Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiogenic brain damage and Alzheimer's disease caused by a progressing degenerative process are listed among the most frequent causes of dementia. These two processes are often concurrent and interrelated. Risk factors for vascular diseases including hypercholesteremia, arterial hypertension, and diabetes are also recognized risk factors for Alzheimer's disease. Results of many studies conducted in recent years suggest that the atheromatous process may be induced by elevated levels of homocysteine. Hyperhomocysteinemia first and foremost accelerates the onset of microangiopathic changes in small vessels. The mechanism underlying atherogenic action of homocysteine is still unclear. Hyperhomocysteinemia, generally assumed to have cytotoxic properties, damages endothelium in blood vessels, enhances thrombotic changes, and directly acts upon nitrogen oxide (NO), a vessel-dilating factor. Homocysteine is a metabolite of methionine. Homocysteine metabolism depends on current needs of the organism and involves either methionine reproduction (the reaction of remethylation, with such cofactors as B12 vitamin and folic acid), or cysteine synthesis (the transsulphuration reaction, with B6 vitamin as a cofactor). The normal range of plasma homocysteine concentration is assumed to be 5-14 mumol/L. The prevalence rates of hyperhomocysteinemia are 3-7% in the general population and 25% among those with vascular diseases. Elevated plasma homocysteine concentrations are due both to genetic and to environmental factors. In 2/3 of cases hyperhomocysteinemia is caused by decreased levels of folic acid, pyridoxine, and cobalamin. Deficiency of these vitamins is often seen in healthy elderly people.
 ...
PMID:[Hyperhomocysteinemia in patients with dementia]. 1474 46

Coronary heart disease (CHD) is a major cause of morbidity and mortality worldwide. Elevated low density lipoprotein-cholesterol (LDL-C) and reduced high density lipoprotein-cholesterol (HDL-C) levels are well recognised CHD risk factors, with recent evidence supporting the benefits of intensive LDL-C reduction on CHD risk. Such observations suggest that the most recent National Cholesterol Education Program Adult Treatment Panel III guidelines, with LDL-C targets of 2.6 mmol/L, may result in under-treatment of a significant number of patients and form the basis for the proposed new joint European Societies treatment targets of 2 and 4 mmol/L, respectively, for LDL and total cholesterol. HMG-CoA reductase inhibitors (statins) reduce LDL-C by inhibiting the rate-limiting step in cholesterol biosynthesis and reduced CHD event rates in primary and secondary prevention trials. The magnitude of this effect is not fully accounted for by LDL-C reduction alone and may relate to effects on other lipid parameters such as HDL-C and apolipoproteins B and A-I, as well as additional anti-inflammatory effects. With increasing focus on the benefits of intensive cholesterol reduction new, more efficacious statins are being developed. Rosuvastatin is a potent, hydrophilic enantiomeric statin producing reductions in LDL-C of up to 55%, with about 80% of patients reaching European LDL-C treatment targets at the 10 mg/day dosage. The Heart Protection Study (HPS) demonstrated that LDL-C reduction to levels as low as 1.7 mmol/L was associated with significant clinical benefit in a wide range of high-risk individuals, including patients with type 2 diabetes mellitus, or peripheral and cerebrovascular disease, irrespective of baseline cholesterol levels, with no apparent lower threshold for LDL-C with respect to risk. Various large endpoint trials, including Treating to New Targets (TNT) and Study of Effectiveness of Additional reductions in Cholesterol and Homocysteine (SEARCH) will attempt to further address the issue of optimal LDL-C reduction. At low LDL-C levels, HDL-C becomes an increasingly important risk factor and is the primary lipid abnormality in over half of CHD patients, with the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study set to assess the effect of raising HDL-C on cardiovascular events in patients with low HDL-C and LDL-C levels below 3 mmol/L. A variety of agents are being developed, which affect both LDL-C and HDL-C metabolism, including inhibitors of acyl-coenzyme A-cholesterol acyl transferase, microsomal transfer protein and cholesterol ester transfer protein, as well as specific receptor agonists. Ezetimibe is a selective cholesterol absorption inhibitor, which produces reductions in LDL-C of up to 25 and 60% reduction in chylomicron cholesterol content with a 10 mg/day dosage. A 1 mmol/L reduction in LDL-C results in a 25% reduction in cardiovascular risk, independent of baseline LDL-C levels. Growing evidence supports the concept that lower is better for LDL-C and that increasing HDL-C represents an important therapeutic target. Furthermore, there is growing appreciation of the role of inflammation in atherogenesis. Consequently, increasing numbers of people should receive lipid-regulating therapy with the development of newer agents offering potential mechanisms of optimising lipid profiles and thus risk reduction. In addition, the pleiotropic anti-inflammatory effects of lipid lowering therapy may provide further risk reduction.
 ...
PMID:Medical lipid-regulating therapy: current evidence, ongoing trials and future developments. 1516 26

