The most common microvascular diabetic complication,
diabetic peripheral polyneuropathy (DPN), affects
type 1 diabetic patients more often and more severely.
In recent decades, it has become increasingly clear that
perpetuating pathogenetic mechanisms, molecular, functional,
and structural changes and ultimately the clinical
expression of DPN differ between the two major types of
diabetes. Impaired insulin/C-peptide action has emerged
as a crucial factor to account for the disproportionate
burden affecting type 1 patients. C-peptide was long believed
to be biologically inactive. However, it has now
been shown to have a number of insulin-like glucoseindependent
effects. Preclinical studies have demonstrated
dose-dependent effects on Na+,K+-ATPase activity, endothelial
nitric oxide synthase (eNOS), and endoneurial
blood flow. Furthermore, it has regulatory effects on neurotrophic
factors and molecules pivotal to the integrity of
the nodal and paranodal apparatus and modulatory effects
on apoptotic phenomena affecting the diabetic nervous system.
In animal studies, C-peptide improves nerve conduction
abnormalities, prevents nodal degenerative changes,
characteristic of type 1 DPN, promotes nerve fiber regeneration,
and prevents apoptosis of central and peripheral nerve
cell constituents. Limited clinical trials have confirmed the
beneficial effects of C-peptide on autonomic and somatic nerve function in patients with type 1 DPN. Therefore, evidence
accumulates that replacement of C-peptide in type 1
diabetes prevents and even improves DPN. Large-scale food
and drug administration (FDA)-approved clinical trials are
necessary to make this natural substance available to the
globally increasing type 1 diabetic population.
