Diabetic peripheral neuropathy: Linking microvascular etiology to potential treatments
For many years clinicians thought that damage to the microvasculature is the underlying cause of diabetic peripheral neuropathy, diabetic nephropathy, and diabetic retinopathy. Now studies have provided considerable epidemiologic, pathologic, pathophysiologic, and molecular evidence to support this long-held clinical hypothesis. Molecular studies have elucidated the sequence of events in microvascular damage and identified several key pathways (eg, protein kinase C [PKC], advanced glycation end products, polyol, and hexosamine) that lead to endothelial cell dysfunction and death and, ultimately, to tissue damage in the retinas, kidneys, and nerves. These pathways, therefore, are potential therapeutic targets. Structural abnormalities in resistance vessels are preceded by functional abnormalities, which are driven by oxidative stress. Superoxide levels are increased and maximal vasodilation is decreased in the streptozotocin diabetic rat. In addition, there is a significant shift in vascular endothelial sensitivity in patients with type 2 diabetes mellitus, and the shift is even more pronounced in those patients with diabetes and hypertension. Impaired vasodilation and an abnormal myogenic response provide no protection to downstream vessels, thus setting the stage for basement membrane thickening and microvascular sclerosis. There is evidence that basement membrane thickening, a hallmark of diabetic microangiopathy, is present in late-stage diabetic peripheral neuropathy. However, recent studies have shown that it is also present in patients with diabetic peripheral impaired glucose tolerance and early stage diabetic peripheral neuropathy. Angiotensin II receptor blockade for the treatment of vascular dysfunction partially restores the blunted vasodilatory response and normalizes the shift in blood vessel sensitivity in patients with type 2 diabetes mellitus. Similarly, angiotensin-converting enzyme inhibition results in significant and meaningful electrophysiologic improvements in nerve conduction velocity, M-wave amplitude, and F-wave latency in patients with mild diabetic peripheral neuropathy. Encouraging data from recently completed studies of the PKC-β inhibitor ruboxistaurin show that it improves symptom scores and nerve function scores in patients with diabetic peripheral neuropathy.