Mechanisms of disease: role of neurotrophins in diabetes and diabetic neuropathy.

Neuropathy is an insidious and devastating consequence of diabetes. Early studies provided a strong rationale for deficient neurotrophin support in the pathogenesis of diabetic neuropathy in a number of critical tissues and organs. It has now been over a decade since the first failed human neurotrophin supplementation clinical trials, but mounting evidence still implicates these trophic factors in diabetic neuropathy. Since then, tremendous advances have been made in our understanding of the complexities of neurotrophin signaling and processing and how the diabetic milieu might impact this. This in turn changes both our perception of how the altered trophic environment contributes to the etiology of diabetic neuropathy and the design of future neurotrophin therapeutic interventions. This chapter summarizes some of these findings and attempts to integrate neurotrophin actions on the nervous system with an increasing appreciation of their role in the regulation of metabolic processes in diabetes that impact the diabetic neuropathic state.