The major clinical consequence of type 2 diabetes is mortality and morbidity from atherosclerotic vascular disease. With regards to the risk factors responsible for the evolution of atherosclerosis, Bierman (1) estimated that typical risk factors, including smoking, cholesterol, and blood pressure, can account for no more than 30% of excess cardiovascular risk factors in diabetic patients. Thus, other factors seem to play a key role in the progression of atherosclerosis in diabetes.

One potential factor is homocysteine. Homocysteine has been shown to contribute to the development of atherosclerosis in diabetic patients (2). Whereas the deficiencies of folate and vitamin B12 lead to hyperhomocysteinemia, these deficiencies alone do not completely account for atherosclerotic changes induced by homocysteine in diabetic patients.

Tumor necrosis factor (TNF) is a potent candidate involved in the pathogenesis of atherosclerosis. Rauchhaus et al. (3) demonstrated that elevated soluble TNF receptor 1 (sTNF-R1) has shown to be predictive of cardiovascular mortality in patients with chronic heart failure. We found that sTNF-R1 is independently associated with albuminuria in type 2 diabetic patients (4). To the best of our knowledge, however, it is not clear whether serum homocysteine is associated with TNF receptor in type 2 diabetic patients. The aim of the present study was therefore to investigate the relationships between serum homocysteine and TNF receptor in patients with type 2 diabetes.

Fifty nonobese Japanese type 2 diabetic patients were studied. Their BMI, HbA1c, and serum creatinine were 22.6 ± 0.3 kg/m2 (range 17.6–26.2), 7.8 ± 0.2% (5.5–12.3), and 0.70 ± 0.02 mg/dl (0.46–0.98), respectively. They had not been treated with insulin or any medications known to alter homocysteine level. In conjunction with homocysteine, systolic and diastolic blood pressure, HbA1c, glucose, lipids, serum creatinine, TNF-α, sTNF-R1, and sTNF-R2 were measured after an overnight fast.

With univariate analysis, serum homocysteine was positively correlated with age (r = 0.361, P = 0.012), diabetes duration (r = 0.292, P = 0.045), serum creatinine (r = 0.623, P < 0.001), sTNF-R1 (r = 0.415, P < 0.005), and sTNF-R2 (r = 0.371, P < 0.01). Other variables including TNF-α, however, were not associated with homocysteine. Multiple regression analyses showed that serum homocysteine was independently associated with serum creatinine (F = 20.1) and sTNF-R1 (F = 6.9), which explained 49.3% of the variability of homocysteine. Thus, TNF system activity may be responsible for the evolution of atherosclerosis induced by homocysteine in nonobese Japanese type 2 diabetic patients.

Bierman EL: George Lyman Duff Memorial Lecture: Atherogenesis in diabetes.
Arterioscler Thromb
Refsum H, Ueland M: Homocysteine and cardiovascular disease.
Annu Rev Med
Rauchhaus M, Doehner W, Francis DP, Davos C, Kemp M, Liebenthal C, Niebauer J, Hooper J, Volk HD, Coats AJS, Anker SD: Plasma cytokine parameters and mortality in patients with chronic heart failure.
Kawasaki Y, Taniguchi A, Fukuhishima M, Nakai Y, Kuroe A, Ohya M, Nagasaka S, Yamada Y, Inagaki N, Seino Y: Soluble TNF receptors and albuminuria in non-obese Japanese type 2 diabetic patients.
Horm Metab Res