Conventional risk factors for macrovascular disease, such as hypertension, raised triglyceride levels, body mass index, and smoking have been shown to be independent predictors of the development of diabetic neuropathy (57). The link between these classical cardiovascular risk factors and diabetic microvascular complications, including neuropathy is not clear, but the development of atherosclerosis of the lower extremities might be one possible explanation. Several of the risk factors associated with neuropathy are also markers of insulin resistance, which is in turn associated with endothelial dysfunction. The latter, as previously discussed, causes tissue functional ischemia and is believed to be a pivotal factor in the development of diabetic neuropathy.
It is clear that impaired blood flow and endoneurial hypoxia are the major pathogenic factors in the development of diabetic peripheral neuropathy. Thus, arterial obstructive lesions, even occurring at the large vessels of the lower extremities might theoretically be responsible for nerve tissue damage by limiting adequate endoneurial oxygenation. This hypothesis was firstly tested by Price more than 100 years ago who detected patchy areas of nerve degeneration in the posterior tibial nerve trunks as a consequence of proximal large vessels atherosclerosis (58). More recent studies in patients without diabetes with peripheral vascular disease confirm the occurrence of significant demyelina-tion and axonal degeneration together with an endoneurial microangiopathy (59,60). Such studies provide support for the role of acute/chronic ischaemic injury resulting in neuronal death.
The most direct evidence of a strict relationship between lower extremity atherosclerosis and diabetic neuropathy is derived from large vessel revascularization studies, which have shown an improvement in nerve conduction velocity in one but not another study (61,62). A longer-term follow-up of the latter study did however show that reversal of hypoxia slows the progression of peroneal nerve conduction velocity deterioration (63). The efficacy of a number of pharmacological treatments that can achieve a similar effect, in improving peripheral nerve function has also been tested. In a double-blind placebo-controlled clinical trial with a vasodilator, Trandalopril, for more than 12 months, peroneal motor nerve conduction velocity, M-wave amplitude F-wave latency, and sural nerve amplitude improved significantly (64). Recently, the appropriate blood pressure control in diabetes trial, aimed to assess the effects of intensive against moderate blood pressure control with either Nisoldipine or enalapril, failed to show any benefit on the progression of diabetic nephropathy, retinopathy, and neuropathy (65).
In summary, despite some evidence that tissue hypoxia related to obstructive atherosclerotic disease can contribute to the development of peripheral neuropathy, the exact mechanisms are not known. Furthermore studies will be required to delineate these mechanisms and the potential of new therapeutic interventions.
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