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Query: UMLS:C0011849 (diabetes)
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Cardiovascular disease is the leading cause of mortality in Mexico, as well as in other Western countries. Conventional risk factors for atherosclerosis, such as cigarette smoking, systemic hypertension, diabetes mellitus, and hypercholesterolemia, do not explain this association completely. Recently, it has been recognized that hyperhomocysteinemia contributes to the atherosclerotic process, promoting endothelial damage and oxidative stress in the vascular wall. Homocysteine, an amino acid generated under physiologic conditions after ingestion of protein-rich foods, is used in a variety of metabolic pathways. Elevated plasma levels of this amino acid (higher than 15 mmol/L or lower in the presence of other cardiovascular risk factors) promote the development of atherosclerosis. Folic acid and vitamin B6 and B12 supplements decrease plasma levels of homocysteine effectively and may play an important role in the prevention and treatment of atherosclerotic vascular disease.
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PMID:[Hyperhomocysteinemia. A new coronary risk factor]. 1151 57

Hyperhomocysteinemia is the result of a disturbed methionine metabolism. It results from enzyme and/or vitamin deficiency. Epidemiological studies have proven, that hyperhomocysteinemia is a risk factor for atherosclerotic cardiovascular diseases, stroke, peripheral arterial occlusive disease and venous thrombosis. Conflicting results come from prospective studies. Trials which are now in progress may clarify the "causality" of high homocysteine concentrations and will assess the value of homocysteine-lowering therapy. The induction of the atherogenic process by hyperhomocysteinemia seems to be associated with an alteration of endothelial and smooth muscle cell function leading to an accelerated formation of reactive oxygen species. An increased endothelial expression of adhesion molecules will then lead to an enhanced deposition of oxidized LDL in the vessel wall with the formation of foam cells. Additionally, hyperhomocysteinemia interferes with the coagulation system and thus also has prothrombotic effects. There is a high prevalence of hyperhomocysteinemia as a sign of a vitamin deficiency in elderly subjects which strongly increases with age. Elderly people have a high frequency of vitamin B12 deficiency which can be diagnosed more reliably by the measurement of serum methylmalonic acid (MMA) level than by serum vitamin B12. Subjects following a strict vegetarian diet also have a high prevalence of hyperhomocysteinemia caused by functional vitamin B12 deficiency (increased MMA level). Last but not least, hyperhomocysteinemia is a factor in the pathogenesis of neural tube defects and pre-eclampsia. An early diagnosis of vitamin B12 deficiency is important for the prevention of neurological damages. Homocysteine should be measured in patients with a history of atherothrombotic vessel diseases, in patients with diabetes or hyperlipidemia, in renal patients, in obese subjects, in elderly people, in postmenopausal women, and in early pregnancy. A specific diagnosis of an underlying vitamin deficiency is important for adequate treatment. Individuals with homocysteine level >12 micromol/l should increase and/or supplement their dietary intake of vitamins.
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PMID:The importance of hyperhomocysteinemia as a risk factor for diseases: an overview. 1159 31

Elevated total plasma homocysteine has been established as an independent risk factor for thrombosis and cardiovascular disease. A strong relationship between plasma homocysteine levels and mortality has been reported in patients with angiographically confirmed coronary artery disease. Homocysteine is a thiol containing amino acid. It can be metabolised by different pathways, requiring various enzymes such as cystathionine beta-synthase and methylenetetrahydrofolate reductase. These reactions also require several co-factors such as vitamin B6 and folate. Medications may interfere with these pathways leading to an alteration of plasma homocysteine levels. Several drugs have been shown to effect homocysteine levels. Some drugs frequently used in patients at risk of cardiovascular disease, such as the fibric acid derivatives used in certain dyslipidaemias and metformin in type 2 (non-insulin-dependent) diabetes mellitus, also raise plasma homocysteine levels. This elevation poses a theoretical risk of negating some of the benefits of these drugs. The mechanisms by which drugs alter plasma homocysteine levels vary. Drugs such as cholestyramine and metformin interfere with vitamin absorption from the gut. Interference with folate and homocysteine metabolism by methotrexate, nicotinic acid (niacin) and fibric acid derivatives, may lead to increased plasma homocysteine levels. Treatment with folate or vitamins B6 and B12 lowers plasma homocysteine levels effectively and is relatively inexpensive. Although it still remains to be demonstrated that lowering plasma homocysteine levels reduces cardiovascular morbidity, surrogate markers for cardiovascular disease have been shown to improve with treatment of hyperhomocystenaemia. Would drugs like metformin, fibric acid derivatives and nicotinic acid be more effective in lowering cardiovascular morbidity and mortality, if the accompanying hyperhomocysteinaemia is treated? The purpose of this review is to highlight the importance of homocysteine as a risk factor, and examine the role and implications of drug induced modulation of homocysteine metabolism.
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PMID:Drugs affecting homocysteine metabolism: impact on cardiovascular risk. 1189 29

