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Abstract. Passaro A, Calzoni F, Volpato S, Dalla Nora E, Pareschi PL, Zamboni PF, Fellin R, Solini A (University of Ferrara; Diabetes Division Arcispedale S. Anna, Ferrara; and University of Pisa, Italy). Effect of metabolic control on homocysteine levels in type 2 diabetic patients: a 3-year follow-up. J Intern Med 2003; 254: 264–271. Objectives. Hyperhomocysteinaemia has emerged as a novel risk factor for cardiovascular disease. The determinants of total homocysteine (tHcy) levels in type 2 diabetic patients (D2p) have not been studied in detail. We examined prospectively the effect of different degrees of metabolic control on plasma tHcy in D2p with preserved kidney function. Subjects and main outcome measurements. Ninety-five D2p were studied. Clinical parameters, fasting plasma glucose, HbA[sub 1c] , serum lipids, blood urea nitrogen (BUN) and creatinine, vitamin B[sub 12] and folate and tHcy were measured at the baseline and after 36 months. The methylentetrahydrofolate reductase (MTHFR) C677T polymorphism was also determined. Subjects were categorized according to δHbA[sub 1c] into group A (±1 point), B (>1 point increase) or C (>1 point decrease). Results. Total homocysteine was reduced in subjects whose HbA[sub 1c] decreased with time, whilst patients showing a worsened metabolic control had an increased tHcy in respect to baseline. A larger response to the improved metabolic control in terms of tHcy reduction was noted in wild type patients versus those homozygous for the mutation. A multivariate analysis revealed MTHFR polymorphism and HbA[sub 1c] as strong determinants of changes in tHcy with time. Conclusions. The findings suggest that in D2p tHcy decreases even with modest improvement of glycaemic control; moreover patients homozygous for the MTHFR C677T mutation show the largest changes in tHcy levels with concomitant changing of HbA[sub 1c] . These results define a further mechanism through which hyperglycaemia might promote cardiovascular damage in diabetic patients. [ABSTRACT FROM AUTHOR]