Neurotrophic Factors in the Pathogenesis and Treatment of Diabetic Neuropathy

Abstract

It is increasingly recognized that diabetic neuropathy has a multifaceted pathogenesis, with risk factors such as hyperglycemia, dyslipidemia, and hypertension driving multiple downstream pathogenic mechanisms. In this respect, neuropathy is broadly similar to other long-term complications of diabetes such as nephropathy, retinopathy, and vasculopathy. However, the nervous system also requires support from an extensive system of factors that regulate survival, growth, and phenotype of neurons and their associated cells. Deficiencies in this neurotrophic support network arising from impaired supply, receptor expression, and/or signaling represent an additional burden to a nervous system that is already stressed by the primary systemic insults of diabetes. This chapter covers the preclinical and, where occasionally available, clinical evidence that diabetes disrupts neurotrophic support to the nervous system and that deficient neurotrophic support contributes to diabetic neuropathy. It also considers the opportunity emerging from these observations—that delivery of exogenous neurotrophic factors or other means of manipulating neurotrophic support may be viable approaches to preventing or reversing diabetic neuropathy. Both direct replacement of deficient trophic support and manipulation of downstream signaling pathways to strengthen the energetic status of the nervous system such that it tolerates and survives the continuing metabolic insults of diabetes have preclinical support as therapeutic approaches. In contrast, clinical trials to date have been limited and use of neurotrophic factors or their surrogates has yet to translate to clinical use.