Relationships of Plasma Interleukin-18 Concentrations to Hyperhomocysteinemia and Carotid Intimal-Media Wall Thickness in Patients With Type 2 Diabetes

Aso, Yoshimasa; Okumura, Ki-ichi; Takebayashi, Kohzo; Wakabayashi, Shigeo; Iwamoto, Toshihiko

doi:10.2337/diacare.26.9.2622

Cited by 112 publications

(85 citation statements)

References 38 publications

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“…6 Increased IL-18 levels were found in obesity, 7 polycystic ovary syndrome, 8 metabolic syndrome 9 and type 2 diabetes. [10][11][12] Elevated IL-18 concentration was also found to be an independent predictor of the development of type 2 diabetes. 13 In line with the above findings, recent studies provided an evidence that IL-18 is directly associated with insulin resistance.…”

Section: Introductionmentioning

confidence: 98%

Increased serum interleukin-18 concentration is associated with hypoadiponectinemia in obesity, independently of insulin resistance

et al. 2006

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Objective: Interleukin-18 (IL-18) is a cytokine with proinflammatory and proatherogenic properties, which might be associated with the development of insulin resistance. In contrast, adiponectin, a protein secreted by adipose tissue, might exert insulinsensitizing and antiatherogenic effects. The aim of the present study was to analyze the association between serum IL-18 and adiponectin in lean and obese subjects, in relation to insulin resistance. Design: Cross-sectional study. Subjects: One hundred and thirty individuals, 62 lean (body mass index (BMI)o25 kg/m 2 , 30 men and 32 women) and 68 with overweight or obesity (BMI425 kg/m 2 , 24 men and 44 women), with normal glucose tolerance and without concomitant diseases. Measurements: Oral glucose tolerance test, euglycemic hyperinsulinemic clamp, serum concentrations of IL-18, IL-6, soluble tumor necrosis factor-a receptors and adiponectin. Results: Obese subjects had lower insulin sensitivity (M value, P ¼ 0.00029) and serum adiponectin (P ¼ 0.01) and higher levels of serum IL-18 (P ¼ 0.00055). Circulating IL-18 was negatively related to adiponectin (r ¼ À0.31, P ¼ 0.00027) and insulin sensitivity (r ¼ À0.33, P ¼ 0.00012). Subgroup analysis revealed that these associations were present in the obese (adiponectin, r ¼ À0.38, P ¼ 0.0014; M, r ¼ À0.29, P ¼ 0.016), but not in lean individuals (r ¼ À0.17, P ¼ 0.18 and r ¼ À0.20, P ¼ 0.12, respectively). Association of IL-18 with adiponectin remained significant after adjustment for other estimated parameters, including insulin sensitivity. Also, relationship between IL-18 and insulin sensitivity was independent of other estimated parameters. Conclusion: Serum IL-18 is inversely related to serum adiponectin, independently of insulin resistance. The relationships of IL-18 with adiponectin and insulin sensitivity are influenced by the presence of overweight/obesity.

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Section: Introductionmentioning

confidence: 98%

Increased serum interleukin-18 concentration is associated with hypoadiponectinemia in obesity, independently of insulin resistance

et al. 2006

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“…Elevated IL-18 levels are found to be associated with increased adiposity and insulin resistance in obese premenopausal women (18,19). IL-18 concentrations are increased in acute hyperglycemia (20) and type 2 diabetes (21,22). Moreover, IL-18 may influence vascular remodeling (23,24).…”

Section: Introductionmentioning

confidence: 99%

Felodipine Reduces Cardiac Expression of IL-18 and Perivascular Fibrosis in Fructose-Fed Rats

Shen

Tan

et al. 2008

Mol Med

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Metabolic syndrome is associated with accelerated macrovascular and microvascular coronary disease, cardiomyopathy, and elevated inflammatory status. To determine whether metabolic syndrome-associated elevation of the inflammatory cytokine interleukin-18 (IL-18) in serum and cardiac tissue, and its potential sequelae could be attenuated pharmacologically, we studied fructose-fed rats. The fructose-fed rats exhibited increases in systolic blood pressure (SBP), body weight, heart weight, left ventricular weight, and blood insulin. Serum IL-18 levels in these rats were also elevated significantly. These changes were significantly different compared to those in control rats. Perivascular fibrosis around coronary arterioles was evident in the fructose-fed rats, accompanied by a paralleled increase in IL-18 by immunohistochemical analysis and real time polymerase chain reaction. Felodipine attenuated the increased levels in serum IL-18 and cardiac IL-18 mRNA as well as coronary perivascular fibrosis. Thus, augmented IL-18 in serum and cardiac tissue in metabolic syndrome may contribute to the coronary perivascular fibrosis; felodipine administration can attenuate the inflammatory and fibrosis process.

