Affiliations: Medizinische Klinik I der Universitat Heidelberg, Bergheimer Str. 58, 69115 Heidelberg, Germany | Asta Medica, Weismüllerstr. 43, 60314 Frankurt/Main, Germany
Note: [] Address correspondence to: Peter P. Nawroth, MD, University of Tuebingen, Section Vascular Medicine, Department of Medicine IV, Offried‐Müller Str. 10, 72076 Tübingen, Germany. Tel.: +49 7071 2980578; Fax: +49 7071 295277; E‐mail: peter. [email protected]‐tuebingen.de.
Abstract: A common endpoint of hyperglycemia dependent cellular changes is the generation of reactive oxygen intermediates (ROIs) and the presence of elevated oxidative stress. Therefore, oxidative stress is supposed to play an important role in the development of late diabetic complications. Formation of advanced glycation end products (AGE’s) due to elevated nonenzymatic glycation of proteins, lipids and nucleic acids is accompanied by oxidative, radical‐generating reactions and thus represents a major source for oxygen free radicals under hyperglycemic conditions. Once formed, AGE’s can influence cellular function by binding to several binding sites including the receptor for AGE’s, RAGE. Binding of AGE’s (and other ligands) to RAGE results in generation of intracellular oxidative stress and subsequent activation of the redox‐sensitive transcription factor NF‐\kappaB in vitro and in vivo. Consistently, activation of NF‐\kappaB in diabetic patients correlates with the quality of glycemic control and can be reduced by treatment with the antioxidant \alpha‐lipoic acid. The development of techiques allowing for a tissue culture independent measurement of NF‐\kappaB activation in patients with diabetes mellitus gives insights into the molecular mechanisms linking diabetes mellitus and hyperglycemia with formation of advanced glycated endproducts and generation of oxidative stress finally resulting in oxidative stress mediated cellular activation.
Journal: Biofactors, vol. 10, no. 2-3, pp. 157-167, 1999
