• 1.

    Cavanagh PR, Lipsky BA, Bradbury AW, et al: Treatment for diabetic foot ulcers. Lancet 366: 1725, 2005.

  • 2.

    Morgan CL, Currie CJ, Stott NC, et al: The prevalence of multiple diabetes-related complications. Diabet Med 17: 146, 2000.

  • 3.

    Ribu L, Hanestad BR, Moum T, et al: A comparison of the health-related quality of life in patients with diabetic foot ulcers, with a diabetes group and a nondiabetes group from the general population. Qual Life Res 16: 179, 2007.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Stockl K, Vanderplas A, Tafesse E, et al: Costs of lower-extremity ulcers among patients with diabetes. Diabetes Care 27: 2129 2004.

  • 5.

    Navarro-González JF, Mora-Fernández C: The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol 19: 433, 2008.

  • 6.

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

  • 7.

    Weigelt C, Rose B, Poschen U, et al: Immune mediators in patients with acute diabetic foot syndrome. Diabetes Care 32: 1491, 2009.

  • 8.

    Reddy P: Interleukin-18: recent advances. Curr Opin Hematol 11: 405, 2004.

  • 9.

    Blankenberg S, Tiret L, Bickel C, et al: Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation 106: 24, 2002.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Oncul O, Yildiz S, Gurer US, et al: Effect of the function of polymorphonuclear leukocytes and interleukin-1 beta on wound healing in patients with diabetic foot infections. J Infect 54: 250, 2007.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Galkowska H, Wojewodzka U, Olszewski WL: Low recruitment of immune cells with increased expression of endothelial adhesion molecules in margins of the chronic diabetic foot ulcers. Wound Repair Regen 13: 248, 2005.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Galkowska H, Wojewodzka U, Olszewski WL: Chemokines, cytokines, and growth factors in keratinocytes and dermal endothelial cells in the margin of chronic diabetic foot ulcers. Wound Repair Regen 14: 558, 2006.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Lobmann R, Schultz G, Lehnert H: Proteases and the diabetic foot syndrome: mechanisms and therapeutic implications. Diabetes Care 28: 461, 2005.

  • 14.

    Lobmann R, Zemlin C, Motzkau M, et al: Expression of matrix metalloproteinases and growth factors in diabetic foot wounds treated with a protease absorbent dressing. J Diabetes Complications 20: 329, 2006.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Mi Q, Rivière B, Clermont G, et al: Agent-based model of inflammation and wound healing: insights into diabetic foot ulcer pathology and the role of transforming growth factor-beta1. Wound Repair Regen 15: 671, 2007.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Levey AS, Bosch JP, Lewis JB, et al: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130: 461, 1999.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Esposito K, Nappo F, Giugliano F, et al: Cytokine milieu tends toward inflammation in type 2 diabetes. Diabetes Care 26: 1647, 2003.

  • 18.

    Aso Y, Okumura K, Takebayashi K, et al: Relationships of plasma interleukin-18 concentrations to hyperhomocysteinemia and carotid intimal-media wall thickness in patients with type 2 diabetes. Diabetes Care 26: 2622, 2003.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Esposito K, Nappo F, Giugliano F, et al: 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, 2003.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Fischer CP, Perstrup LB, Berntsen A, et al: Elevated plasma interleukin-18 is a marker of insulin-resistance in type 2 diabetic and non-diabetic humans. Clin Immunol 117: 152, 2005.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Thorand B, Kolb H, Baumert J, et al: Elevated levels of interleukin-18 predict the development of type 2 diabetes: results from the MONICA/KORA Augsburg Study, 1984–2002. Diabetes 54: 2932, 2005.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Karthikesalingam A, Holt PJ, Moxey P, et al: A systematic review of scoring systems for diabetic foot ulcers. Diabet Med 27: 544, 2010.

  • 23.

    Mast BA, Schultz GS: Interactions of cytokines, growth factors, and proteases in acute and chronic wounds. Wound Repair Regen 4: 411, 1996.

  • 24.

