Mechanisms of diabetic neuropathy: axon dysfunction

Abstract

Diabetic neuropathy is the most common complication of diabetes. It shows a progressive development with sensory loss, pain and autonomic dysfunction as common symptoms. Pathologically it is characterized by a series of interrelated metabolic abnormalities with insulin deficiency and hyperglycemia as the initiating culprits. The neuropathy accompanying type 2DM (insulin resistance) and type 1DM (insulin deficiency) appears to differ as to their structural changes; the former showing a milder axonal involvement and segmental myelin breakdown, whereas the latter shows a more severe axonal atrophy and axonal loss. Based mainly on animal data we will describe the sequential neuropathologic changes and differences in the two types of diabetes. These differences are related to differences in a myriad of underlying sequential metabolic abnormalities, which will be dealt with in detail. How metabolic defects affect nerve function will be elaborated upon. The disorder does not only involve somatic peripheral nerves but also autonomic and central nerve tracts. Today no successful therapy exists for diabetic neuropathy. During the last 30 years several experimental drugs targeting the polyol-pathway and oxidative stress have been tested, but with limited or no success. Instead therapies targeting the initiating and overriding pathogenetic abnormalities, such as insulin-deficiency and hyperglycemia need to be employed. One such agent is the insulinomimetic C-peptide which has demonstrated significant therapeutic and preventive effects in type 1 diabetic patients. Not surprisingly this has been particularly successful following early intervention. However diabetic neuropathy still remains a major medical problem affecting millions of patients.

Keywords: C-peptide; Insulin deficiency; Na/K-ATPase defect; atrophy and loss; axonal dysfunction; neurotrophic factors deficiencies.