Journal of Molecular Medicine

, Volume 85, Issue 4, pp 389–396 | Cite as

The metabolic syndrome sensitizes leukocytes for glucose-induced immune gene expression

  • K. KempfEmail author
  • B. Rose
  • C. Herder
  • B. Haastert
  • A. Fusbahn-Laufenburg
  • A. Reifferscheid
  • W. A. Scherbaum
  • H. Kolb
  • S. Martin
Original Article


Definitions of the metabolic syndrome (MetS) include obesity, dyslipidemia, elevated levels of fasting blood glucose, and blood pressure as criteria, but it is also known that the MetS is associated with chronic, subclinical inflammation. Hyperglycemia (fasting and postprandial) may be important in exacerbating this proinflammatory state. We aimed to assess the impact of oral glucose challenge and in vitro glucose-stimulation on gene expression and secretion of inflammatory parameters in peripheral blood leukocytes and to investigate whether presence of the MetS could “prime” leukocytes to up-regulate proinflammatory markers in response to glucose. Using quantitative real-time PCR, we could show that the expression of intercellular adhesion molecule 1 (ICAM-1), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6) significantly increased in peripheral blood leukocytes from “MetS” subjects (n = 39) compared to “no MetS” subjects (n = 35) 2 h after an oral glucose tolerance test (ICAM-1 +52%, TNF-α +107%, and IL-6 +38%) and also in vitro after 72 h cultivation in high-glucose medium (ICAM-1 +74%, TNF-α +71%, and IL-6 +44%). Using ELISA and Luminex technique, we further observed a trend towards increased immune mediator concentrations in the corresponding cell culture supernatants from MetS patients (ICAM-1 +21%, TNF-α +31%, and IL-6 +175%). Thus, the MetS may support peripheral inflammation by sensitizing leukocytes to up-regulate proinflammatory markers in response to glucose, which in turn increases the risk for type-2 diabetes mellitus and cardiovascular disease.


MetS Hyperglycemia Oral glucose challenge 



We would like to thank A. Neudam for performance of OGTTs; G. Gornitzka, A. Hoffmann, W. Mohné, U. Poschen, and R. Rütter for excellent technical assistance; and W. Rathmann for helpful suggestions and discussions. The work was supported by the German Federal Ministry of Health and Social Security; the German Federal Ministry of Education, Science, Research and Technology; and the Ministry of Science and Research of the State North Rhine-Westphalia.


