Biological Effects of C‐peptide and Proinsulin

C-peptide: In contrast to the earlier view, new data now indicate that proinsulin C-peptide does exert important physiological effects and shows the characteristics of an endogenous peptide hormone. C-peptide in nanomolar concentrations binds specifically to cell membranes, probably to a G-protein coupled receptor, resulting in subsequent activation of Ca2+- and MAP-kinase-dependent signaling pathways. C-peptide's binding to cell membranes is stereospecific and the C-terminal pentapeptide segment participates in the process. Some studies indicate that C-peptide and insulin may exert a synergistic effect on the insulin signaling pathway. C-peptide stimulates Na+,K+-ATPase and endothelial nitric oxide synthase activities. C-peptide administration in replacement doses in animal models of diabetes or in type 1 diabetic patients results in increased blood flow in skeletal muscle, myocardium, kidney, nerve, and skin. C-peptide replacement decreases glomerular hyperfiltration, reduces urinary albumin excretion, and corrects glomerular expansion. It also increases nerve conduction velocity, improves sensory nerve function, and reduces or reverses the characteristic diabetes-induced nodal and paranodal nerve structural changes. The evidence suggests that replacement of C-peptide together with insulin may be beneficial in patients with type 1 diabetes and serve to retard or prevent the development of long-term complications.Proinsulin: Only a very small proportion of proinsulin is released in its intact form to the circulation in healthy subjects. In contrast, in type 2 diabetes, plasma proinsulin and its conversion intermediates may be higher than in healthy individuals. Proinsulin binds to the insulin receptor with approximately 10% of insulin's affinity. The suggestion of a specific effect of proinsulin in lowering hepatic glucose output has not been verified in direct studies. Clinical trials designed to evaluate the usefulness of proinsulin as an insulin analogue in type 2 diabetic patients were discontinued because of increased incidence of myocardial infarction. Recent reports of specific high affinity proinsulin receptors in several tissues are intriguing and warrant further investigation. Keywords: G-protein; intracellular Ca2+; Na+, K+-ATPase; endothelial NO synthase; nephropathy; neuropathy; glomerular filtration; nerve conduction velocity