Neuropathy will afflict over half of the estimated 460 million people worldwide who have diabetes, of whom approximately one-third will also develop neuropathic pain.² The pathogenesis of diabetic neuropathy is uncertain, and attaining and maintaining close glycemic control remains the only universal recommendation for preventing or slowing progression of the condition. Although there has been considerable progress in β-cell, stem cell, and whole pancreas transplantation and ongoing refinement of continuous glucose monitors for maintaining consistent euglycemia, these advanced bioengineering solutions are unlikely to become available for the majority of the diabetic population worldwide in the foreseeable future. Although the mechanisms driving degenerative neuropathy and pain are likely intertwined, the unpredictability of which patients with neuropathy also exhibit pain suggests as yet ill-defined pathways unique for pain generation. Treatment of painful diabetic neuropathy is limited to analgesics,with efficacy of any given agent limited to unpredictable subpopulations of patients. This somewhat bleak landscape has prompted extensive investigation of the pathogenic consequences of hyperglycemia and, more recently, glucose-independent neurotoxic mechanisms as downstream sites for therapeutic intervention.

The most common presentation of diabetic neuropathy is as a distal symmetrical polyneuropathy with numbness in the distal extremities. Loss of sensation can lead to unattended wounds that, when combined with peripheral vascular disease and impaired wound healing, may lead to infection and ultimately amputation. Indications of motor and autonomic nerve dysfunction may also be present. Early quantifiable features of distal symmetrical polyneuropathy (from herein termed “diabetic neuropathy,” unless stated otherwise) include slowing of large sensory and motor fiber conduction velocity (SNCV and MNCV) and depletion of small sensory nerves in the skin and cornea. Peripheral nerves also exhibit resistance to ischemic conduction blockade/failure, which patients may become aware of as an ability to squat or kneel for lengthy periods of time without developing paresthesias and that can be confirmed using routine electrophysiology and a blood pressure cuff. Microvascular lesions similar to those reported in other organs during diabetes are also an early feature. Biopsy studies have identified segmental demyelination in large fibers and axonal degeneration of all fiber classes with clusters of regenerating fibers, but regeneration is clearly insufficient to overcome ongoing distal degenerative processes. It is now widely accepted that diabetes damages all components of the nervous system, not just peripheral nerves. Historical autopsy evidence of demyelination and neuronal degeneration in the spinal cord has been supported by more recent noninvasive imaging studies and there is an emerging recognition of structural and functional impairments in the higher central nervous system (CNS).

Around one-third of patients with diabetic neuropathy report intermittent or continuous paresthesias and/or pain. The most frequent descriptors are of numbness, tingling, burning, pins and needles, electric shock, and pain to cold. Pain may develop during the prediabetic period or relatively early after diagnosis of diabetes but tends to be associated with advanced degenerative neuropathy. A separate and distinct pain condition, historically termed insulin neuritis, can also develop after instigation of tight glycemic control.

Regards,

Jessica

Managing Editor

Pancreatic disorder and therapy