Horm Metab Res 2004; 36(9): 630-638
DOI: 10.1055/s-2004-825904
Original Clinical
© Georg Thieme Verlag KG Stuttgart · New York

Reduction of Postprandial Hyperglycemia in Patients with Type 2 Diabetes Reduces NF-κB Activation in PBMCs

G.  Rudofsky, Jr.1 , P.  Reismann1 , S.  Schiekofer1 , D.  Petrov1 , M.  von  Eynatten1 , P.  M.  Humpert1 , B.  Isermann1 , C.  Müller-Hoff1 , T.-P.  Thai1 , S.  Lichtenstein1 , U.  Bärtsch1 , A.  Hamann1 , P.  Nawroth1 , A.  Bierhaus1
  • 1Department of Medicine I, University of Heidelberg, Germany
Further Information

Publication History

Received 5 January 2004

Accepted after revision 24 March 2004

Publication Date:
05 October 2004 (online)

Abstract

Aims/hypothesis: Short-lasting hyperglycemia results in activation of the transcription factor NF-κB in peripheral blood mononuclear cells. We therefore studied whether the postprandial increase in glucose is sufficient to induce mononuclear NF-κB activation and whether blunting postprandial hyperglycemia with the alpha-glucosidase inhibitor acarbose reduces NF-κB activation.

Methods: 20 patients with type 2 diabetes were included in a double-blind randomized trial receiving 100 mg acarbose or placebo three times a day over a period of eight weeks. Peripheral blood mononuclear cells were isolated before and 120 minutes after a standardized breakfast. NF-κB binding activity was estimated by electrophoretic mobility shift assay and NF-κB-p65; translocation was determined by Western blot.

Results: Eight weeks of treatment with acarbose significantly reduced postprandial hyperglycemia (p = 0.004 when compared to placebo), postprandial mononuclear NF-κB-binding activity (p = 0.045) and nuclear translocation of NF-κB-p65 (p = 0.02).

Conclusion: Reduction of postprandial glucose peak levels by acarbose reduces postprandial mononuclear NF-κB activation.

