Nerve Axon Reflex-related

Endothelial dysfunction i_

iCapillary blood flow^ Endoneurial hypoxia

Nerve dysfunction i

¿NCV, ¿regeneration, structural

Fig. 1. New concepts in the pathogenesis of diabetic neuropathy.

Fig. 2. Expression of eNOS in patients with diabetic neuropathy (black columns), patients with both diabetic neuropathy and peripheral vascular disease (hatched columns) and healthy subjects (white columns). The expression of eNOS was reduced in both the diabetic groups compared with the healthy subjects (data from ref. 18).

Fig. 2. Expression of eNOS in patients with diabetic neuropathy (black columns), patients with both diabetic neuropathy and peripheral vascular disease (hatched columns) and healthy subjects (white columns). The expression of eNOS was reduced in both the diabetic groups compared with the healthy subjects (data from ref. 18).

microcirculatory beds, related to the orthostatic posture, affects the foot microcirculation more than at the forearm level. The endothelium dependent and independent vasodilation is in fact lower at the foot level when compared with the forearm in healthy subjects and both nonneuropathic and neuropathic patients with diabetes (23). This forearm-foot gradient exists despite a similar baseline blood flow at the foot and forearm level. Therefore, it is reasonable to believe that erect posture might be a contributing factor for the early development of the nerve damage at the foot, in comparison with the forearm.

Role of Autonomic Neuropathy

Autonomic neuropathy can compromise the diabetic microcirculation because of the development of arterio-venous shunting because of sympathetic denervation. The opening of these shunts might lead to a maldistribution of blood between the nutritional capillaries and subpapillary vessels, and consequent aggravation of microvascular ischemia. Studies using sural nerve photography and fluorescein angiography as well as other elegant techniques seem to support this concept (24,25).

A loss of sympathetic tone is also responsible for an increased capillary permeability in patients with diabetes with neuropathy (26). This might cause endoneurial edema, as demonstrated by using magnetic resonance spectroscopy, which can in turn represent another mechanism leading to a reduction of endoneurial perfusion and a worsening of the nerve damage (27). The increased lower extremity capillary pressure upon assuming the erect posture, because of early loss of postural vasoconstriction (mediated by the sympathetic fibers), might amplify this edematous effect.

Role of Somatic Neuropathy: The Neurovascular Response

Diabetic somatic neuropathy can further affect the skin microcirculation by the impairment of the axon reflex related-vasodilatation (Lewis' flare) (28). Under normal conditions, the stimulus of the c-nociceptive nerve fibers not only travels in the normal direction, centrally toward the spinal cord, but also peripherally (antidromic conduction) to local cutaneous blood vessels, causing a vasodilatation by the release of vasoactive substances, such as calcitonin gene-related peptide (CGRP), Neuropeptide Y, substance P, and bradykine by the c-fibers and initiates neurogenic inflammation (Fig. 3). This short circuit, or nerve axon reflex, is responsible for the Lewis' triple flare response to injury and plays an important role in increasing local blood flow when it is mostly needed, i.e., in condition of stress.

This neurovascular (N-V) response is significantly reduced at the foot level in patients with diabetes with peripheral somatic neuropathy, autonomic neuropathy, and peripheral artery disease in comparison with patients with diabetes without complications and healthy control subjects (Fig. 4) (23,29). Moreover, local anaesthesia significantly reduces the nerve axon reflex-related vasodilation at the foot of patients without peripheral neuropathy, whereas it has no effect on the amount of the preanesthesia N-V vasodilation—which is already very low—at the foot of neuropathic patients (30). This suggests that the main determinant of the presence of the neurovascular vasodilation is c-fiber function and that its measurement could be used as a surrogate measure of the function of these fibers.

Axon Reflex Sweating
Fig. 3. The nerve axon reflex-related vasodilation or neurovascular response: stimulation of the c-nociceptive nerve fibers by acetylcholine or other noxious stimuli leads to antidromic stimulation of the adjacent c-fibers, which secrete CGRP that causes vasodilation and increased local blood flow.

Fig. 4. The neurovascular response (expressed as percentage of blood flow increase over the baseline blood flow) is significantly reduced at the foot level of patients with diabetes with peripheral somatic neuropathy (DN), autonomic neuropathy (DA) and peripheral artery disease (DV) compared with patients with diabetes without complications (DC) and healthy controls (C) *p < 0.001 (data from ref. 29).

