(Witztum and Steinberg 1991), and activated NF-κB is found in vascular smooth muscle cells, endothelial cells, and macrophages in atherosclerotic lesions of human patients (Brand et al 1996). It has been postulated that NF-κB promotes chronic inﬂammation and may accelerate diabetic vascular disease. In this context, it is of importance that NF-κB activity is increased during hyperglycemia (Pieper and Riaz-ul-Haq 1997; Yerneni et al 1999). The inhibition of protein kinase C (PKC), an upstream regulator of NF-κB activity, has been shown to inhibit hyperglycemia-induced NF-κB activation in vascular smooth muscle cells and aortic endothelial cells (Pieper and Riaz-ul-Haq 1997; Yerneni et al 1999). In Swiss 3T3 ﬁbroblasts, C-peptide (1 nM) has been shown to stimulate the PKC/NF-κB signaling pathway (Kitazawa et al 2006). During disease progression in type II diabetes there is typically an increase in circulating concentrations of C-peptide. This correlation may indicate that C-peptide has negative effects on diabetes-associated complications. Alternatively, it is possible to argue that C-peptide is indeed renoprotective, and that disease progression would be further accelerated in the absence of the peptide. Notably, diabetes- associated complications normally develop slower in patients with type I diabetes, where patients have a relative lack of C-peptide, as compared to patients with type II diabetes, where patients typically have increased circulating C-peptide. However, potential mechanisms for this discrepancy have not been thoroughly investigated. In this context, it is intriguing that serum concentrations of the cytokine tumor necrosis factor-alpha (TNF-α) correlates with plasma C-peptide concentrations (Hotamisligil et al 1994; Hotamisligil 1999a, 1999b). TNF-α has been implicated as a causative key mediator of insulin resistance through direct interference with insulin signal transduction, TNF-α is an activator of NF-κB (Yerneni et al 1999) and has been implicated in the pathogenesis of diabetic nephropathy (Moriwaki et al 2007). During the development of diabetic nephropathy, TNF-α has been shown to be expressed in renal glomeruli and proximal renal tubules (Nakamura et al 1993, Sugimoto et al 1999; DiPetrillo and Gesek 2004). Furthermore, disease progres- sion is associated with increased serum concentrations of TNF-α and shows a positive correlation with urinary protein excretion (Hasegawa et al 1991; Kalantarina et al 2003). Additional studies have demonstrated that the administra- tion of TNF-α impairs renal function (Schmidt et al 2007), and that inhibition of TNF-α decreases urinary albumin excretion in rats with experimental diabetes (Moriwaki et al 2007). Cumulatively, the evidence suggests a direct role for Vascular Health and Risk Management 2008:4(6) C-peptide and diabetes complications TNF-α in the development of diabetic nephropathy, but the link to C-peptide remains controversial. PI-3 kinase is necessary for cell proliferation and survival, and is involved in TNF-α signaling. The PI-3 pathway is implicated in the pathogenesis of diabetic endothelial dysfunction and atherosclerosis, and also this pathway has been shown to be increased by C-peptide (Brownlee 2001; Grunberger et al 2001; Kitamura et al 2001; Li et al 2003; Walcher et al 2006), implicating a synergistic effect of C-peptide and TNF-α in aggravating diabetes-associated complications. On the other hand, administration of C-peptide prevented TNF-α-mediated apoptosis in opossum proximal tubular cells (Al-Rasheed et al 2006), suggesting a protective role of C-peptide in the progression of diabetes-related kidney disease. Hence, the interactions between TNF-α and C-peptide occur on multiple levels and outcomes may differ between different organs. In addition to its causal role in vascular disease, NF-κB is also essential for neuronal development and differentiation (Brand et al 1996; O’Neill and Kaitschmidt 1997; Denk et al 2000). In neurons, it may play a pro- or antiapoptotic role, depending on the cell type and the state of the cell (Brand et al 1996; O’Neill and Kaitschmidt 1997; Denk et al 2000). In the presence of insulin, C-peptide has been shown to exert antiapoptotic effects on neuroblastoma cells, and to increase the production of NF-κB (Li et al 2003). C-peptide has been suggested to be beneﬁcial in diabetic neuropathy (Sima et al 2004) by promoting neuronal development, regeneration and cell survival. C-peptide prevents neuronal apoptosis in type 1 diabetes and in vitro, C-peptide induces neurite outgrowth and cell-growth of the neuroblastoma cell line SH-SY5Y (Li et al 2003; Li and Sima 2004). To summarize, accumulating data suggest that C-peptide is involved in regulation of cell proliferation and apoptosis on multiple levels, mainly due to its association with inﬂamma- tory mediators, such as NF-κB and TNF-α. C-peptide appears to have predominantly antiproliferative effects in smooth muscle cells and beneﬁcial roles in diabetic neuropathy, while renal effects of C-peptide remain controversial. C-peptide may, on the other hand, play a negative role in endothelial dysfunction due to activation of the PI-3 pathway. Immunoregulatory effects of C-peptide Nitric oxide synthase (NOS) and nitric oxide (NO) regulation are known to be altered in diabetic and inflammatory states (Scalia et al 2000; Langer et al 2002; Marx et al 2004). C-peptide increases eNOS and NO activity (Johansson 1285