References

  • 1 Ceriello A. Oxidative stress and glycemic regulation.  Metabolism. 2000;  49 (2 Suppl 1) 27-29
  • 2 Ceriello A. Acute hyperglycemia and oxidative stress generation.  Diabet Med. 1997;  14 S45-S49
  • 3 Ceriello A, Falleti E, Motz E, Taboga C, Tonutti L, Ezsol Z, Gonano F, Bartoli E. Hyperglycemia-induced circulating ICAM-1 increase in diabetes: the possible role of oxidative stress.  Horm Metab Res. 1998;  30 146-149
  • 4 Ceriello A. The post-prandial state and cardiovascular disease: relevance to diabetes mellitus.  Diabetes Metab Res Rev. 2000;  16 125-132
  • 5 Ceriello A, Bortolotti N, Motz E, Crescentini A, Lizzio S, Russo A, Tonutti L, Taboga C. Meal-generated oxidative stress in type 2 diabetic patients.  Diabetes Care. 1998;  21 1529-1533
  • 6 Tessier D, Khalil A, Fulop T. Effects of an oral glucose challenge on free radicals/antioxidants balance in an older population with type II diabetes.  J Gerontol A Biol Sci Med Sci. 1999;  54 M 541-545
  • 7 Cummings P M, Giddens K, Nassar B A. Oral glucose loading acutely attenuates endothelium-dependent vasodilatation in healthy adults without diabetes: an effect prevented by vitamins C and E.  J AM Coll Cardiol. 2000;  36 2185-2191
  • 8 Kawano H, Motoyama T, Hirashima O, Hirai N, Miyao Y, Sakamoto T, Kugiyama K, Ogawa H, Yasue H. Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery.  J Am Coll Cardiol. 1999;  34 146-154
  • 9 Shige H, Ishikawa T, Suzukawa M, Ito T, Nakajima K, Higashi K, Ayaori M, Tabata S, Ohsuzu F, Nakamura H. Endothelium-dependent flow-mediated vasodilation in the postprandial state in type 2 diabetes mellitus.  Am J Cardiol. 1999;  84 1272-1274, A9
  • 10 Graier W F, Posch K, Wascher T C, Kostner G M. Role of superoxide anions in changes of endothelial vasoactive response during acute hyperglycemia.  Horm Metab Res. 1997;  29 622-626
  • 11 Title L M, Cummings P M, Giddens K, Nassar B A. Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E.  J Am Coll Cardiol. 2000;  36 2185-2191
  • 12 Hattori Y, Hattori S, Sato N, Kasai K. High-glucose-induced nuclear factor kappaB activation in vascular smooth muscle cells.  Cardiovasc Res. 2000;  46 188-197
  • 13 Meigs J B, Mittleman M A, Nathan D M, Tofler G H, Singer D E, Murphy-Sheehy P M, Lipinska I, D'Agostino R B, Wilson P W. Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study.  JAMA. 2000;  283 221-228
  • 14 Evans J L, Goldfine I D, Maddux B A, Grodsky G M. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes.  Endocr Rev. 2002;  23 599-622
  • 15 Brownlee M. Negative consequences of glycation.  Metabolism. 2000;  49 (2 Suppl 1) 9-13
  • 16 Brownlee M. Biochemistry and molecular cell biology of diabetic complications.  Nature. 2001;  414 813-820
  • 17 Hammes H P, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy.  Nat Med. 2003;  9 294-299
  • 18 Schmidt A M, Yan S D, Stern D M. The dark side of glucose.  Nat Med. 1995;  1 1002-1004
  • 19 Baeuerle P A, Baltimore D. NF-kappa B: ten years after.  Cell. 1996;  87 3-20
  • 20 Wautier J L, Wautier M P, Schmidt A M, Anderson G M, Hori O, Zoukourian C, Capron L, Chappey O, Yan S D, Brett J, Guillausseau P-J, Stern DM. Advanced glycation end products (AGEs) on the surface of diabetic erythrocytes bind to the vessel wall via a specific receptor inducing oxidant stress in the vasculature: a link between surface-associated AGEs and diabetic complications.  Proc Natl Acad Sci U S A. 1994;  91 7742-7746
  • 21 Yan S D, Schmidt A M, Anderson G M, Zhang J, Brett J, Zou Y S, Pinsky D, Stern D. Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins.  J Biol Chem. 1994;  269 9889-9897
  • 22 Baynes J W, Thorpe S R. Glycoxidation and lipoxidation in atherogenesis.  Free Radic Biol Med. 2000;  28 1708-1716
  • 23 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. Acute hyperglycemia causes intracellular foprmation of CML and activation of ras, p42/44 MAPK, and nuclear factor kappa B in PBMCs.  Diabetes. 2003;  52 621-633
