Cavanagh PR, Lipsky BA, Bradbury AW, et al: Treatment for diabetic foot ulcers. Lancet 366: 1725, 2005.
Morgan CL, Currie CJ, Stott NC, et al: The prevalence of multiple diabetes-related complications. Diabet Med 17: 146, 2000.
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.
Stockl K, Vanderplas A, Tafesse E, et al: Costs of lower-extremity ulcers among patients with diabetes. Diabetes Care 27: 2129 2004.
Navarro-González JF, Mora-Fernández C: The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol 19: 433, 2008.
Kolb H, Mandrup-Poulsen T: An immune origin of type 2 diabetes? Diabetologia 48: 1038, 2005.
Weigelt C, Rose B, Poschen U, et al: Immune mediators in patients with acute diabetic foot syndrome. Diabetes Care 32: 1491, 2009.
Reddy P: Interleukin-18: recent advances. Curr Opin Hematol 11: 405, 2004.
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.
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.
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.
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.
Lobmann R, Schultz G, Lehnert H: Proteases and the diabetic foot syndrome: mechanisms and therapeutic implications. Diabetes Care 28: 461, 2005.
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.
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.
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.
Esposito K, Nappo F, Giugliano F, et al: Cytokine milieu tends toward inflammation in type 2 diabetes. Diabetes Care 26: 1647, 2003.
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.
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.
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.
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.
Karthikesalingam A, Holt PJ, Moxey P, et al: A systematic review of scoring systems for diabetic foot ulcers. Diabet Med 27: 544, 2010.
Mast BA, Schultz GS: Interactions of cytokines, growth factors, and proteases in acute and chronic wounds. Wound Repair Regen 4: 411, 1996.
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.
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.
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.
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.
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.
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.
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.
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.
Upchurch GR Jr, Keagy BA, Johnson G Jr: An acute phase reaction in diabetic patients with foot ulcers. Cardiovasc Surg 5: 32, 1997.
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.
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.
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.
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.
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.
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.