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Schiekofer, S. et al.

Schiekofer, Andrassy, Chen, Rudofsky, Schneider, Wendt, Stefan, Humpert, Fritsche, Stumvoll, Schleicher, Häring, Nawroth, Bierhaus,

Acute hyperglycemia causes intracellular formation of CML and activation of ras, p42/44 MAPK, and nuclear factor kappaB in PBMCs.

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 p21(ras) and p42/44 mitogen-activated protein kinase ( MAPK) phosphorylation was observed at the end of a 2-h hyperglycemic clamp. The nuclear factor (NF)-kappaB (but not Oct-1) binding activity increased significantly in the hyperglycemic clamp. Western blots confirmed NF-kappaB-p65-antigen translocation into the nucleus. IkappaBalpha did not change significantly in both groups. Hyperglycemia-mediated NF-kappaB activation and increase of CML content, p21(ras), 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-kappaB activation in ex vivo-isolated PBMCs stimulated with 10 mmol/l glucose. Similar data were obtained using an NF-kappaB-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-kappaB activation and results in transcriptional activity in PBMCs.[1]

References

Acute hyperglycemia causes intracellular formation of CML and activation of ras, p42/44 MAPK, and nuclear factor kappaB in PBMCs. Schiekofer, S., Andrassy, M., Chen, J., Rudofsky, G., Schneider, J., Wendt, T., Stefan, N., Humpert, P., Fritsche, A., Stumvoll, M., Schleicher, E., Häring, H.U., Nawroth, P.P., Bierhaus, A. Diabetes (2003) [Pubmed]

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