New Tricks by an Old Dog

It is generally recognized that the connecting peptide (C-peptide) of proinsulin fulfills an important function in the biosynthesis of insulin. It brings together the A-and B-chains such that the initial folding and interchain disulfide bonds can be formed. Evolutionary considerations suggest that a length of approximately 30 residues for the connecting segment, as is the case for human C-peptide, is optimal for the efficient further processing of the molecule (i.e., its cleavage into insulin and C-peptide). Following this, the two are stored in secretory granules and eventually coreleased into the circulation. Because of its intimate connection to the insulin biosynthesis, C-peptide has been used as a marker of insulin secretion. As such, it has contributed importantly to our understanding of the pathophysiology of several metabolic disorders, notably type 1 and type 2 diabetes. The possibility that C-peptide may possess biological effects of its own was considered but received relatively little attention at the time of its discovery in 1968. No detectable influence on glucose metabolism or on lipolysis of isolated fat cells could be observed. In the absence of any insulin-like effect by C-peptide in isolated cell systems or when administered to healthy individuals, it was concluded that C-peptide was without biological effect other than its role in the biosynthesis of insulin; for a review see [1]. Consequently, C-peptide as a bioactive peptide left the scientific limelight and the interest was focused instead on its usefulness as a marker of insulin secretion. It was not until the early 1990s that direct C-peptide effects were re-evaluated. A series of studies was undertaken involving administration of the peptide in type 1 diabetes patients, who lack C-peptide [2]. This proved a useful approach and it became apparent that replacement of physiological concentrations of C-peptide in this patient group results in significant amelioration of diabetes-induced abnormalities of regional blood flow as well as improvements in peripheral nerve and kidney function. These surprising findings, subsequently confirmed and extended by several laboratories, prompted a renewed interest in C-peptide as a bioactive peptide in its own right. Since then, a steadily increasing number of reports on new aspects of C-peptide physiology have been presented. Today, a vast body of scientific evidence is available comprising in vitro studies of the peptide's membrane interaction and cellular effects, in vivo studies in animal models of type 1 diabetes defining C-peptide's influence on functional and structural abnormalities of the kidneys and …