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 becoming 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 B(12), and vitamin B(6) deficiency 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 percent of total risk. Elevated plasma homocysteine levels (> 12 micromol/l; moderate hyperhomocysteinemia) are considered cytotoxic and are found in 5 to 10 percent of the general population and in up to 40 percent of patients with vascular disease. Additional risk factors (smoking, arterial hypertension, diabetes, and hyperlipidemia) may additively or, by interacting with homocysteine, synergistically (and hence overproportionally) increase overall risk. Hyperhomocysteinemia is associated with alterations in vascular morphology, loss of endothelial antithrombotic function, and induction of a procoagulant environment. Most known forms of damage or injury are due to homocysteine-mediated oxidative stresses. Especially when acting as direct or indirect antagonists of cofactors and enzyme activities, numerous agents, drugs, diseases, and life style 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 percent 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.
 ...
PMID:Clinical use and rational management of homocysteine, folic acid, and B vitamins in cardiovascular and thrombotic diseases. 1525 38

Homocysteine is an intermediate product in the methionine metabolism, which is catalysed by several enzymes with B2, B6, B12 vitamins and folic acid as cofactors. Moderate hyperhomocysteinemia, defined as total homocysteine concentration between 12 to 30 micromol/l, represents an independent risk factor for heart disease, vascular brain disease, phlebothrombosis and thromboembolic complications. It is related to placental abruptions, spina bifida and some neuropsychiatric disorders. Hyperhomocysteinemia is a metabolic syndrome based on interaction between genetic factors (most frequently 677C/T polymorphism of methylentetrahydrofolate reductase), diseases and demographic factors (smoking, aging, hormonal and nutritional factors). Moderate hyperhomocysteinemia occurs in about 20 to 30% of patients with clinical complications of atherosclerosis. Prospective and genetic studies have shown, that moderate hyperhomocysteinemia in healthy persons is only a weak predictor of cardiovascular diseases. Contrary to it, in patients with ischaemic heart disease, renal failure or diabetes mellitus and in thromboembolic disease, hyperhomocysteinemia represents a strong predictor of vascular morbidity and mortality. Toxic effects of hyperhomocysteinemia on the vascular wall can be explained by a chemical modification of lipoproteins and vascular structure, oxidative stress, endothelial dysfunction, inadequate endothelial cell regeneration, smooth muscle cell proliferation or by an accumulation of functionally non sufficient connective tissue. Also thrombogenic effects or an increased expression of cholesterol level controlling proteins and fatty acids in the liver can be considered. Treatment of hyperhomocysteinemia is based on the administration of pharmacological doses of folic acid, B6 and B12 vitamins, which can decrease total homocysteine concentration by 25 to 30%. Such decrease, which is in average 3 micromol/l, results in the decrease of relative risk of ischaemic heart disease by 11 to 16%, phlebothrombose by 25% and vascular brain diseases by 19 to 24%.
 ...
PMID:[Consequences of moderate hyperhomocysteinemia in internal medicine]. 1530 62

Hyperhomocysteinemia is thought to have an important role in the pathogenesis of ischemic cerebral infarction. When associated with diabetes mellitus, it might worsen the neurologic course. The aim of the study was to clarify the relation between plasma homocysteine (Hcy) concentrations and silent brain infarction (SBI) in patients with type 2 diabetes mellitus. Total plasma Hcy levels were prospectively studied in 46 patients with type 2 diabetes and SBI (group I), mean age 56+/-5.4 years, as compared to 38 diabetic patients without SBI (group II) and with 31 controls (group III). Homocysteine concentrations were determined using a high-performance liquid chromatography assay. The results were compared using the Student's t test. The mean level of Hcy was 22.6+/-2.4 micromol/l in group I, 19.7+/-1.6 micromol/l in group II and 11.4+/-1.4 micromol/l in group III; between group I and group II p < or = 0.001. These data are consistent with increased Hcy levels in type 2 diabetic patients, contributing to the onset of SBI in some patients. The phenomenon should be considered in any future strategy for the therapy of hyperhomocyst(e)inemia (HHcy).
 ...
PMID:Study of total homocyst(e)ine levels in type 2 diabetic patients with silent brain infarction. 1552 24

