Elevated Plasma Homocysteine and Diabetic Vascular Disease

Progressive vascular disease of the large and small vessels is characteristic of the diabetic state. Individuals affected by diabetes and health care professionals are well aware of the consequences of accelerated vascular disease in diabetes, as they struggle to deal with complications of the retina, kidney, and nerves as well as myocardial infarctions, cardiovascular deaths, and peripheral vascular disease. Investigators have spent countless hours exploring mechanisms that may be responsible for microvascular and/or macrovascular disease in diabetes, and a consensus has gradually emerged. Accelerated atherosclerosis may be simplistically viewed as progressing from endothelial dysfunction to accumulation of lipid-laden macrophages, smooth muscle cell proliferation, cellular interactions by advanced glycation products, and, all too often, vascular occlusion by a thrombus that is very resistant to clot lysis. The process is magnified by a number of risk markers, including prolonged hyperglycemia, hypertension, cigarette smoking, qualitative or quantitative changes in lipoproteins, altered platelet behavior, changes in fibrinogen levels, and decreased fibrinolytic activity (1). For many years, it has been appreciated that individuals who are homozygous for homocysteinemia have accelerated atherosclerosis, characterized by an unusually high incidence of serious cardiovascular events (2). More recently, it has been recognized that a modest elevation of plasma homocysteine, either before or after methionine loading, may be a predictor of clinical cardiovascular events, including stroke and myocardial infarction. If there is coexistent hypertension, hypercholesterolemia, or cigarette smoking, the risks are greatly magnified. In this issue of Diabetes Care, Hofmann et al. (3) present evidence that ~35% of people with type 1 diabetes whom they studied had elevated plasma homocysteine levels. In most subjects, levels were elevated in the fasting state; however, in a small subgroup, methionine loading was necessary to bring out an elevated level. The patients were prescreened to include only those type 1 diabetic individuals who were in very good metabolic control, with plasma cholesterol levels <240 mg/dl, without hypertension (or with adequately treated hypertension), and with no recent history of cigarette smoking. Individuals with elevated plasma homocysteine levels had a significantly greater prevalence of retinopathy (69 vs. 51%, P < 0.05), nephropathy (76 vs. 33%, P < 0.001), and macrovascular disease of heart or leg vessels (57 vs. 33%, P < 0.001). Individuals with homocysteinemia also had increased plasma levels of thrombomodulin (an endothelial marker) and urinary albumin when compared with individuals with normal levels. The authors conclude that homocysteneima is common in type 1 diabetes if it is complicated by nephropathy and that it may contribute to increased mortality and morbidity from cardiovascular disease in these patients. This conclusion appears to be justified by the data presented and suggests that an intervention trial with folic acid therapy should be considered to determine if macrovascular event rates could be altered in type 1 diabetic individuals with nephropathy. The authors speculate that homocysteine could contribute to microvascular disease of the eyes or kidneys in type 1 diabetes. This is supported by the comparative data cited above and by in vitro studies of the effects of homocysteine on human venous endothelial cells. After exposure to advanced glycation end product (AGE) albumin, these endothelial cells release increased amounts of thrombomodulin, an endothelial marker, when exposed to homocysteine. This suggests that homocysteine may produce endothelial damage in vessels exposed to AGEs and, by this mechanism, could contribute to microvascular damage. In this cross-sectional study, the authors were careful to match patients with and without elevated plasma homocysteine levels regarding other risk factors, including HbAlc, smoking, hypertension, and hyperlipidemia. The subjects were also well matched regarding sex and duration of diabetes. Yet, one group had higher plasma homocysteine levels, significantly greater albuminuria, and a higher prevalence of retinopathy, neuropathy, and macroangiopathy This finding prompted the authors to speculate that homocysteine could be a causative agent for microvascular disease. There were clues, however, that the group with higher homocysteine levels had been at higher vascular risk before the study This group was slightly older, had higher cholesterol levels, and had higher diastolic blood pressures than the other group. Further, 53% of the hyperhomocysteinemic group were being treated for hypertension versus 16% in the normal homocysteine group (P < 0.0001). Thus, although the mean blood pressures were not significantly different at the time of the study, hypertension had been a significant vascular risk factor in one group before entry into this study. The authors recognize the issues raised by such findings in a cross-sectional study and point out that a longitudinal study is needed to determine the progression of vascular events that lead to clinically apparent microvascular and macrovascular disease. There is evidence from previous studies that endothelial damage, as indicated by elevated plasma levels of the endothelial marker von Willebrand factor, may occur shortly after the onset of experimental diabetes (4). Functional alterations of the endothelium and of blood platelets may occur very early in the course of type 1 diabetes in humans (5). Recent evidence indicates that endothelial damage precedes albuminuria in type 1 diabetes (6). Thus, it is more likely that the microand macrovascular damage seen in type 1 diabetes begins at the onset of the disease, probably via endothelial damage. Such clinically apparent findings as albuminuria, retinopathy, macrovascular events, and neuropathy follow gradually over the years. Additional risk factors, such as hypertension, hyperlipidemia, cigarette smoking, hyperglycemia, and homocysteinemia, magnify the extent and rate of progression of the vascular lesions. Longitudinal studies of people with type 1 diabetes over the course of their disease (like that now underway in the Epidemiology of Diabetes Intervention and Complications [EDIC] study)