Fig. 4. The neurovascular response (expressed as percentage of blood flow increase over the baseline blood flow) is significantly reduced at the foot level of patients with diabetes with peripheral somatic neuropathy (DN), autonomic neuropathy (DA) and peripheral artery disease (DV) compared with patients with diabetes without complications (DC) and healthy controls (C) *p < 0.001 (data from ref. 29).

As a matter of fact, it has been shown that the N-V response significantly correlates with different measures of peripheral nerve function (30,31). Studies in our units have shown that a N-V response lower than 50% is highly sensitive (90%) and adequately specific (74%) in identifying patients with diabetes with peripheral neuropathy (31).

Fig. 5. The nerve axon reflex-related vasodilation at the foot level in a population with diabetes stratified on the basis of the degree of peripheral somatic neuropathy in patients without neuropathy (D), with mild neuropathy (DN mild), with moderate neuropathy (DN moderate) and with severe neuropathy (DN severe) compared with healthy controls (C). Median (25-75 percentile). The nerve axon reflex-related vasodilation is already significantly reduced in the early stages of neuropathy (subclinical neuropathy), supporting the belief that small fiber dysfunction might precede large fiber impairment in the natural history of diabetic nerve damage.

Fig. 5. The nerve axon reflex-related vasodilation at the foot level in a population with diabetes stratified on the basis of the degree of peripheral somatic neuropathy in patients without neuropathy (D), with mild neuropathy (DN mild), with moderate neuropathy (DN moderate) and with severe neuropathy (DN severe) compared with healthy controls (C). Median (25-75 percentile). The nerve axon reflex-related vasodilation is already significantly reduced in the early stages of neuropathy (subclinical neuropathy), supporting the belief that small fiber dysfunction might precede large fiber impairment in the natural history of diabetic nerve damage.

Besides, the finding that this response is significantly reduced even in the early stages of peripheral neuropathy supports the hypothesis that small fiber damage is a precocious event in the clinical history of diabetic neuropathy—even preceding large fibers' impairment (Fig. 5). This leads to impaired vasodilation under conditions of stress, such as injury or inflammation. Therefore, it is possible to speculate that small fiber neuropathy might further contribute to nerve hypoxic damage by the impairment of this hyperemic response, determining a vicious cycle of injury.

The previous conclusions are supported by recent studies in experimental diabetes which have demonstrated that epineurial arterioles of the sciatic nerve are innervated by sensory nerves that contain CGRP and mediate a hyperemic response at this level (32). Furthermore, it has been shown that in long-term diabetic rats the amount of CGRP present in epineurial arterioles is diminished, which could be because of a denervation process (33). Exogenous CGRP-mediated vasodilation of these arterioles is also impaired in experimental diabetes, indicating a reduced CGRP bioactivity (33). All these findings furthermore support a role of small sensory nerve fibers' impairment in the development and progression of diabetic neuropathy.

The impairment of the nerve axon reflex-related vasodilation is not affected by successful bypass surgery in patients with peripheral arterial disease. In addition, the endothelium-dependent and -independent vasodilation that are not related to the nerve axon reflex, remain impaired after successful revascularization. Therefore, despite correction in obstructive lesions and restoration of normal blood flow in the large vessels, the changes in microcirculation continue to be present and cause tissue hypoxia under conditions of stress (34).

Anatomical Changes

Although the structural alterations detected in diabetic capillaries do not cause vessel occlusion, their role in causing a reduction of nerve blood flow supply can not be completely ruled out. According to Pouiselle's law, in fact, the blood flow is proportional to the fourth power of the radius of a vessel. Therefore, the capillary blood flow can be significantly reduced by even slight narrowing of the capillary lumen. Many studies have now confirmed the presence of endoneurial microangiopathy, characterized by basement membrane thickening, endothelial cell hyperplasia and hypertrophy, and peri-cyte cell degeneration in patients with diabetes with peripheral neuropathy, the degree of which correlates with the severity of the clinical disease (35,36).

In summary, both the functional and structural changes observed in diabetic microcirculation contribute to the shift of blood flow away from the nutritive capillaries to low resistance arterio-venous shunts leading to functional ischemia of tissues including peripheral nerves and, consequently, to the development of diabetic peripheral neuropathy and other diabetic chronic complications.

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