C-peptide and diabetic neuropathy.

Diabetic polyneuropathy (DPN) is the most common chronic complication of diabetes and affects Type 1 diabetic patients disproportionately. In the last two decades it has become increasingly evident that underlying metabolic, molecular and functional mechanisms and, ultimately, structural changes differ in DPN between the two major types of diabetes. In Type 1 diabetes, impaired insulin/C-peptide action has emerged as a prominent pathogenetic factor. C-peptide was long considered to be biologically inactive. During the last number of years it has been shown to have a number of insulin-like effects but without affecting blood glucose levels. Preclinical studies have demonstrated effects on Na(+)/K(+)-ATPase activity, endothelial nitric oxide synthase, expression of neurotrophic factors and regulation of molecular species underlying the degeneration of the nodal apparatus in Type 1 diabetic nerves, as well as DNA binding of transcription factors and modulation of apoptotic phenomena. In animal studies, these effects have translated into protection and improvement of functional abnormalities, promotion of nerve fibre regeneration, protection of structural changes and amelioration of apoptotic phenomena targeting central and peripheral nerve cell constituents. Several small-scale clinical trials confirm these beneficial effects on autonomic and somatic nerve function and blood flow in a variety of tissues. Therefore, evidence to date indicating that replacement of C-peptide in patients with Type 1 diabetes will retard and prevent chronic complication is real and encouraging. Large-scale clinical trials necessary to bring this natural substance into the clinical arena should, therefore, be encouraged and accelerated.