Nordquist and Johansson However, recombinant insulin does not contain the C-peptide and recent research indicates that this peptide may play an important physiological role. The current knowledge regarding the effects of C-peptide on proliferation, immune response, and cell growth will be reviewed brieﬂy. Beneﬁcial effects of C-peptide Exogenous C-peptide administration has beneﬁcial effects in many tissues commonly affected by diabetic complications, a ﬁnding supported by the fact that pancreas transplantation reduces diabetic lesions after ten years of normoglycemia, when compared to treatment with recombinant insulin (Fioretto et al 1998; Fiorina et al 2003). Diabetes-induced cardiovascular complications, such as decreased blood ﬂow in the extremities, have been shown to be prevented by C-peptide (Johansson et al 1992, 2003; Forst et al 1998b; Hansen et al 2002). In addition, C-peptide improves diabetes-induced erythrocyte deformability, which in turn likely improves oxygen availability and uptake in affected tissues (Johansson et al 1992; De la Tour et al 1998; Kunt et al 2000). Furthermore, C-peptide prevents diabetic neuropathy via improvements of endoneural blood ﬂow and by preventing axonal swelling (Johansson et al 2000; Sima et al 2004). In the kidneys, C-peptide prevents renal damage by reducing glomerular hyperﬁltration, hypertrophy, and proteinuria (Forst et al 1998a; Sjoquist et al 1998; Johansson et al 2000; Samnegard et al 2001, 2004; Huang et al 2002; Nordquist et al 2007; Stridh et al 2008). Several studies report a reduction of microvascular complications in patients with type 1, as well as type 2, diabetes with circulating concen- trations of C-peptide close to physiological levels (Fiorina et al 2003; Manzella et al 2003; Steffes et al 2003; Sari and Balci 2005; Shapiro et al 2006). Pancreatic transplantation, which restores not only insulin secretion, but also that of C-peptide, is associated with prevention and even reversal of diabetic complications (Lee et al 2006). Despite this, recent research indicates that C-peptide may not be beneﬁcial under all circumstances. Type 2 diabetes is a disease associated with endothelial dysfunction and the development of insulin resistance. Type 2 diabetes progresses through two stages. In the ﬁrst stage, tissue insulin action decreases, resulting in increased insulin and C-peptide production. The second stage is reached when “pancreatic exhaustion” causes insulin and C-peptide production to cease. Thus, during disease progression, patients exhibit high circulating concentrations of C-peptide. Atherosclerosis is an inﬂammatory process, and in addition to hemodynamic and metabolic factors, inﬂammation appears 1284 to be a potential pathogenic mechanism in the development of the disease (Navarro et al 2003). Although it has not been elucidated whether type 2 diabetics suffer from inﬂammation to a greater extent than type 1 diabetic patients, plasma levels of interleukin-6 (IL-6) appear to be associated with C-peptide concentrations in type 2 diabetic patients (Heliövaara et al 2005). Interestingly, C-peptide depositions have been found in arteriosclerotic lesions of patients with diabetes (Marx et al 2004). Effects of C-peptide on cell proliferation and apoptosis Atherosclerosis is characterized by features of chronic inﬂammation and proliferative processes. In the development of atherosclerosis, pathological proliferation and migration of vascular smooth muscle cells are critically involved in the formation of atherosclerotic plaques. C-peptide has been shown to prevent vascular dysfunction in diabetic rats (Ido et al 1997), and to possess antiproliferative effects on vascular smooth muscle cells (Kobayashi et al 2005), which indicates that treatment with C-peptide may delay disease progression in atherosclerosis. The administration of C-peptide (1 to 100 nM) appears to suppress hyperglycemia- induced hyperproliferation of aortic smooth muscle cells (Kobayashi et al 2005). The antiproliferative effects of C-peptide on vascular smooth muscle cells are mediated through the inhibited expression of the platelet-derived growth factor-β (PDGF-β) receptor and increased phos- phorylation of mitogen-activated protein kinase (MAPK) (Kobayashi et al 2005). This stimulating effect on MAPK has been described also for other cell types and experimental settings (Kitamura et al 2001; Zhong et al 2004, 2005). Para- doxically, in other studies, C-peptide has been reported to act as a mitogen by the induction of vascular smooth muscle cell proliferation (Walcher et al 2006), a ﬁnding suggesting proatherogenic activities of the peptide. Whether these effects occur in vivo remains to be determined. Atherosclerotic lesions originate from inﬂammatory and proliferative responses elicited by injuries to the endothelium and smooth muscle of arterial walls. A large number of growth factors, as well as cytokines, chemokines, and vasoregulators, interact to initiate and propagate the disease. The transcription factor nuclear factor kappa B (NF-κB) is of particular interest and plays a pivotal role in the early stages of disease progression. NF-κB orchestrates transcrip- tion of genes encoding various cell-adhesion molecules, as well as inducible nitric oxide synthase (iNOS). NF-κB can be activated by inﬂammatory and proliferative stimuli Vascular Health and Risk Management 2008:4(6)