Plasma homocysteine and Cystatin C levels of 360 chronic haemodialysed patients were measured in fasting (191 men, mean age: 55.5 years; and 169 women, mean: 62.9 years). The patients were divided into subgroups: diabetes mellitus (34 men and 38 women 7 vs 8 IDDM). obliterative arteriosclerosis (68 men and 61 women), cardiovascular complications (75 men and 84 women) and stroke (16 men and 12 women), and after renal transplantation in chronic rejection (15 men and 5 female). Homocysteine was determined by IMx analyser from Abbott by FPIA method. Immunoturbidimetric method was used for quantification of Cystatin C (PETIA). The lowest Cystatin C concentration was found in diabetic patients (4.35 +/- 0.15 mg/l in men and 3.18 +/- 1.77 mg/l in women) and the highest one occurred in anuric and bilateral nephrectomised and transplanted chronic rejected patients (6.075 mg/l in men and 6.35 mg/l in women: p<0.001). The homocysteine levels (24.98 +/- 2.94 micromol/l in men and 23.88 +/- 1.76 micromol/l in women) exceeded the upper limit of reference range (<15.0 micromol/l). There was a significant difference in favour of subgroup of cardiovascular (27.25 micromol/l in men and 26.87 micromol/l in women) and stroke patients (27.16 micromol/l in men and 30.76 micromol/l in women p<0.001). Elevated levels were found in chronic rejected patients with accelerated arteriosclerotic events (25.94 micromol/l in men and 27.43 micromol/l in women). Good positive linear correlation was found between serum homocysteine and Cystatin C levels (r=0.2393 and 0.2252). The authors demonstrated hyperhomocysteinaemia associated with high Cystatin C concentration in four subgroups of haemodialysed patients (obliterative and accelerated arteriosclerosis, cardiovascular disease, and cerebrovascular complications and stroke).
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PMID:Homocysteine and cystatin C level changes in haemodialysed patients and connection with cerebro- and cardiovascular complications. 1216 87

Homocysteinemia is an independent risk factor for cardiovascular disease, but information on its association with type 2 diabetes and mild renal dysfunction is limited. Plasma total homocysteine (tHcy) concentration is partly determined by renal plasma clearance. Serum cystatin C (Cys C) concentration has been introduced as a marker of renal function, specifically as an indicator of glomerular filtration rate (GFR). The aim of this study was to explore the relationships among tHcy, creatinine clearance (Ccr), serum Cys C, and microalbuminuria in a population with type 2 diabetes. Fasting plasma tHcy, serum homocysteine-related vitamins (folate and vitamin B12), serum Cys C, serum creatinine, urine microalbumin, and creatinine clearance were determined in 75 type 2 diabetic patients and 40 healthy control subjects. The patients were assigned to two groups based on urinary albumin excretion (UAE): normoalbuminuric (NAU, UAE < 30 mg/24 hr, n = 35) and microalbuminuric (MAU, UAE 30-300 mg/24 hr, n = 40). Ccr was calculated using the Cockroft-Gault formula. Plasma Hcy levels were determined by HPLC with fluorescence detection and serum Cys C by automated particle enhanced immunoturbidimetry. Plasma tHcy levels were significantly higher in normoalbuminuric and microalbuminuric patients than in controls (10.64 +/- 0.53, 13.29 +/- 0.78, 6.91 +/- 0.37 mmol/L, respectively). Serum Cys C levels in microalbuminuric diabetics were higher than in normoalbuminurics and controls (1.36 +/- 0.06, 1.12 +/- 0.04, 1.10 +/- 0.06 mg/ L, respectively). Positive correlations were noted between tHcy and Cys C levels in normoalbuminuric and microalbuminuric diabetics (r = 0.72, r = 0.64, respectively). Homocysteine and creatinine concentrations were correlated in both diabetic groups (r = 0.89, r = 0.93, NAU and MAU, respectively). Elevated plasma total homocysteine concentrations in type 2 diabetics suggest an association between homocysteinemia and deterioration of renal function, evidenced by increased serum creatinine and Cys C, Ccr, and microalbuminuria. These findings implicate homocysteinemia in the relationship between diabetic nephropathy and cardiovascular complications of diabetes.
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PMID:Association between homocysteinemia and renal function in patients with type 2 diabetes mellitus. 1217 91

