Hyperhomocysteinemia as a Component of Syndrome X Mor Oron-Herman, Talma Rosenthal, and Ben-Ami Sela Syndrome X, a cluster of several metabolic disorders that includes hyperinsulinemia, hypertriglyceridemia, and hypertension, is associated with severe vascular morbidity. Hyperhomocysteinemia is another risk factor for cardiovascular and cerebro- vascular diseases, often exhibited by insulin-resistant patients. In the current study, we investigated the relationship between syndrome X and hyperhomocysteinemia in a rat model. Two groups of rats were fed either fructose-enriched diet or standard rat chow for 5 weeks. Systolic blood pressure (SBP), as well as fasting plasma insulin, triglycerides, total cholesterol, and total homocysteine levels, were determined at the beginning and at the end of the study. A complete metabolic syndrome was induced by the fructose-enriched diet, including hyperinsulinemia, hypertriglyceridemia, and hypertension. Homocysteine concentration was 72% higher after 5 weeks on the fructose diet (8.49  1.6 v 4.92  0.9 mol/l, P < .01). Insulin, triglycerides, SBP, and homocysteine levels were insignificantly changed during 5 weeks on standard rat chow. Homocysteine was positively and significantly correlated with any original component of syndrome X (r  0.565, P  .014 with insulin, r  0.662, P  .001 with triglycerides, and r  0.774, P < .001 with SBP). The results of the present study indicate that hyperhomocys- teinemia is an integral component of this rat model of syndrome X. It is thus highly likely that hyperhomocysteinemia is an integral component of the human syndrome X as well, and thereby contributes to the overall high vascular risk associated with this condition. © 2003 Elsevier Inc. All rights reserved. I MPAIRED glucose tolerance (IGT), glucose intolerance, insulin resistance syndrome (IRS), and non–insulin-depen- dent diabetes mellitus (NIDDM) are all clinical definitions for states in which the normal response of insulin secretion to glucose uptake is not adequate to efficiently transfer the glu- cose from blood into cells. Age-related decline in insulin sen- sitivity is common, although even within any given age group, a wide range of glucose clearance rate is frequent. 1 With the decline in insulin action, a considerable amount of insulin is secreted by  cells of the pancreas as a compensatory mecha- nism aimed at maintaining normal plasma glucose level. Un- fortunately, even when glucose level is successfully main- tained, the resultant extra insulin secretion is in itself harmful. Chronic hyperinsulinemia has been known for decades as an important risk factor for atherosclerotic cardiovascular morbid- ity and mortality, as documented in both prospective 2,3 and retrospective 1,4-6 epidemiological studies. Moreover, the coex- istence of insulin resistance and compensatory hyperinsulin- emia is often accompanied by additional disorders such as hypertension and dyslipidemia, which are also known risk factors for coronary artery disease (CAD) and stroke. In 1988 Reaven proposed the general name “syndrome X” for the cluster of abnormalities stemming from insulin resistance: hy- perinsulinemia, hypertriglyceridemia, and hypertension. 7 Since each component of syndrome X is a vascular risk factor by itself, 2-6,8,9 the combination of all of them together makes it an extremely high-risk syndrome. An expert panel of the National Cholesterol Education Program recently recognized syndrome X as a new target of risk reduction therapy. 10 Homocysteine emerges as another important independent risk factor for atherosclerotic morbidity and mortality. This thiol-containing amino acid is produced during metabolism of the essential amino acid methionine, which is consumed via dietary proteins. Direct correlation, without threshold effect, between plasma level of homocysteine and vascular morbidity was found in many population studies. 11-20 The involvement of homocysteine in vascular diseases was recently systematically reviewed by Ford et al. 21 The summarized hazard odds ratio for a 5-mol/L increase in homocysteine concentration, as gath- ered from publications of case-control studies, was 1.70 (95% confiedence interval [CI], 1.50 to 1.93) for coronary heart disease and 1.58 (95% CI, 1.35 to 1.85) for cerebrovascular morbidity. These values are similar to those previously reported by Boushey et al. 15 Recently, conflicting data have been accumulating on the relationship between insulin resistance and homocysteine me- tabolism. 22-30 In the present study we used a fructose-induced hyperinsulinemic rat model 31 to determine whether hyperho- mocysteinemia is an integral component of syndrome X. MATERIALS AND METHODS Animals, Diets, and Study Design Twenty male Sprague-Dawley rats weighing 200  20 g were purchased from Harlan, Israel. The animals were kept on a 14 hour/10 hour light/dark cycle and at a constant temperature (22°C). Food and water were supplied ad libitum. All rats were fed a standard rat chow prior to beginning the study, and then divided randomly into 2 equal groups. For 5 weeks the control group continued to consume standard rat chow (Koffolk, Israel) composed of 21% protein, 4% fat, 50% carbohydrate (vegetable starch), and 4.5% cellulose, while the study group was fed fructose-enriched chow (Harlan Teklad, Madison, WI) consisting of 21% protein, 5% fat, 60% carbohydrate (mainly fructose), and 8% cellulose. Both diets contained a standard mineral and vitamin mixture. Fasting plasma insulin, triglycerides, total cholesterol, and homocysteine levels, as well as systolic blood pressure (SBP), were measured at the beginning of the study (t = 0) and once again at the end (t = 5 weeks). The study protocol was approved by the hospital supervisory committee for animal studies and adhered to their guide- lines. From the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Chorley Institute of Hypertension, Sheba Medical Center, Tel Hashomer; and the Institute of Chemical Pathology, Sheba Medical Center, Tel Hashomer, Israel. Submitted February 18, 2003; accepted April 12, 2003. Address reprint requests to Mor Oron-Herman, MSc, Chorley Insti- tute of Hypertension, Sheba Medical Center, Tel Hashomer, 52621, Israel. © 2003 Elsevier Inc. All rights reserved. 0026-0495/03/5211-0051$30.00/0 doi:10.1016/S0026-0495(03)00262-2 1491 Metabolism, Vol 52, No 11 (November), 2003: pp 1491-1495