LAUSR

PURPOSE OF REVIEW The current review addresses one of the most common neurological disorders, diabetic polyneuropathy (DPN). DPN is debilitating, irreversible and dwarfs the prevalence of most other chronic disorders of the nervous system. Its complications include foot ulceration, amputation, falling and intractable neuropathic pain. Moreover, tight control of hyperglycemia reduces the incidence of DPN in type 1 diabetes mellitus but its role in type 2 diabetes mellitus is less clear. RECENT FINDINGS New therapeutic options to reverse the development of DPN or its associated pain have been proposed but none have significantly changed the clinical approach. The cause of DPN remains controversial traditionally focused on the impact of metabolic abnormalities, polyol flux, microvascular changes, mitochondria, oxidative stress, lipid biology and others. In particular, there has been less attention toward how this chronic disorder alters peripheral neurobiology. It is now clear that in chronic models of diabetes mellitus there exists a unique form of neurodegeneration with a range of protein, mRNA and microRNA alterations to consider. How to reconcile these molecular and structural alterations with metabolic mechanisms is a challenge. In sensory neurons alone, a primary target of DPN, both central perikaryal cytoplasmic and nuclear changes and altered distal sensory axon terminal plasticity may be involved. SUMMARY In this review, the current therapeutic status of DPN is described with greater emphasis on some new but selected thoughts on its neurobiology. New mechanistic understanding will be essential to developing precision therapeutics for DPN.