Homocysteine metabolism is altered in diabetic patients. Cystathionine beta-synthase (CBS), a key enzyme involved in the transsulfuration pathway, which irreversibly converts homocysteine to cysteine, catalyzes the condensation of serine and homocysteine to cystathionine. Studies in streptozotocin-induced diabetic rats have shown that CBS enzyme activity is elevated in the liver but not in the kidney, and this effect is reversed by insulin treatment. To determine whether these effects resulted from alterations at the level of gene transcription, CBS mRNA was measured in diabetic and insulin-treated diabetic rats. CBS mRNA levels were found to be markedly higher in streptozotocin-induced diabetic rat livers; these were reduced by insulin administration. In H4IIE cells, a rat hepatoma cell culture model, glucocorticoids increased the cellular levels of CBS enzyme protein and CBS mRNA; insulin inhibited this stimulatory effect. Treatment with insulin also decreased CBS levels in HepG2 cells, a human hepatoma cell line. Nuclear run-on experiments in the rat cells confirmed that stimulation of CBS gene expression by glucocorticoids and the inhibition by insulin occurred at the transcriptional level. Transient transfections of HepG2 cells with a CBS-1b promoter luciferase reporter construct showed that the promoter activity was decreased by 70% after insulin treatment. These results show that insulin has a direct role in regulating homocysteine metabolism. Altered insulin levels in diseases such as diabetes may influence homocysteine metabolism by regulating the hepatic transsulfuration pathway.
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PMID:Hormonal regulation of cystathionine beta-synthase expression in liver. 1219 28

The objective of this study was to determine the prognostic value of serum homocysteine levels in patients with coronary heart disease. Homocysteine was assayed in 76 coronary patients with a mean age of 59.2 years hospitalized for myocardial ischaemia or myocardial infarction. Percutaneous transluminal angioplasty was performed in 47 (70%) of these patients during this hospitalization. The mean follow-up for these patients was 22 months (range: 11 to 67 months). In these patients, serum homocysteine levels were not correlated with the usual risk factors of coronary heart disease (age, sex, treated hypercholesterolaemia, smoking, diabetes) except for hypertension. It was strongly correlated with serum creatinine (R = 0.61; p = 0.0001). Eleven patients presented a major event during follow-up (8 deaths, 1 nonfatal myocardial infarction, 1 cardiac transplantation) and 16 underwent a revascularization procedure. The blood homocysteine level does not have any prognostic value for any coronary events. However, it is higher in patients who develop a major event than in those which do not (15.8 +/- 4 mumol/l versus 11.5 +/- 6.6 mumol/l, p = 0.05). Using multivariate analysis, taking into account age, serum creatinine and serum homocysteine, only serum homocysteine was predictive of major event-free survival (p = 0.02).
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PMID:[Homocysteine and coronary events in coronary disease patients]. 1255 79

Although white coat hypertension has been widely studied in the last years, its risk profile is not yet completely clear. The aim of this study was to evaluate circulating homocysteine levels, an emerging cardiovascular risk factor, in subjects with white coat and sustained hypertension. We selected 31 sustained hypertensive subjects, 31 white coat hypertensive subjects and 31 normotensive subjects matched for age, gender, body mass index and occupation. Women were also matched for menopausal status. Subjects with smoking habit, dyslipidaemia and diabetes mellitus were excluded from the study. White coat hypertension was defined as clinical hypertension and daytime ambulatory blood pressure <135/85 mmHg. Blood samples were drawn after a fasting period of 12 h for routine laboratory tests and homocysteine determination. Homocysteine levels were evaluated by fluorescence polarization immunoassay. Creatinine, glucose, cholesterol and triglycerides were not different among the groups. White coat hypertensive subjects had significantly lower homocysteine levels than sustained hypertensive patients (8.2+/-2.0 vs 12.6+/-3.9 micromol/l, P=0.0003). No significant difference was observed between white coat hypertensive and normotensive subjects regarding this parameter (8.2+/-2.0 vs 7.6+/-1.9 micromol/l, P=0.9). In conclusion, our data show that middle-aged white coat hypertensive subjects without other cardiovascular risk factors have lower circulating homocysteine levels than sustained hypertensive patients suggesting that they are at lower cardiovascular risk.
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PMID:Circulating homocysteine levels in sustained and white coat hypertension. 1262 6

