Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Eckel RH, Grundy SM, Zimmet PZ (2005) The metabolic syndrome. Lancet 365:1415–1428

    Article  PubMed  CAS  Google Scholar 

  2. Alberti KG, Zimmet P, Shaw J (2005) The metabolic syndrome—a new worldwide definition. Lancet 366:1059–1062

    Article  PubMed  Google Scholar 

  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 111:1448–1454

    Article  PubMed  Google Scholar 

  4. Kolb H, Mandrup-Poulsen T (2005) An immune origin of type 2 diabetes? Diabetologia 48:1038–1050

    Article  PubMed  CAS  Google Scholar 

  5. Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126

    Article  PubMed  CAS  Google Scholar 

  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 11:183–190

    Article  PubMed  CAS  Google Scholar 

  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 11:191–198

    Article  PubMed  CAS  Google Scholar 

  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 112:1796–1808

    Article  PubMed  CAS  Google Scholar 

  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 53:1285–1292

    Article  PubMed  CAS  Google Scholar 

  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 53:701–710

    Article  PubMed  CAS  Google Scholar 

  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 106:2067–2072

    Article  PubMed  CAS  Google Scholar 

  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 39:1145–1150

    Article  PubMed  CAS  Google Scholar 

  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–E772

    Article  PubMed  CAS  Google Scholar 

  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 10:133–139

    Article  PubMed  CAS  Google Scholar 

  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 38:346–351

    Article  PubMed  CAS  Google Scholar 

  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 748:562–570

    Article  PubMed  CAS  Google Scholar 

  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 45:954–959

    Article  PubMed  Google Scholar 

  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 85:2970–2973

    Article  PubMed  CAS  Google Scholar 

  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 111:2518–2524

    Article  PubMed  CAS  Google Scholar 

  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 91:336–340

    Article  PubMed  CAS  Google Scholar 

  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 55:1177–1185

    Article  PubMed  CAS  Google Scholar 

  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 53:330–334

    Article  PubMed  CAS  Google Scholar 

  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 110:1564–1571

    Article  PubMed  CAS  Google Scholar 

  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)

  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 78:1135–1140

    PubMed  CAS  Google Scholar 

  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)

  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 89:3048–3054

    Article  PubMed  CAS  Google Scholar 

  28. Deacon CF (2005) What do we know about the secretion and degradation of incretin hormones? Regul Pept 128:117–124

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. German Diabetes Clinic, German Diabetes Center, Leibniz Institute at Heinrich-Heine-University Düsseldorf, Auf’m Hennekamp 65, 40225, Düsseldorf, Germany

    K. Kempf, B. Rose, C. Herder, W. A. Scherbaum, H. Kolb & S. Martin

  2. Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute at Heinrich-Heine-University Düsseldorf, Auf’m Hennekamp 65, 40225, Düsseldorf, Germany

    B. Haastert

  3. Medical Corporate Department, Henkel KGaA, Düsseldorf, Germany

    A. Fusbahn-Laufenburg & A. Reifferscheid

Authors
  1. K. Kempf
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. Rose
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Herder
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B. Haastert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Fusbahn-Laufenburg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Reifferscheid
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W. A. Scherbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H. Kolb
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K. Kempf.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kempf, K., Rose, B., Herder, C. et al. The metabolic syndrome sensitizes leukocytes for glucose-induced immune gene expression. J Mol Med 85, 389–396 (2007). https://doi.org/10.1007/s00109-006-0132-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-006-0132-7

Keywords

Search

Navigation