Elevated homocysteine is widely regarded as an independent risk factor for macrovascular disease, particularly in patients with type 2 diabetes (1). The increased prevalence of macroangiopathy in type 2 diabetes is further demonstrated by Buysschaert et al. (2). The authors found a significant increase in the prevalence of macroangiopathy in type 2 diabetic patients with hyperhomocysteinemia. Their data, however, should not be overinterpreted because the etiological role of homocysteine in atherosclerosis in the presence of macroangiopathy is far from clear (3).

First, the metabolism of homocysteine is altered for a period of several days following acute ischemic events, such as myocardial infarction (4) and stroke (5), as a result of an increased release from damaged tissues. This is caused by methylation of DNA, RNA, and various proteins, leading to an increase in S-adenosylhomocysteine and subsequently to increased homocysteine production (3). Furthermore, nephropathy may reduce homocysteine clearance in type 2 diabetic patients. To our knowledge, there are no published studies examining the time course of homocysteine concentrations following acute ischemia, which may be silent. Hence, assessing homocysteine levels in patients with preexistent macroangiopathy may produce misleading results. This may in part account for the conflicting results regarding the association of homocysteine levels with insulin resistance that have been reported in various studies (6).

Second, in their study, Buysschaert et al. (2) have rightly taken into account the prevalence of potential confounders of plasma homocysteine concentrations, namely fibrate and metformin therapy (2,7). However, the authors failed to comment on the use of hormone replacement therapy (HRT) in their cohort of patients (mean age 63 ± 10 years), the majority of whom were women (82 of 122). Combined estrogen-progesterone HRT has been shown to lower homocysteine concentrations in postmenopausal women (8,9), with the greatest benefit being seen in women with high levels of homocysteine (8). Estrogens may lower homocysteine through several mechanisms that include changes in the transamination pathway of methionine catabolism (10) and an increased activity of renal methionine synthase (11), the enzyme responsible for the remethylation of homocysteine to methionine. Additionally, estrogens may increase LDL-receptor expression, which facilitates LDL binding to homocysteine and its subsequent clearance (12). While the debate goes on regarding the potential cardiovascular benefit of HRT in general use, its selective use in subjects with high homocysteine concentrations may be justified. It would therefore be important for Buysschaert et al. to clarify the distribution of homocysteine and folate concentrations in relation to the prevalence of HRT usage in their study.

In summary, there is little doubt that homocysteine is implicated in the pathogenesis of diabetic macroangiopathy. The correlation of its level would be most valuable in primary prevention studies because its concentration in patients with macroangiopathy is difficult to interpret.

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Hoogeveen EK, Kostense PJ, Beks PJ, MacKaay AJC, Jakobs C, Bouter LM, Heine RJ, Stehouwer CDA: Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus: a population-based study.
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Dudman NPB: An alternative view of homocysteine.
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Egerton W, Silberberg JS, Crooks R, Ray C, Xie L, Dudman NPB: Plasma levels of homocysteine during acute phase response.
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Lindgren A, Brattstrom LE, Norrving B, Hultberg B, Anderson A, Johansson BB: Plasma homocysteine in the acute and convalescent phase after stroke.
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Chan NN: Homocysteine and insulin levels in type 2 diabetic patients (Letter).
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Chan N, Chan JCN: Implication of fibrate therapy for homocysteine.
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Van Baal WM, Smolders RGV, Van der Mooren MJ, Teerlink T, Kenemans P: Hormone replacement and plasma homocysteine levels.
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Walsh BW, Paul S, Wild RA, Dean RA, Tracy RP, Cox DA, Anderson PW: The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenpausal women: a randomized, controlled trial.
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Blom HJ, Boers GHJ, Elzen JPAM, van Roessel JJM, Trijbels JMF, Tangerman A: Difference between premenopausal women and young men in the transamination pathway of methionine catabolism and the protection against vascular disease.
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Finkelstein J: Methionine metabolism in mammals: effect of age, diet, and hormones on three enzymes of the pathway in rat tissues.
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Olszewski AJ, McCully KS: Homocysteine content of lipoproteins in hypercholesterolemia.
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Address correspondence to Dr. N. Norman Chan, Department of Diabetes, Endocrinology and Metabolism, South House, The Middlesex Hospital, Mortimer Street, London,W1N 8AA, U.K. E-mail: NNKAChan@aol.com.