Since the neuropathy begins distally in the feet and involves unmyelinated axons, nerve conduction studies of sensory and motor nerves of the leg may initially show mild changes as electrophysiological studies seldom detect abnormalities in unmyelinated axons. With more symptoms developing, nerve conduction velocities slow due to demyelination and loss of myelinated fibers. As the neuropathy progresses, the findings of axonal degeneration predominate with diminished amplitude of compound muscle action potentials and sensory nerve action potentials—due to nerve fiber loss. Needle electromyography of intrinsic foot muscles shows denervation potentials. There is relative preservation of proximal conduction velocities.

A nerve biopsy, while seldom performed, shows non-specific axonal damage to both myelinated and unmyelinated axons. A nerve biopsy should come from a sensory nerve (like the sural nerve) that has a small area of sensory innervation. Biopsy of a mixed nerve will lead to paralysis of innervated muscles and thus is only performed on an intercostal nerve.

Skin punch biopsy (3–4 mm full thickness biopsy) with immunohistochemical staining for peripheral nerve axons is becoming more popular. The histologic sections demonstrate marked reduction in the density of epidermal nerve fibers that is helpful, but not diagnostic, for diabetic neuropathy. Thus, the diagnosis relies mainly on the clinical history, neurologic examination of the peripheral nervous system , and exclusion of other etiologies. However, when a peripheral nerve is affected by two different diseases, the signs and symptoms of a peripheral neuropathy develop earlier, produce more intense symptoms, and have a poorer recovery.

The management of diabetic neuropathy can be divided into preventing progression of the neuropathy, minimizing problems from anesthesia of feet and hands, and reducing the burning foot pain.

Numerous studies demonstrate that good control of blood glucose can slow, halt, or reverse progression of the neuropathy. Glucose control involves weight loss, exercise, and use of hypoglycemic agents. While optimum glycemic control can reduce the risk of neuropathy, the risk of transient hypoglycemia increases.

Foot anesthesia predisposes to ulceration and infection. Proper footwear minimizes foot and ankle trauma. The individual should be instructed to regularly inspect their feet for signs of infection or ulceration and to place their hand in shoes to detect objects in the soles. If loss of position sense in the feet declines, the patient should use night-lights and caution when walking on uneven surfaces or in the dark.

Treating the patient with a painful peripheral neuropathy is a challenge. For many patients, the pain is reduced with tricyclic antidepressants (amitriptyline and nortriptyline) in low doses. Tricyclic antidepressant medications occasionally can increase the effects of postural hypotension in patients with autonomic neuropathy. Anticonvulsants, such as gabapentin or carbamazepine, may be slowly added if the pain relief is insufficient. In some patients, the foot pain spontaneously subsides when the sensory neuropathy progresses to anesthesia.