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Activation of the transcription factor nuclear factor-B (NF-B) has been suggested to participate in chronic disorders, such as diabetes and its complications. In contrast to the short and transient activation of NF-B in vitro, we observed a long-lasting sustained activation of NF-B in the absence of decreased IB␣ in mononuclear cells from patients with type 1 diabetes. This was associated with increased transcription of NF-Bp65. A comparable increase in NF-Bp65 antigen and mRNA was also observed in vascular endothelial cells of diabetic rats. As a mechanism, we propose that binding of ligands such as advanced glycosylation end products (AGEs), members of the S100 family, or amyloid-␤ peptide ( T issue culture models of cellular activation provide easily accessible systems for detailed analysis of mechanisms potentially underlying the pathogenesis of human disease. However, the time course of such in vitro models is usually significantly abbreviated, limited to hours to days, compared with the pace of disorders under study in vivo. This indicates the importance of seeking out mechanisms in cell culture that might bridge the gap that accounts for the chronicity of cellular perturbation observed in the intact organism.The transcription factor nuclear factor-B (NF-B) has been proposed as a critical bridge between oxidant stress and gene expression (1-8). Exposure of cells to inflammatory, infectious, or other stressful stimuli results in rapid phosphorylation and degradation of IB␣ and the subsequent release and translocation of NF-B into the nucleus (1-11). This mechanism ensures quick and finely tuned cellular responses in the absence of de novo protein synthesis. Because transcription of IB␣ is positively autoregulated by NF-B (9 -11), activation of NF-B is usually self-terminated within minutes to hours (1-11). Such a scenario lends itself to analysis by short-term in vitro studies in which stimulus-induced responses are transient and the system returns to the baseline state over hours. Consequently, induction of NF-B and enhanced transcription of its target genes in vitro have been studied mainly in the setting of acute cellular responses.Reactive oxygen intermediates are generated by processes that occur over seconds. However, increasing evidence suggests a role for oxidative stress in chronic degenerative diseases such as atherosclerosis (1,6,12,13), diabetes (14 -16), and Alzheimer's disease (17)(18)(19). This indicates the relevance of signal transduction systems such as NF-B, which are capable of transforming the appearance and disappearance of short-lived oxygen free radicals into more sustained signals for cellular activation

SummaryThis review summarises the results and discussions of an UNESCO-MCBN supported symposium on oxidative stress and its role in the onset and progression of diabetes. There is convincing experimental and clinical evidence that the generation of reactive oxygen species (ROI) is increased in both types of diabetes and that the onset of diabetes is closely associated with oxidative stress. Nevertheless there is controversy about which markers of oxidative stress are most reliable and suitable for clinical practice. There are various mechanisms that contribute to the formation of ROI. It is generally accepted that vascular cells and especially the endothelium become one major source of ROI. An important role of oxidative stress for the development of vascular and neurological complications is suggested by experimental and clinical studies. The precise mechanisms by which oxidative stress may accelerate the development of complications in diabetes are only partly known. There is however evidence for a role of protein kinase C, advanced glycation end products (AGE) and activation of transcription factors such as NFkB, but the exact signalling pathways and the interactions with ROI remain a matter of discussion. Additionally, results of very recent studies suggest a role for ROI in the development of insulin resistance. ROI interfere with insulin signalling at various levels and are able to inhibit the translocation of GLUT4 in the plasma membrane. Evidence for a protective effect of antioxidants has been presented in experimental studies, but conclusive evidence from patient studies is missing. Large-scale clinical trials such as the DCCT Study or the UKPDS Study are needed to evaluate the long-term effects of antioxidants in diabetic patients and their potential to reduce the medical and socio-economic burden of diabetes and its complications.

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These studies suggest that LA improves SDN, in significant part by reducing the effects of oxidative stress. The drug may have potential in the treatment of human diabetic neuropathy.