About half of all deaths are due to cardiovascular disease and its complications. The economic burden on society and the healthcare system from cardiovascular disability, complications, and treatments is huge and getting larger in the rapidly aging populations of developed countries. As conventional risk factors fail to account for part of the cases, homocysteine, a "new" risk factor, is being viewed with mounting interest. Homocysteine is a sulfur-containing intermediate product in the normal metabolism of methionine, an essential amino acid. Folic acid, vitamin B12, and vitamin B6 deficiencies and reduced enzyme activities inhibit the breakdown of homocysteine, thus increasing the intracellular homocysteine concentration. Numerous retrospective and prospective studies have consistently found an independent relationship between mild hyperhomocysteinemia and cardiovascular disease or all-cause mortality. Starting at a plasma homocysteine concentration of approximately 10 micromol/l, the risk increase follows a linear dose-response relationship with no specific threshold level. Hyperhomocysteinemia as an independent risk factor for cardiovascular disease is thought to be responsible for about 10% of total risk. Elevated plasma homocysteine levels (>12 micromol/l; moderate hyperhomocysteinemia) are considered cytotoxic and are found in 5 to 10% of the general population and in up to 40% of patients with vascular disease. Additional risk factors (smoking, arterial hypertension, diabetes, and hyperlipidemia) may additively or, by interacting with homocysteine, synergistically (and hence over-proportionally) increase overall risk. Hyperhomocysteinemia is associated with alterations in vascular morphology, loss of endothelial anti-thrombotic function, and induction of a procoagulant environment. Most known forms of damage or injury are due to homocysteine-mediated oxidative stress. Especially when acting as direct or indirect antagonists of cofactors and enzyme activities, numerous agents, drugs, diseases, and lifestyle factors have an impact on homocysteine metabolism. Folic acid deficiency is considered the most common cause of hyperhomocysteinemia. An adequate intake of at least 400 microg of folate per day is difficult to maintain even with a balanced diet, and high-risk groups often find it impossible to meet these folate requirements. Based on the available evidence, there is an increasing call for the diagnosis and treatment of elevated homocysteine levels in high-risk individuals in general and patients with manifest vascular disease in particular. Subjects of both populations should first have a baseline homocysteine assay. Except where manifestations are already present, intervention, if any, should be guided by the severity of hyperhomocysteinemia. Consistent with other working parties and consensus groups, we recommend a target plasma homocysteine level of <10 micromol/l. Based on various calculation models, reduction of elevated plasma homocysteine concentrations may theoretically prevent up to 25% of cardiovascular events. Supplementation is inexpensive, potentially effective, and devoid of adverse effects and, therefore, has an exceptionally favorable benefit/risk ratio. The results of ongoing randomized controlled intervention trials must be available before screening for, and treatment of, hyperhomocysteinemia can be recommended for the apparently healthy general population.
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PMID:DACH-LIGA homocystein (german, austrian and swiss homocysteine society): consensus paper on the rational clinical use of homocysteine, folic acid and B-vitamins in cardiovascular and thrombotic diseases: guidelines and recommendations. 1465 16

Homocysteine is a sulphur aminoacid with a free thiol group which is not present in dietary protein. This aminoacid is a secondary f methionine by-product from cysteine metabolism. The pathogenic mechanisms of homocysteine in vascular damage have not been clarified. At present, it is no possible to develop an atherogenic and thrombogenic hypothesis. Yet high levels of homocysteine can cause endothelial damage, with increased thrombosis and atherosclerosis. Hyperhomocysteinemia has been reported in patients with diabetes mellitus type 1 and type 2; the prevalence and secondary cardiovascular risk is higher in patients with diabetes type 2 than those with diabetes type 1. In patients with diabetes mellitus type 1, microvascular and macrovascular complications and neuropathy are found to be increased in those with hyperhomocysteinemia. In patients with diabetes mellitus type 2, the relationship between hyperhomocysteinemia, macrovascular complications and renal disease is unclear; however, a higher prevalence of macrovascular complications in diabetic patients with hyperhomocisteinemia is associated with a higher prevalence of renal disease. Moreover, patients with hyperhomocysteinemia have hypertension and dyslipemia. Multivariate regression analyses have shown an independent relationship between homocysteine and macrovascular complications. The relationship between retinopathy and homocysteine has not been clarified. In summary, hyperhomocysteinemia could be a risk factor accounting for chronic complications in diabetic patients. Nevertheless, it is necesary to perform more prospective and intervention studies to clarify the independent risk of homocysteine and thus assay alternative treatments.
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PMID:[Homocysteine in patients with diabetes mellitus]. 1473 72


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