    Kämpfer H, Kalina U, Mühl H, et al: Counterregulation of interleukin-18 mRNA and protein expression during cutaneous wound repair in mice. J Invest Dermatol 113: 369, 1999.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Kämpfer H, Paulukat J, Mühl H, et al: Lack of interferon-gamma production despite the presence of interleukin-18 during cutaneous wound healing. Mol Med 6: 1016, 2000.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Fujita T, Ogihara N, Kamura Y, et al. Interleukin-18 contributes more closely to the progression of diabetic nephropathy than other diabetic complications. Acta Diabetol 49: 111, 2012.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Araki S, Haneda M, Koya D, et al: Predictive impact of elevated serum level of IL-18 for early renal dysfunction in type 2 diabetes: an observational follow-up study. Diabetologia 50: 867, 2007.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Nakamura A, Shikata K, Hiramatsu M, et al: Serum interleukin-18 levels are associated with nephropathy and atherosclerosis in Japanese patients with type 2 diabetes. Diabetes Care 28: 2890, 2005.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Suchanek H, Myśliwska J, Siebert J, et al: High serum interleukin-18 concentrations in patients with coronary artery disease and type 2 diabetes mellitus. Eur Cytokine Netw 16: 177, 2005.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Zaki Mel- S, Elgendy MY, El-Mashad NB, et al: IL-18 level correlates with development of sepsis in surgical patients. Immunol Invest 36: 403, 2007.

  • 31.

    Nassif A, Moslehi H, Le Gouvello S, et al: Evaluation of the potential role of cytokines in toxic epidermal necrolysis. J Invest Dermatol 123: 850, 2004.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Upchurch GR Jr, Keagy BA, Johnson G Jr: An acute phase reaction in diabetic patients with foot ulcers. Cardiovasc Surg 5: 32, 1997.

  • 33.

    Altinova AE, Yetkin I, Akbay E, et al: Serum IL-18 levels in patients with type 1 diabetes: relations to metabolic control and microvascular complications. Cytokine 42: 217, 2008.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Kawasaki D, Tsujino T, Morimoto S, et al: Plasma interleukin-18 concentration: a novel marker of myocardial ischemia rather than necrosis in humans. Coron Artery Dis 16: 437, 2005.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

High Serum Concentration of Interleukin-18 in Diabetic Patients with Foot Ulcers

Tevfik Sabuncu Department of Endocrinology, Harran University Faculty of Medicine, Sanliurfa, Turkey.

Search for other papers by Tevfik Sabuncu in
Current site
Google Scholar
PubMed
Close
 MD
,
Mehmet Ali Eren Department of Endocrinology, Harran University Faculty of Medicine, Sanliurfa, Turkey.

Search for other papers by Mehmet Ali Eren in
Current site
Google Scholar
PubMed
Close
 MD
,
Suzan Tabur Department of Endocrinology, Harran University Faculty of Medicine, Sanliurfa, Turkey.

Search for other papers by Suzan Tabur in
Current site
Google Scholar
PubMed
Close
 MD
,
Omer Faruk Dag Department of Internal Medicine, Harran University Faculty of Medicine, Sanliurfa, Turkey.

Search for other papers by Omer Faruk Dag in
Current site
Google Scholar
PubMed
Close
 MD
, and
Omer Boduroglu Department of Internal Medicine, Harran University Faculty of Medicine, Sanliurfa, Turkey.

Search for other papers by Omer Boduroglu in
Current site
Google Scholar
PubMed
Close
 MD

Background

It is well known that interleukin-18 (IL-18) plays a key role in the inflammatory process. However, there are limited data on the role IL-18 plays with diabetic foot ulcers, an acute and complex inflammatory situation. Therefore, we aimed to evaluate serum IL-18 levels of diabetic patients with foot ulcers.

Methods

Twenty diabetic patients with acute foot ulcers, 21 diabetic patients without a history of foot ulcers, and 21 healthy volunteers were enrolled in our study. Circulating levels of IL-18, and other biochemical markers are parameters of inflammation and were measured in all three groups.

Results

Diabetic patients both with and without foot ulcers had high IL-18 concentrations (P < 0.001 and P = 0.020, respectively) when compared with the nondiabetic volunteers. Those with foot ulcers had higher levels of IL-18 level (P < 0.001), high-sensitivity C-reactive protein (hsCRP) (P = 0.001), and erythrocyte sedimentation rate (ESR) (P < 0.001) than those without foot ulcers.

Conclusions

We found that serum IL-18 concentrations were elevated in diabetic patients with acute diabetic foot ulcers. However, these findings do not indicate whether the IL-18 elevation is a cause or a result of the diabetic foot ulceration. Further studies are needed to show the role of IL-18 in the course of these ulcers.

Corresponding author: Mehmet Ali Eren, MD, Department of Endocrinology, Harran University Faculty of Medicine, Yenisehir Campus, Sanliurfa, Turkey, 63300. (E-mail: drmalieren@hotmail.com)
Save