Proinsulin C-peptide--biological activity?

Insulin—a hormone critical for the control of blood glucose—is first synthesized as a longer prohormone. During its maturation, a peptide, C-peptide, is cleaved from the protein, but has been thought to be biologically inert. [HN2], [HN3] Defying the rule that peptide hormones act only by binding to stereospecific receptors, Ido et al. (1) report on page 563 of this issue that C-peptide not only produces biological effects, but does so by an unusual mechanism that depends on structural features of the C-peptide related to its sequence but independent of its direction or chirality. [HN4], [HN5] These effects include a restoration toward normal of the diabetes-induced decrease in cellular sodium-potassium adenosine triphosphatase (ATPase) activity and impaired nerve conduction, and reductions in the diabetes-induced increase in vascular permeability and blood flow, changes that are concomitants of the hyperglycemia associated with diabetes. These beneficial effects are seen after prolonged treatment of diabetic rats with pharmacological doses of C-peptide, as well as in specially designed skin chambers in which granulation tissue can be exposed to various agents while blood flow is maintained to supply nutrients and endogenous hormones. Normalization of these parameters, argue the authors, could prevent or slow the progression of some of the complications of this chronic and often debilitating disorder.