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Diabetes 52:621-633, 2003
© 2003 by the American Diabetes Association, Inc.

Acute Hyperglycemia Causes Intracellular Formation of CML and Activation of ras, p42/44 MAPK, and Nuclear Factor {kappa}B in PBMCs

Stephan Schiekofer1, Martin Andrassy1, Jiang Chen1, Gottfried Rudofsky1, Jochen Schneider1, Thoralf Wendt1, Norbert Stefan2, Per Humpert1, Andreas Fritsche2, Michael Stumvoll2, Erwin Schleicher2, Hans-Ulrich Häring2, Peter P. Nawroth1, and Angelika Bierhaus1

1 Department of Medicine I, University of Heidelberg, Heidelberg, Germany
2 Department of Medicine IV, University of Tübingen, Tübingen, Germany

Twenty-three nondiabetic volunteers were divided into three groups. In group A (n = 9), the glucose infusion was adjusted to maintain blood glucose at 5 mmol/l (euglycemic clamp). In group B (n = 9), the glucose infusion was adjusted to maintain blood glucose at 10 mmol/l (hyperglycemic clamp) over 2 h. Group C consisted of five volunteers who were studied as the control group. Peripheral blood mononuclear cells (PBMCs) were isolated before and at the end of a 2-h clamp. In group C, PBMCs were isolated before and after 2 h without performing a clamp. The euglycemic clamp as well as "no clamp" had no effects on all parameters studied. In contrast, a significant increase in carboxymethyllysine (CML) content and p21ras and p42/44 mitogen-activated protein kinase (MAPK) phosphorylation was observed at the end of a 2-h hyperglycemic clamp. The nuclear factor (NF)-{kappa}B (but not Oct-1) binding activity increased significantly in the hyperglycemic clamp. Western blots confirmed NF-{kappa}B-p65-antigen translocation into the nucleus. I{kappa}B{alpha} did not change significantly in both groups. Hyperglycemia-mediated NF-{kappa}B activation and increase of CML content, p21ras, and p42/44 MAPK phosphorylation was also seen in ex vivo–isolated PBMCs stimulated with 5 or 10 mmol/l glucose. Addition of insulin did not influence the results. Inhibition of activation of ras, MAPK, or protein kinase C blocked hyperglycemia-mediated NF-{kappa}B activation in ex vivo–isolated PBMCs stimulated with 10 mmol/l glucose. Similar data were obtained using an NF-{kappa}B-luciferase reporter plasmid. Therefore, we can conclude that an acute hyperglycemia-mediated mononuclear cell activation is dependent on activation of ras, p42/p44 MAPK phosphorylation, and subsequent NF-{kappa}B activation and results in transcriptional activity in PBMCs.


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