Proinsulin C-peptide: Friend or foe in the development of diabetes-associated R E V I E W complications? Lina Nordquist1 M Johansson2 1Department of Medical Cell Biology, Division of Integrative Physiology, Uppsala University, Uppsala, Sweden; 2Department of Pathology, University of California, San Francisco, San Francisco, USA Correspondence: Lina Nordquist Uppsala University, Department of Medical Cell Biology, Biomedical Centre, Box 571, 751 23 Uppsala, Sweden Tel +46 18 471 4182 Fax +46 18 471 4938 Email Lina.Nordquist@mcb.uu.se Abstract: The proinsulin connecting peptide, C-peptide, is a cleavage product of insulin synthesis that is co-secreted with insulin by pancreatic β-cells following glucose stimulation. Recombinant insulin, used in the treatment of diabetes, lacks C-peptide and preclinical and clinical studies suggest that lack of C-peptide may exacerbate diabetes-associated complications. In accordance with this, several studies suggest that C-peptide has beneﬁcial effects in a number of diabetes-associated complications. C-peptide has been shown to prevent diabetic neuropathy by improving endoneural blood ﬂow, preventing neuronal apoptosis and by preventing axonal swelling. In the vascular system, C-peptide has been shown to prevent vascular dysfunction in diabetic rats, and to possess anti-proliferative effects on vascular smooth muscle cells, which may prevent atherosclerosis. However, C-peptide depositions have been found in arteriosclerotic lesions of patients with hyperinsulinemic diabetes and C-peptide has been shown to induce pro-inﬂammatory mediators, such as nuclear factor kappa B, inducible nitric oxide synthase, and cyclooxygenase-2, indicating that C-peptide treatment could be associated with side-effects that may accelerate the development of diabetes-associated complications. This review provides a brief summary of recent research in the ﬁeld and discusses potential beneﬁcial and detrimental effects of C-peptide supplementation. Keywords: C-peptide, proinsulin, diabetes, cardiovascular Introduction The vascular endothelium is pivotal in all aspects of cardiovascular physiology and pathology. It is well known that patients with diabetes mellitus are subject to an increased risk of developing atherosclerosis, which is the principal cause of heart attack, stroke, and gangrene of the extremities. Diabetes accelerates atherosclerosis (Brownlee 2001), microangiopathy and abnormalities in small vessel function, complications that signiﬁcantly contribute to diabetes-induced morbidity (Jensen et al 1989). Aggressive treatment of hyperglycemia has been shown to be associated with a decrease in diabetes-associated complications, but is not sufﬁcient to fully normalize the incidence of cardiovascular disease in patients with diabetes (DCCT 1993). This clinical observation suggests that there may be other factors that causally contribute to the development of diabetes complications. During insulin biosynthesis, the hormone is synthesized as a single polypeptide, proinsulin, which is subsequently proteolytically processed into insulin inside insulin granules. The mature hormone consists of two polypeptides, the so called A- and B-chain, while the connecting peptide is detached and released into the circulation. This proinsulin-connecting peptide, ie, C-peptide, is thus a product of insulin synthesis, and is released together with the mature hormone during hyperglycemia. Thus, when insulin synthesis is impaired, patients will also become C-peptide-deﬁcient. Vascular Health and Risk Management 2008:4(6) 1283–1288 © 2008 Nordquist and Johansson, publisher and licensee Dove Medical Press Ltd.This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. 1283