E-peptide is part of proinsulin and necessary for the spacing and secondary and tertiary configuration of insulin . It is secreted in equimolar concentrations with insulin. It was long believed to have no physiological functions. However, in recent years it has become clear that C-peptide has a myriad of functions (see reviews [2, 3]) and that it synergizes the nonhypoglycemic effects of insulin, particularly at low insulin concentrations [4-6]. The chronic complications of diabetes constitute a major component of the costs of the increasing global epidemic of diabetes. The microvascular complications strike type 1 patients disproportionately with a higher prevalence, more rapid developments and more severe clinical pictures as compared to type 2 diabetes. Until recently, it was generally believed that the microvascular complications in type 1 and type 2 diabetes were the same and that the overriding culprit was hyperglycemia and its downstream consequences such as activation of the polyol-pathway and oxidative stress [7, 8]. Only recently has it become clear that underlying pathogenetic mechanisms, as well as structural substrates for the complications, differ between those associated with type 1 and type 2 diabetes . These differences have been extensively explored in diabetic neuropathy and have been accounted for by perturbed insulin and C-peptide actions  in addition to hyperglycemia common for both types of diabetes.