The epidemiology and natural history of DN remain poorly defined, in part because of variable criteria for the diagnosis, failure of many physicians to recognize and diagnose the disease and lack of standardized methodologies used for the evaluation of these patients (12).It has nonetheless been estimated that 50% of patients with diabetes have DN and 2.7 million have painful neuropathy in the US. DN is grossly under diagnosed and under treated The natural history of neuropathies separates them into two very distinctive entities, namely those which progress gradually with increasing duration of diabetes, and those which remit usually completely. Sensory and autonomic neuropathies generally progress, while mononeuropathies, radiculopathies, and acute painful neuropathies, although symptoms are severe, are short-lived and tend to recover (18). Progression of DN is related to glycemic control in both type 1 and type 2 diabetes (19) (20). It appears that the most rapid deterioration of nerve function occurs soon after the onset of type 1 diabetes and within 2-3 years there is a slowing of the progress with a shallower slope to the curve of dysfunction. In contrast, in type 2 diabetes, slowing of nerve conduction velocities (NCVs) may be one of the earliest neuropathic abnormalities and often is present even at diagnosis (21). After diagnosis, slowing of NCV generally progresses at a steady rate of approximately 1 m/sec/year, and the level of impairment is positively correlated with duration of diabetes. Although most studies have documented that symptomatic patients are more likely to have slower NCVs than patients without symptoms, these do not relate to the severity of symptoms. In a long term follow up study of type 2 diabetes patients (22), electrophysiologic abnormalities in the lower limb increased from 8% at baseline to 42% after 10 years, with a decrease in sensory and motor amplitudes, indicating axonal destruction, was more pronounced than the slowing of the NCVs. Using objective measures of sensory function such as the vibration perception threshold test, the rate of decline in function has been reported as 1-2 vibration units/year. However, there now appears to be a decline in this rate of evolution. It appears that host factors pertaining to general health and nerve nutrition are changing. This is particularly important when doing studies on treatment of DN, which have always relied on differences between drug treatment and placebo and have apparently been successful because of the decline in placebo-treated patients (23). Recent studies have pointed out the changing natural history of DN with the advent of therapeutic lifestyle change, and the use of statins and ACE inhibitors, which have slowed the progression of DN and drastically changed the requirements for placebo-controlled studies. (24). It is also important to recognize that DN is a disorder wherein the prevailing abnormality is loss of axons that electrophysiologically translates to a reduction in amplitudes and not conduction velocities, and changes in NCV may not be an appropriate means of monitoring progress or deterioration of nerve function. Small, unmyelinated nerve fibers are affected early in DM and are not reflected in NCV studies. Other methods, that do not depend on conduction velocities, such as quantitative sensory testing, autonomic function testing or skin biopsy with quantification of intraepidermal nerve fibers (IENF), are necessary to identify these patients (25) (26) (27)