  • 24 King G L, Brownlee M. The cellular and molecular mechanisms of diabetic complications.  Endocrinol Metab Clin North Am. 1996;  25 255-270
  • 25 Hernández-Presa M A, Bustos C, Ortego M. et al . Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-κB activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis.  Circulation. 1997;  95 1532-1541
  • 26 Balkau B, Shipley M, Jarnett R J, Pyorala M, Forhan A, Eschwege E. High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men. 20-year follow-up in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study.  Diabetes Care. 1998;  21 360-367
  • 27 Ceriello A. The emerging role of post-prandial hyperglycaecimic spikes in the pathogenesis of diabetic complications.  Diabet Med. 1998;  15 188-193
  • 28 DECODE Study Group . Glucose tolerance and cardiovascular mortality: comparison of the fasting and the 2-hour diagnostic criteria.  Arch Intern Med. 2001;  161 397-404
  • 29 De Vegt F, Dekker J M, Ruhe H G, Stehouwer C D, Nijpels G, Bouter L M, Heine R J. Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study.  Diabetologia. 1999;  42 926-931
  • 30 Del Prato S. Metabolic control in Type 2 diabetes: the impact of postprandial glucose.  Curr Opin Endocrinol Diabetes. 1999;  6 (Suppl) S1-S6
  • 31 Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck U, Schmechel H, Ziegelasch H J, Lindner J. Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up.  Diabetologia. 1996;  39 1577-1583
  • 32 Shaw J E, Hodge A M, de Courten M, Chitson P, Zimmet P Z. Isolated post-challenge hyperglycaemia confirmed as a risk factor for mortality.  Diabetologia. 1999;  42 1050-1054
  • 33 Sheetz M J, King G L. Molecular understanding of hyperglycemia's adverse effects for diabetic complications.  JAMA. 2002;  288 2579-2588
  • 34 Baynes J W. Role of oxidant stress in development of complications in diabetes.  Diabetes. 1991;  40 405-412
  • 35 Hammes H P. Pathophysiological mechanisms of diabetic angiopathy.  J Diabetes Complications. 2003;  17 (2 Suppl) 16-9
  • 36 Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications.  Diabetes Care. 1996;  19 257-267
  • 37 Hofmann M A, Schiekofer S, Isermann B, Kanitz M, Henkels M, Joswig M, Treusch A, Morcos M, Weiss T, Borcea V, Abdel K halek , Amiral J, Tritschler H, Ritz E, Wahl P, Ziegler R, Bierhaus A, Nawroth P P. Peripheral blood mononuclear cells isolated from patients with diabetic nephropathy show increased activation of the oxidative-stress sensitive transcription factor NF-kappaB.  Diabetologia. 1999;  42 222-232
  • 38 Hofmann M A, Schiekofer S, Kanitz M, Klevesath M S, Joswig M, Lee V, Morcos M, Tritschler H, Ziegler R, Wahl P, Bierhaus A, Nawroth P P. Insufficient glycemic control increases nuclear factor-kappa B binding activity in peripheral blood mononuclear cells isolated from patients with type 1 diabetes.  Diabetes Care. 1998;  21 1310-1316
  • 39 Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert P M, Chen J, Hong M, Luther T, Henle T, Kloting I, Morcos M, Hofmann M, Tritschler H, Weigle B, Kasper M, Smith M, Perry G, Schmidt A M, Stern D M, Haring H U, Schleicher E, Nawroth P P. Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB.  Diabetes. 2001;  50 2792-2808
  • 40 Yerneni K K, Bai W, Khan B V, Medford R M, Natarajan R. Hyperglycemia-induced activation of nuclear transcription factor kappaB in vascular smooth muscle cells.  Diabetes. 1999;  48 855-864
  • 41 Schiekofer S, Rudofsky G, Andrassy M, Schneider J, Chen J, Isermann B, Kanitz M, Elsenhans S, Heinle H, Balletshofer B, Haring H U, Schleicher E, Nawroth P P, Bierhaus A. Glimepiride reduces mononuclear activation of the redox-sensitive transcription factor nuclear factor-kappa B.  Diabetes Obes Metab. 2003;  5 251-261
