High plasma homocysteine concentrations are associated with plasma concentrations of thrombomodulin in patients with type 2 diabetes and link diabetic nephropathy to macroangiopathy

In type 2 diabetic patients with or without nephropathy, we examined relationships between plasma concentrations of total homocysteine (tHcy) and clinical macroangiopathy, as well as endothelial dysfunction indicated by plasma thrombomodulin (TM) concentrations. We studied 103 type 2 diabetic patients including 26 with macroangiopathy (12 patients with coronary artery disease [CAD], 10 with stroke, and 4 with peripheral vascular disease [PVD]). Plasma tHcy was measured by high-performance liquid chromatography. Plasma TM was determined by enzyme immunoassay. As an index of glomerular filtration rate, creatinine clearance (Ccr) also was determined in a 24-hour urine collection. Considering all diabetic patients, plasma tHcy concentrations were significantly higher in those with macroangiopathy than in those without (10.4 +/- 3.7 v 8.5 +/- 2.8 mumol/L, P = .0077). By univariate and multivariate analyses, plasma tHcy was correlated inversely with Ccr. Plasma tHcy concentrations were significantly higher in the patients with overt albuminuria than in those with normoalbuminuria or microalbuminuria, After exclusion of patients with renal insufficiency (Ccr < 60 mL/min), differences in plasma tHcy concentrations between patients with and without macroangiopathy were abolished. By multivariate analysis, total cholesterol, urinary albumin, Ccr, C-peptide, and tHcy retained significant influence on the plasma TM. Even in patients with normal renal function (Ccr greater than or equal to 80 mL/min), plasma tHcy was correlated positively with plasma TM. In conclusions, diabetic nephropathy is a main determinant of plasma tHcy elevation in type 2 diabetic patients. Since plasma TM is independently associated with plasma tHcy, in diabetic patients with overt nephropathy, elevation of tHcy reflecting reduced clearance is a likely cause of endothelial dysfunction, resulting in the atherosclerosis underlying development of cardiovascular disease. (C) 2003 Elsevier Inc. All rights reserved.