Nordquist and Johansson et al 2003; Tsimaratos et al 2003; Walcher et al 2004; Maezawa et al 2006). In smooth muscle cells (Chakrabarti et al 2004) and aortic endothelial cells (Young et al 2000; Tsimaratos et al 2003), C-peptide has been shown to increase intracellular Ca2+, thereby inducing NO production by endo- thelial NOS (eNOS) and iNOS, causing an NO-dependent vasodilation. In myocardial ischemia-reperfusion, C-peptide has been shown to exert cardioprotective effects through the release of NO (Young et al 2000). The impaired release of NO from the vascular bed will up-regulate adhesion molecules on endothelial cells, thereby increasing leukocyte-endothelium interactions (known as “rolling” and “sticking”) (Scalia et al 2000). Early in the development of atherosclerosis, circulating monocytes adhere and migrate into the subendothelial space (Marx et al 2004). In isolated ischemic and reperfused rat hearts, C-peptide reduces polymorphonuclear cell adherence to vascular endo- thelium (Young et al 2000), and in an in vivo rat model of inﬂammatory vascular dysfunction, a single bolus injection of C-peptide decreased the expression of endothelial cell adhesion molecules on the rat microvascular endothelium, leading to reduced leukocyte rolling and adhesion as well as transmigration in mesenteric venules (Scalia et al 2000). This attenuation of leukocyte-endothelial interactions is mediated by an increase in eNOS synthesis and subsequent release of NO (Scalia et al 2000). Overall, these reports suggest that administration of C-peptide in physiological doses exerts antiinﬂammatory, and thus antiatherosclerotic effects. Paradoxically, C-peptide has also been reported to possess proinﬂammatory properties. C-peptide improves dermal wound healing associated with an increased number of leukocytes adherent to the endothelium (Langer et al 2002). C-peptide has been reported to co-localize with macrophages and monocytes in artery specimens from diabetic subjects (Marx et al 2004), and to co-localize with and act as a chemoattractant for CD4-positive lymphocyte and monocytes in early atherosclerotic lesions (Walcher et al 2004). In Swiss 3T3 ﬁbroblasts, C-peptide (1 nM) has been shown to stimulate the transcription of inﬂammatory genes, such as cyclooxygenase-2 (COX-2), via the activation of a PKC/NF-κB signaling pathway (Kitazawa et al 2006). In view of these potential effects of C-peptide, it is important to determine whether the net effect of C-peptide supplemen- tation is beneﬁcial or detrimental for the development of diabetes-associated complications. In summary, the role of C-peptide in the regulation of inﬂammation remains controversial, and further studies are needed in order to determine in which contexts treatment with 1286 C-peptide would be beneﬁcial from an immunomodulatory point of view. C-peptide-induced effects on angiogenesis It has been suggested that C-peptide has effects on angiogenesis (Chakrabarti et al 2004). There are indica- tions that diabetes induces the up-regulation of oncofetal ﬁbronectin in the retina (Khan et al 2004), a substance believed to be involved in angiogenesis and normally not found in mature tissue (Castellani et al 1994; Karelina and Eisen 1998). Increased retinal expression of oncofetal fibronectin in diabetic rats is completely prevented by C-peptide treatment (Chakrabarti et al 2004). This normal- ization of the diabetes-induced up-regulation of oncofetal ﬁbronectin in diabetic retinas, may suggest an important role of C-peptide for the development of microangiopathy. Conclusion Given C-peptide’s effects on NF-κB, TNF-α, and PKC, plasma C-peptide concentrations may play a pivotal role in the regulation of endothelial function. Thus, prescribed to the right patients, it is likely that C-peptide substitution would reduce the prevalence of diabetes complications. Accumulated evidence suggest that exogenous C-peptide possesses beneﬁcial effects on diabetic complications in type 1 diabetic patients, and likely also in type 2 diabetic patients with relative C-peptide deﬁciency. However, it may be that C-peptide does not prevent, but rather contributes to and promotes atherogenesis in patients with excess C-peptide production. It remains to be determined whether these seemingly divergent effects reﬂect tissue- or state-speciﬁc mechanisms. So far, C-peptide studies have given several opportu- nities for new drug targets and research directions. Also, C-peptide-induced effects on NO production are not restricted to the diabetic state, but have been reported in models of ischemia-reperfusion as well as during inﬂam- mation. Concomitantly, the effectiveness of C-peptide in the prevention and reversal of diabetic complications merits further investigation, particularly in human subjects. Protection from diabetes-induced vascular dysfunction by C-peptide administration has been reported in small-scale clinical trials (Johansson et al 2000; Hansen et al 2002), but long-term, large-scale studies need to be conducted in order to determine safety and health outcomes of long-term administration of C-peptide to patients with diabetes. It is not unlikely that C-peptide substitution in physiological doses Vascular Health and Risk Management 2008:4(6)