  1. 1.
    Eckel RH, Grundy SM, Zimmet PZ (2005) The metabolic syndrome. Lancet 365:1415–1428PubMedCrossRefGoogle Scholar
  2. 2.
    Alberti KG, Zimmet P, Shaw J (2005) The metabolic syndrome—a new worldwide definition. Lancet 366:1059–1062PubMedCrossRefGoogle Scholar
  3. 3.
    Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R (2005) Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation 111:1448–1454PubMedCrossRefGoogle Scholar
  4. 4.
    Kolb H, Mandrup-Poulsen T (2005) An immune origin of type 2 diabetes? Diabetologia 48:1038–1050PubMedCrossRefGoogle Scholar
  5. 5.
    Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126PubMedCrossRefGoogle Scholar
  6. 6.
    Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11:183–190PubMedCrossRefGoogle Scholar
  7. 7.
    Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11:191–198PubMedCrossRefGoogle Scholar
  8. 8.
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808PubMedCrossRefGoogle Scholar
  9. 9.
    Curat CA, Miranville A, Sengenes C, Diehl M, Tonus C, Busse R, Bouloumie A (2004) From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes. Diabetes 53:1285–1292PubMedCrossRefGoogle Scholar
  10. 10.
    Ceriello A, Quagliaro L, Piconi L, Assaloni R, Da Ros R, Maier A, Esposito K, Giugliano D (2004) Effect of postprandial hypertriglyceridemia and hyperglycemia on circulating adhesion molecules and oxidative stress generation and the possible role of simvastatin treatment. Diabetes 53:701–710PubMedCrossRefGoogle Scholar
  11. 11.
    Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, Quagliaro L, Ceriello A, Giugliano D (2002) Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 106:2067–2072PubMedCrossRefGoogle Scholar
  12. 12.
    Nappo F, Esposito K, Cioffi M, Giugliano G, Molinari AM, Paolisso G, Marfella R, Giugliano D (2002) Postprandial endothelial activation in healthy subjects and in type 2 diabetic patients: role of fat and carbohydrate meals. J Am Coll Cardiol 39:1145–1150PubMedCrossRefGoogle Scholar
  13. 13.
    Krogh-Madsen R, Moller K, Dela F, Kronborg G, Jauffred S, Pedersen BK (2004) Effect of hyperglycemia and hyperinsulinemia on the response of IL-6, TNF-alpha, and FFAs to low-dose endotoxemia in humans. Am J Physiol Endocrinol Metab 286:E766–E772PubMedCrossRefGoogle Scholar
  14. 14.
    de Jager W, te Velthuis H, Prakken BJ, Kuis W, Rijkers GT (2003) Simultaneous detection of 15 human cytokines in a single sample of stimulated peripheral blood mononuclear cells. Clin Diagn Lab Immunol 10:133–139PubMedCrossRefGoogle Scholar
  15. 15.
    Kempf K, Haltern G, Futh R, Herder C, Muller-Scholze S, Gulker H, Martin S (2006) Increased TNF-alpha and decreased TGF-beta expression in peripheral blood leukocytes after acute myocardial infarction. Horm Metab Res 38:346–351PubMedCrossRefGoogle Scholar
  16. 16.
    Morohoshi M, Fujisawa K, Uchimura I, Numano F (1995) The effect of glucose and advanced glycosylation end products on IL-6 production by human monocytes. Ann N Y Acad Sci 748:562–570PubMedCrossRefGoogle Scholar
  17. 17.
    Morohoshi M, Fujisawa K, Uchimura I, Numano F (1996) Glucose-dependent interleukin 6 and tumor necrosis factor production by human peripheral blood monocytes in vitro. Diabetes 45:954–959PubMedCrossRefGoogle Scholar
  18. 18.
    Mohanty P, Hamouda W, Garg R, Aljada A, Ghanim H, Dandona P (2000) Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J Clin Endocrinol Metab 85:2970–2973PubMedCrossRefGoogle Scholar
  19. 19.
    Ceriello A, Assaloni R, Da Ros R, Maier A, Piconi L, Quagliaro L, Esposito K, Giugliano D (2005) Effect of atorvastatin and irbesartan, alone and in combination, on postprandial endothelial dysfunction, oxidative stress, and inflammation in type 2 diabetic patients. Circulation 111:2518–2524PubMedCrossRefGoogle Scholar
  20. 20.
    Gonzalez F, Rote NS, Minium J, Kirwan JP (2006) Reactive oxygen species-induced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome. J Clin Endocrinol Metab 91:336–340PubMedCrossRefGoogle Scholar
  21. 21.
    Aljada A, Friedman J, Ghanim H, Mohanty P, Hofmeyer D, Chaudhuri A, Dandona P (2006) Glucose ingestion induces an increase in intranuclear nuclear factor kappaB, a fall in cellular inhibitor kappaB, and an increase in tumor necrosis factor alpha messenger RNA by mononuclear cells in healthy human subjects. Metabolism 55:1177–1185PubMedCrossRefGoogle Scholar
  22. 22.
    Dhindsa S, Tripathy D, Mohanty P, Ghanim H, Syed T, Aljada A, Dandona P (2004) Differential effects of glucose and alcohol on reactive oxygen species generation and intranuclear nuclear factor-kappaB in mononuclear cells. Metabolism 53:330–334PubMedCrossRefGoogle Scholar
  23. 23.
    Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P (2004) Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation 110:1564–1571PubMedCrossRefGoogle Scholar
  24. 24.
    Kempf K, Rose B, Herder C, Kleophas U, Martin S, Kolb H (2006) Inflammation in metabolic syndrome and type 2 diabetes: impact of dietary glucose. Ann N Y Acad Sci (in press)Google Scholar
  25. 25.
    Esposito K, Nappo F, Giugliano F, Di Palo C, Ciotola M, Barbieri M, Paolisso G, Giugliano D (2003) Meal modulation of circulating interleukin 18 and adiponectin concentrations in healthy subjects and in patients with type 2 diabetes mellitus. Am J Clin Nutr 78:1135–1140PubMedGoogle Scholar
  26. 26.
    van Oostrom AJ, Alipour A, Plokker TW, Sniderman AD, Cabezas MC (2006) The metabolic syndrome in relation to complement component 3 and postprandial lipemia in patients from an outpatient lipid clinic and healthy volunteers. Atherosclerosis (in press)Google Scholar
  27. 27.
    Erdmann J, Topsch R, Lippl F, Gussmann P, Schusdziarra V (2004) Postprandial response of plasma ghrelin levels to various test meals in relation to food intake, plasma insulin, and glucose. J Clin Endocrinol Metab 89:3048–3054PubMedCrossRefGoogle Scholar
  28. 28.
    Deacon CF (2005) What do we know about the secretion and degradation of incretin hormones? Regul Pept 128:117–124PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • K. Kempf
    • 1
    Email author
  • B. Rose
    • 1
  • C. Herder
    • 1
  • B. Haastert
    • 2
  • A. Fusbahn-Laufenburg
    • 3
  • A. Reifferscheid
    • 3
  • W. A. Scherbaum
    • 1
  • H. Kolb
    • 1
  • S. Martin
    • 1
  1. 1.German Diabetes Clinic, German Diabetes CenterLeibniz Institute at Heinrich-Heine-University DüsseldorfDüsseldorfGermany
  2. 2.Institute of Biometrics and Epidemiology, German Diabetes CenterLeibniz Institute at Heinrich-Heine-University DüsseldorfDüsseldorfGermany
  3. 3.Medical Corporate DepartmentHenkel KGaADüsseldorfGermany

Personalised recommendations