The causal relation of total Homocysteine (tHcy) to coronary heart diseases (CHD) is unclear. In vitro studies suggest a proinflammatory effect. Among 32,826 women from the Nurses' Health Study who provided blood samples in 1989-1990, 237 CHD events were documented during 8 years of follow-up. The cases (1:2) were matched to controls on age, smoking, and month of blood draw. Plasma tHcy was inversely associated with blood levels of folate (partial r = -0.3, P < 0.0001) and B1(2) (r = -0.2, P < 0.0001) and with dietary intake of folate (r = -0.1, P < 0.01) and B(2) vitamin (r = -0.1, P = 0.01). tHcy was positively associated with soluble tumor necrosis receptor (sTNF-R) 1 and 2 (partial r = 0.2, P < 0.0001). In a multivariate model adjusted for age, smoking, BMI, parental history, hypertension, diabetes, postmenopausal hormone use, physical activity and alcohol intake, the relative risk of CHD between the extreme quartiles of tHcy was 1.66 (95% CI; 1.05-2.64, P trend = 0.02). The association was not appreciably attenuated after further adjustments for sTNF-R1, sTNF-R2, CRP, or Total Cholesterol:/HDL-c ratio. tHcy is an independent risk predictor of CHD and modestly associated with TNF-receptors. However, the inflammatory biomarkers measured could not explain its role in CHD.
 ...
PMID:Homocysteine as a risk factor for coronary heart diseases and its association with inflammatory biomarkers, lipids and dietary factors. 1553 Sep 13

Accumulation of oxidized-matrix (fibrosis) between the endothelium (the endothelial cells embedded among the myocytes) and cardiomyocytes is a hallmark of diabetes mellitus and causes diastolic impairment. In diabetes mellitus, elevated levels of homocysteine activate matrix metalloproteinase and disconnect the endothelium from myocytes. Extracellular matrix functionally links the endothelium to the cardiomyocyte and is important for their synchronization. However, in diabetes mellitus, a disconnection is caused by activated metalloproteinase, with subsequent accumulation of oxidized matrix between the endothelium and myocyte. This contributes to endothelial-myocyte uncoupling and leads to impaired diastolic relaxation of the heart in diabetes mellitus. Elevated levels of homocysteine in diabetes are attributed to impaired homocysteine metabolism by glucose and insulin and decreased renal clearance. Homocysteine induces oxidative stress and is inversely related to the expression of peroxisome proliferators activated receptor (PPAR). Several lines of evidence suggest that ablation of the matrix metalloproteinase (MMP-9) gene ameliorates the endothelial-myocyte uncoupling in diabetes mellitus. Homocysteine competes for, and decreases the PPARgammaactivity. In diabetes mellitus, endothelial-myocyte uncoupling is associated with matrix metalloproteinase activation and decreased PPARgamma activity. The purpose of this review is to discuss the role of endothelial-myocyte uncoupling in diabetes mellitus and increased levels of homocysteine, causing activation of latent metalloproteinases, decreased levels of thioredoxin and peroxiredoxin, and cardiac tissue inhibitor of metalloproteinase (CIMP) in response to antagonizing PPARgamma.
 ...
PMID:Hyperhomocysteinemic diabetic cardiomyopathy: oxidative stress, remodeling, and endothelial-myocyte uncoupling. 1582 33

