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Serum Interleukin-18 Levels Are Associated With Nephropathy and Atherosclerosis in Japanese Patients With Type 2 Diabetes

¹ Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
² Department of Internal Medicine, Okayama Saiseikai General Hospital, Okayama, Japan

Address correspondence and reprint requests to Kenichi Shikata, MD, Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama 700-8558, Japan. E-mail: shikata{at}md.okayama-u.ac.jp

OBJECTIVE—Interleukin (IL)-18 is a proinflammatory cytokine secreted from mononuclear cells. Serum concentration of IL-18 is a strong predictor of death in patients with cardiovascular diseases. Recent studies have shown that microinflammation is involved in the pathogenesis of diabetic nephropathy as well as of cardiovascular diseases. This study aimed to test the hypothesis that the serum level of IL-18 is a common predictor of nephropathy and atherosclerosis in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS—Eighty-two Japanese patients with type 2 diabetes and 55 age- and sex-matched healthy control subjects were enrolled. Patients with renal dysfunction (creatinine clearance <1 ml/s) were excluded. We assessed clinical parameters and measured serum and urinary IL-18 levels, serum IL-6 levels, carotid intima-media thickness (IMT), and brachial-ankle pulse wave velocity (baPWV) in all patients. Further, we evaluated changes of urinary albumin excretion rate (AER) after 6 months in 76 diabetic patients.

RESULTS—Serum and urinary IL-18 levels were significantly elevated in patients with type 2 diabetes as compared with control subjects (serum IL-18 179 ± 62 vs. 121 ± 55 pg/ml, P < 0.001; urinary IL-18 97 ± 159 vs. 47 ± 54 pg/ml, P = 0.035). Univariate linear regression analysis showed significant positive correlations between serum IL-18 and AER (r [correlation coefficient] = 0.525, P < 0.001), HbA_1c (r = 0.242, P = 0.029), high-sensitivity C-reactive protein (hs-CRP) (r = 0.240, P = 0.031), and urinary ß-2 microglobulin (r = 0.235, P = 0.036). Serum IL-18 levels also correlated positively with carotid IMT (r = 0.225, P = 0.042) and baPWV (r = 0.232, P = 0.040). We also found a significant correlation between urinary IL-18 and AER (r = 0.309, P = 0.005). Multivariate linear regression analysis showed that AER (standard correlation coefficients [B] = 0.405, P < 0.001) and hs-CRP (B = 0.207, P = 0.033) were independently associated with serum IL-18 levels. AER was also independently associated with urinary IL-18 levels (B = 0.295, P = 0.005). Moreover, serum and urinary IL-18 levels correlated positively with AER after 6 months (r = 0.489, P < 0.001 and r = 0.320, P = 0.005) and changes in AER during the follow-up period (r = 0.268, P = 0.018 and r = 0.234, P = 0.042).

CONCLUSIONS—Serum levels of IL-18 might be a predictor of progression of diabetic nephropathy as well as cardiovascular diseases.

Abbreviations: ACEI, ACE inhibitor • AER, albumin excretion rate • ARB, angiotensin II type 1 receptor blocker • baPWV, brachial-ankle pulse wave velocity • DBP, diastolic blood pressure • hs-CRP, high-sensitivity C-reactive protein • ICAM, intercellular adhesion molecule • IL, interleukin • IMT, intima-media thickness • SBP, systolic blood pressure • TNF, tumor necrosis factor

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