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OBJECTIVE -We compared plasma interleukin (IL)-18 concentrations in patients with type 2 diabetes with those in age-matched control subjects and investigated whether plasma IL-18 was associated with plasma total homocysteine (tHcy) concentration or carotid intimalmedia wall thickness (IMT), an early marker of atherosclerosis, in these patients.RESEARCH DESIGN AND METHODS -We measured plasma IL-18 in 103 type 2 diabetic patients and 45 age-matched control subjects. We also measured patients' plasma tHcy and serum high-sensitivity C-reactive protein (hs-CRP). IMT was evaluated for both common carotid arteries.RESULTS -Plasma IL-18 was significantly higher in diabetic patients than in control subjects (203 Ϯ 153 vs. 118 Ϯ 37 pg/ml, P Ͻ 0.001). High IL-18 was defined as equaling or exceeding the mean ϩ 2 SD of plasma IL-18 in control subjects (192 pg/ml). Patients with high IL-18 showed a greater carotid IMT than those with normal IL-18. Carotid plaques were more numerous in diabetic patients with high IL-18 than in those with normal IL-18. Plasma tHcy concentrations were significantly higher in patients with high IL-18 than in those with normal IL-18. Univariate and multivariate analyses showed a strong independent association between tHcy and IL-18. Plasma IL-18 also correlated positively with serum hs-CRP.CONCLUSIONS -In patients with type 2 diabetes, plasma IL-18 concentrations are greater than in nondiabetic subjects. Plasma IL-18 is an independent determinant of plasma tHcy, which is linked independently with atherosclerotic carotid wall thickening. Diabetes Care 26:2622-2627, 2003P atients with type 2 diabetes have a high incidence of atherosclerosis, which leads to increased morbidity and mortality from coronary artery disease (CAD), cerebrovascular disease, and peripheral vascular disease (PVD) (1-3). Atherosclerosis is a chronic low-grade inflammatory disease (4 -6). Plasma concentrations of several inflammatory markers such as C-reactive protein (CRP) and interleukin (IL)-6 have been linked with future cardiovascular disease (CVD) in a variety of clinical settings (7,8). IL-18 stimulates release of interferon-␥, shows potent activities on inflammatory and vascular cells, and is considered a proinflammatory cytokine (9). Recently, increased expression of IL-18 has been reported in carotid ulcerated atherosclerotic plaques (10), suggesting that IL-18 also plays a role in plaque destabilization. A recent study (11) identified high serum IL-18 concentrations as a strong predictor of death from cardiovascular causes in patients with CAD.Hyperhomocysteinemia has been associated with atherothrombotic vascular diseases such as CAD, stroke, and PVD (12-14). A previous study (15) demonstrated that moderate hyperhomocysteinemia is a stronger risk factor for CVD in patients with type 2 diabetes than in nondiabetic subjects, suggesting a synergistic effect of diabetes with hyperhomocysteinemia that accelerates the development of atherosclerosis. Although homocysteine can exert vascular toxicity via several mechanis...

Pregnancy-associated plasma protein (PAPP)-A, a superfamily of metalloproteinase, has been implicated in acute coronary syndrome. We compared PAPP-A concentrations in sera from patients with type 2 diabetes with those in sera from age-matched control subjects and also investigated whether serum PAPP-A was associated with carotid intima-media wall thickness (IMT), an early marker of atherosclerosis, and indices of peripheral vascular disease in the diabetic patients. Serum PAPP-A was measured by an ELISA in 103 type 2 diabetic patients and 32 age-matched control subjects. All subjects were not pregnant. IMT was evaluated ultrasonographically in both common carotid arteries. As measures of peripheral vascular disease, we also determined the ankle-brachial index and toe-brachial index (TBI) for systolic blood pressure. Hypercholesterolemia was defined as a serum low-density lipoprotein-cholesterol concentration exceeding 3.6 mmol/liter or alternatively as a treatment with hydroxymethylglutaryl coenzyme A reductase inhibitor. Serum PAPP-A was significantly higher in diabetic patients than control subjects (P < 0.0001). In diabetic patients, serum PAPP-A correlated positively with serum total cholesterol (r = 0.289, P = 0.0041) and IMT (r = 0.315, P = 0.0017) and negatively with TBI (r = -0.294, P = 0.0039) but not ankle-brachial index. Diabetic patients with hypercholesterolemia had higher PAPP-A concentrations than those without hypercholesterolemia [median (interquartile ranges): 8.37 (6.93, 11.6) vs. 7.29 (5.65, 9.21) mIU/liter; P = 0.0209]. Multivariate analysis identified only serum total cholesterol as an independent determinant of serum PAPP-A in patients with type 2 diabetes (partial coefficient 0.454, P = 0.020). In conclusion, serum PAPP-A concentrations were significantly elevated in diabetic patients with hypercholesterolemia and were associated positively with carotid atherosclerosis and negatively with TBI in type 2 diabetes.