The association between homocysteine and sustained hypertension (HT) has been studied. The aim of this study was to assess homocysteine levels in white coat hypertension (WCH) as an indicator of increased risk in the development of cardiovascular diseases. WCH was defined as clinical hypertension and a daytime ambulatory blood pressure of < 135/85 mmHg. Plasma levels of homocysteine were determined in patients with WCH, hypertension, and normotension (NT). The study group included 100 subjects, 33 with WCH (16 males, 17 females) aged 49.1 +/- 1.9; 35 sustained hypertensives (17 males,18 females) aged 48.5 +/- 1.7 and 32 normotensive control subjects (15 males, 17 females) aged 48.8 +/- 2.2. The subjects were matched for age, gender, and body mass index. Patients with a smoking habit, dyslipidemia, or diabetes mellitus were not included in the study. Homocysteine levels were analyzed by ELISA. Plasma homocysteine levels were significantly higher in the WCH group compared to the controls (12.32 +/- 1.07 versus 5.35 +/- 1.38 micromol/L; P < 0.001) and the WCH group had significantly lower homocysteine values than the hypertensives (19.03 +/- 0.76 micromol/L P < 0.001). Total cholesterol and tri-glycerides were not different among the groups. There were no statistically significant differences in urinary albumin excretion (UAE) or creatinine clearance between the three groups. Hypertensive retinopathy was observed in the WCH group, but was less severe and less frequent compared to HTs. LVMI was greater in the WCH group compared to the NTs, but significantly less than HTs. The data demonstrate that WCH is associated with high levels of homocysteine. The increase in homocysteine level in WCH is not as high as in SHT. Since an elevated plasma homocysteine level is a strong risk factor for coronary artery disease and there was target organ damage in our WCH group, we conclude that WCH should not be considered to be an innocent trait.
 ...
PMID:Hyperhomocysteinemia: an additional risk factor in white coat hypertension. 1587 8

Cardiovascular disease is a major problem in diabetes, and risk factors presumably unrelated to diabetes, such as hyperhomocysteinaemia, may be related to the development of cardiovascular complications in diabetic individuals. Plasma homocysteine levels are usually normal in diabetes, although both lower and higher levels have been reported. Homocysteine levels in diabetes are modulated by hyperfiltration and renal dysfunction, as well as low folate status. Insulin resistance does not appear to be a major determinant of plasma homocysteine level. Hyperhomocysteinaemia has been associated with microalbuminuria and retinopathy in type 1 and type 2 diabetes. In patients with type 2 diabetes, plasma homocysteine concentration is a significant predictor of cardiovascular events and death. This relation seems to be stronger in subjects with diabetes than without. The underlying pathophysiological mechanism of this increased vascular risk remains unexplained, but may be related to worsening of endothelial dysfunction and/or structural vessel properties induced by oxidative stress. Because homocysteine and diabetes have apparent synergistic detrimental vascular effects, patients with diabetes are candidates for screening and treatment with folic acid until the results of ongoing clinical trials are available.
 ...
PMID:Homocysteine and vascular disease in diabetes: a double hit? 1619 87

Atherosclerosis, and its most common manifestation, coronary artery disease (CAD), are rather common causes of morbidity and mortality worldwide. Recognition of its various risk factors is important to planning effective preventive measures. After the homocysteine theory was presented in 1969, attention has been directed toward the serum homocysteine level as a coronary artery disease risk factor. The authors aimed to assess the relationship between hyperhomocysteinemia and CAD in an Iranian population. In a case control study, 197 individuals (male: 123 [62.4%]) who were scheduled for coronary angiography were selected. Venous samples were taken from the patients in fasting state before angiography. Data about age, sex, risk factors (eg, hypertension, diabetes, smoking, hyperlipidemia, obesity) were obtained from prepared questionnaires. Homocysteine levels in patients were measured by ELISA method. A homocysteine level above 15 mumol/liter was considered high. Angiography reports and homocysteine levels were analyzed by independent sample t test, one-way ANOVA, multiple linear regression, and stratified analysis. In comparison with the patients with normal angiography reports (32.5%), patients with abnormal angiography reports (67.5%) had increased levels of homocysteine (p = 0.001). About 28.1% of patients with normal angiography reports had hyperhomocysteinemia. After further evaluation, linear correlations were detected between the numbers of involved vessels and homocysteine level (p = 0.000). Multiple linear regression analysis of data detected that in individuals without any risk factors, the relationship was stronger and more meaningful (p = 0.000). These data show that hyperhomocysteinemia is related to CAD as an independent risk factor. In individuals without any risk factors a linear correlation between homocysteine level and numbers of coronary artery involvement was present. If this equation is confirmed prospectively in other studies, the level of plasma homocysteine may he used as a noninvasive way of predicting the number of diseased coronary arteries.
 ...
PMID:Homocysteine level and coronary artery disease. 1644 51


<< Previous 1 2 3 4 5 6 Next >>