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It is well known that C-peptide fulfills an important function in the synthesis of insulin. After cleavage of proinsulin in the pancreatic β-cells, the 31-amino acid C-peptide is secreted into the portal circulation in equimolar concentrations with insulin. After its discovery in 1967 (1), it was believed that C-peptide might exert physiological effects similar to those of insulin. However, no influence on glucose or lipid metabolism could be demonstrated, and C-peptide was subsequently regarded as a waste product of insulin synthesis. Nevertheless, it was found to be useful as an indicator of β-cell function, and since the mid-1970s, C-peptide has been used as a surrogate marker for monitoring the course of type 1 and type 2 diabetes and determining the effects of interventions designed to preserve and improve residual β-cell function.Several studies demonstrate that patients with type 1 diabetes who show a degree of remaining β-cell activity are considerably less prone to develop microvascular complications than those who are totally C-peptide deficient (2). The possibility that C-peptide may exert direct effects of its own was reevaluated in the early 1990s. A series of studies was undertaken involving administration of the peptide to patients with type 1 diabetes, who lack C-peptide. This approach gave positive results, and it became apparent that replacement of C-peptide in physiological concentrations resulted in significant improvements in several diabetes-induced functional abnormalities (3–7). These surprising findings prompted a renewed interest in C-peptide physiology, and during the past 15 years, a steadily increasing number of reports on new aspects of C-peptide physiology have emerged. The information available today includes studies of the peptide’s interaction with cell membranes and its intracellular signaling properties (8). In vivo studies in animal models of type 1 diabetes have defined a beneficial influence of C-peptide on diabetes-induced functional and structural …

The Clinical Potential of C-Peptide Replacement in Type 1 Diabetes