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“…In the present study, we also found that serum IL-18 levels were positively correlated with carotid IMT and baPWV in patients with type 2 diabetes. Several studies have reported that carotid IMT (11,12) and baPWV (31) are useful markers for evaluation of atherosclerosis in type 2 diabetes. A clinical study reported that decrease in glomerular filtration rate is linked to atherosclerosis (32).…”

Section: Il-18 Is a Predictor Of Diabetic Nephropathymentioning

confidence: 99%

“…Recently, serum IL-18 levels have been reported elevated in patients with diabetic nephropathy (19). IL-18 is known to lead to production of other proinflammatory cytokines (20), endothelial apoptosis (21), upregulation of ICAM-1 (22), and hyperhomocysteinemia (12). Thus, IL-18 might be an important factor not only in the process of atherosclerosis but also in the development and progression of diabetic nephropathy.…”

mentioning

confidence: 99%

“…A major mechanism of cardiovascular events mediated by IL-18 is decreased stability of plaque. Carotid intima-media thickness (IMT) measured by carotid ultrasound is a useful tool for assessing cardiovascular diseases in diabetes (11), and a clinical study demonstrated that carotid IMT in patients with high IL-18 shows a greater thickness than in patients with normal IL-18 (12).…”

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confidence: 99%

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

et al. 2005

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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 Ͻ1 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 Ϯ 62 vs. 121 Ϯ 55 pg/ml, P Ͻ 0.001; urinary IL-18 97 Ϯ 159 vs. 47 Ϯ 54 pg/ml, P ϭ 0.035). Univariate linear regression analysis showed significant positive correlations between serum IL-18 and AER (r [correlation coefficient] ϭ 0.525, P Ͻ 0.001), HbA 1c (r ϭ 0.242, P ϭ 0.029), high-sensitivity C-reactive protein (hs-CRP) (r ϭ 0.240, P ϭ 0.031), and urinary ␤-2 microglobulin (r ϭ 0.235, P ϭ 0.036). Serum IL-18 levels also correlated positively with carotid IMT (r ϭ 0.225, P ϭ 0.042) and baPWV (r ϭ 0.232, P ϭ 0.040). We also found a significant correlation between urinary IL-18 and AER (r ϭ 0.309, P ϭ 0.005). Multivariate linear regression analysis showed that AER (standard correlation coefficients [B] ϭ 0.405, P Ͻ 0.001) and hs-CRP (B ϭ 0.207, P ϭ 0.033) were independently associated with serum IL-18 levels. AER was also independently associated with urinary IL-18 levels (B ϭ 0.295, P ϭ 0.005). Moreover, serum and urinary IL-18 levels correlated positively with AER after 6 months (r ϭ 0.489, P Ͻ 0.001 and r ϭ 0.320, P ϭ 0.005) and changes in AER during the follow-up period (r ϭ 0.268, P ϭ 0.018 and r ϭ 0.234, P ϭ 0.042).CONCLUSIONS -Serum levels of IL-18 might be a predictor of progression of diabetic nephropathy as well as cardiovascular diseases. Diabetes Care 28:2890 -2895, 2005L ow-grade inflammation (microinflammation) occurs in diabetic patients as well as those with cardiovascular diseases (1,2). Several reports indicate that high-sensitivity C-reactive protein (hs-CRP) (3) and proinflammatory cytokines such as interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-␣, and IL-18 are elevated in patients with type 2 diabetes (4 -7). The mechanisms for elevation of serum IL-18 levels in type 2 diabetes remain unclear, although oxidative stress is a candidate (8). Activation of nuclear factor-B through oxidative stress induced by hyperglycemia increas...

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Relationships of Plasma Interleukin-18 Concentrations to Hyperhomocysteinemia and Carotid Intimal-Media Wall Thickness in Patients With Type 2 Diabetes

Cited by 112 publications

References 38 publications

Increased serum interleukin-18 concentration is associated with hypoadiponectinemia in obesity, independently of insulin resistance

Increased serum interleukin-18 concentration is associated with hypoadiponectinemia in obesity, independently of insulin resistance

Felodipine Reduces Cardiac Expression of IL-18 and Perivascular Fibrosis in Fructose-Fed Rats

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

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