator between the metabolic and vascular abnormalities detected in diabetes (14). The impaired synthesis and/or degradation of nitric oxide, the main vasodilator released by the endothelium, is believed to determine microvascular insufficiency, tissue hypoxia, and degeneration (15).
Diabetes mellitus, even in the absence of complications, impairs the vascular reactivity that is the endothelium-dependent and -independent vasodilation in the skin microcirculation (16). Many glucose-related metabolic pathways can determine endothelium dysfunction: increased aldose reductase activity leading to the imbalance in nicotinamide adenine dinucleotide phosphate (NADP)/nicotinamide adenine dinu-cleotide phosphate reduced form (NADPH); auto-oxidation of glucose leading to the formation of reactive oxygen species; "advanced glycation end products" produced by nonenzymatic glycation of proteins; abnormal n6-fatty acid metabolism and inappropriate activation of protein kinase-C. All these different pathways lead to an increase of oxidative stress which is responsible for a reduced availability of nitric oxide and in turn, for a functional tissue hypoxia and the development of diabetic chronic complications (17) (Fig. 1).
Microvascular reactivity is further reduced at the foot level in presence of peripheral diabetic neuropathy. Endothelial nitric oxide synthase (eNOS) is a key regulator of vascular nitric oxide production. Immunostaining of foot skin biopsies in our unit, with antiserum to human eNOS glucose transporter I, which is a functional marker of the endothelium and von Willebrand factor, an anatomical marker, showed no difference among patients with diabetes with or without peripheral neuropathy in the staining of glucose transporter I and von Willebrand factor, whereas the staining for the eNOS was reduced in neuropathic patients (Fig. 2) (18). Another study documented increased levels of iNOS and reduced eNOS levels in skin from the foot of patients with diabetes with severe neuropathy and foot ulceration (19).
It has also been suggested that polymorphism of the eNOS gene is implicated in cardiovascular and renal diseases, thus indicating its potential role as a genetic marker of susceptibility to both type 2 diabetes and its renal complications (20,21). However, a relationship between eNOS gene polymorphism and diabetic neuropathy has not been clearly demonstrated (22). Nonetheless, all these findings suggest that the reduced eNOS expression/activity might be related to the development of diabetic peripheral neuropathy.
Differences in the microcirculation between the foot and forearm levels have also been investigated, the main hypothesis being that increased hydrostatic pressure in distal
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