  • 42 Bierhaus A, Chevion S, Chevion M, Quehenberger P, Hofmann M, Illmer T, Luther T, Berentshtein E, Tritschler H, Müller M. Advanced glycation endproducts (AGEs) induced activation of NF-κB is suppressed by α-lipoic acid in cultured endothelial cells.  Diabetes. 1997;  46 1481-1490
  • 43 Bierhaus A, Zhang Y, Deng Y, Mackman N, Quehenberger P, Haase M, Luther T, Müller M, Böhrer H, Greten J. Mechanism of the TNF α mediated induction of endothelial tissue factor.  J Biol Chem. 1995;  270 26 419-26 432
  • 44 Bradford M M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.  Anal Biochem. 1996;  72 248-254
  • 45 Pahl H L, Baeuerle P A. Expression of influenza virus hemagglutinin activates the transcription factor NFκB.  J Virol. 1995;  69 1480-1484
  • 46 Fujita N, Furukawa Y, Du J, Itabashi N, Fujisawa G, Okada K, Saito T, Ishibashi S. Hyperglycemia enhances VSMC proliferation with NF-kappaB activation by angiotensin II and E2F-1 augmentation by growth factors.  Mol Cell Endocrinol. 2002;  192 75-84
  • 47 Guha M, Bai W, Nadler J L, Natarajan R. Molecular mechanisms of tumor necrosis factor alpha gene expression in monocytic cells via hyperglycemia-induced oxidant stress-dependent and -independent pathways.  J Biol Chem. 2000;  275 17 728-17 739
  • 48 Bierhaus A, Wolf J, Andrassy M, Rohleder N, Humpert P M, Petrov D, Ferstl R, von Eynatten M, Wendt T, Rudofsky G, Joswig M, Morcos M, Schwaninger M, McEwen B, Kirschbaum C, Nawroth P P. A mechanism converting psychosocial stress into mononuclear cell activation.  Proc Natl Acad Sci USA. 2003;  100 1920-1925
  • 49 Bierhaus A, Hemmer C J, Mackman N, Kutob R, Ziegler R, Dietrich M, Nawroth P P. Antiparasitic treatment of patients with P. falciparum malaria reduces the ability of patient serum to induce tissue factor by decreasing NF-kappa B activation.  Thromb Haemost. 1995;  73 39-48
  • 50 Nawroth P P, Bierhaus A, Vogel G E, Hofmann M A, Zumbach M, Wahl P, Ziegler R. Nicht enzymatische Glykierung und oxidativer Stress bei chronischen Erkrankungen und Diabetes mellitus.  Med Klinik. 1999;  94 29-38
  • 51 Blanco-Colio L M, Valderrama M, Alvarez-Sala L A, Bustos C, Ortego M, Hernandez-Presa M A, Cancelas P, Gomez-Gerique J, Millan J, Egido J. Red wine intake prevents nuclear factor-kappaB activation in peripheral blood mononuclear cells of healthy volunteers during postprandial lipemia.  Circulation. 2000;  102 1020-1026
  • 52 Malaguarnera M, Giugno I, Ruello P, Maugeri D, Pistone G. Treatment of familial hypertriglyceridaemia with acarbose.  Diabetes Obes Metab. 2000;  2 33-38
  • 53 Ceriello A, Taboga C, Tonutti L, Quagliaro L, Piconi L, Bais B, Da Ros R, Motz E. Evidence for an Independent and Cumulative Effect of Postprandial Hypertriglyceridemia and Hyperglycemia on Endothelial Dysfunction and Oxidative Stress Generation Effects of Short- and Long-Term Simvastatin Treatment.  Circulation. 2002;  106 1211-1218
  • 54 Carrascosa J M, Molero J C, Fermin Y, Martinez C, Andres A, Satrustegui J. Effects of chronic treatment with acarbose on glucose and lipid metabolism in obese diabetic Wistar rats.  Diabetes Obes Metab. 2001;  3 240-248
  • 55 Salman S, Salman F, Satman I, Yilmaz Y, Ozer E, Sengul A, Demirel H O, Karsidag K, Dinccag N, Yilmaz M T. Comparison of acarbose and gliclazide as first-line agents in patients with type 2 diabetes.  Curr Med Res Opin. 2001;  16 296-306
  • 56 Ceriello A, Quagliaro L, Piconi L, Assaloni R, Da Ros R, Maier A, Esposito K, Giugliano D. Effect of postprandial hypertriglyceridemia and hyperglycemia on circulating adhesion molecules and oxidative stress generation and the possible role of simvastatin treatment.  Diabetes. 2004;  53 701-710

Angelika Bierhaus, Ph.D.

Medizinische Klinik I der Universität Heidelberg, Otto-Meyerhof-Zentrum ·

Im Neuenheimer Feld 350 · 69120 Heidelberg · Germany

Phone: +49 (6221) 564752

Fax: +49 (6221) 564754 ·

Email: angelika_bierhaus@med.uni-heidelberg.de