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

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

In the present study, the determinants of fasting plasma homocysteine in diabetic subjects were examined; whether plasma homocysteine and vascular disease are related and the influence of the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene on serum and erythrocyte folate, plasma homocysteine and vascular disease. Diabetic clinic subjects (Type I, n=354; Type II, n=392) were recalled for a cross-sectional survey. Standard methods were used to measure biochemical variables and to characterize vascular disease and MTHFR genotype. Plasma homocysteine was significantly and directly related to age, male sex and serum urea, and inversely related to serum folate and vitamin B12, independently in stepwise regression. When corrected for age and sex, homocysteine was significantly related to hard end points of coronary artery disease and stroke (each P<0.01), remaining significant when additionally adjusted for serum folate (P=0.043 and P=0.019 respectively). Serum folate was not clearly related to these events, although there was a trend to associate with the lower quintile of serum folate. The MTHFR genotype was not a determinant of plasma homocysteine, even in those in the lowest quintile of serum folate, nor of vascular disease. TT homozygosity at residue 677 was associated with elevation of total erythrocyte folate compared with both other genotypes (P<0.0001), almost certainly due to the diversion of 5,10-methylenetetrahydrofolate into derivates subsequent to the partial metabolic block that results from the MTHFR enzyme defect. In conclusion, in this clinic cohort of people with diabetes, vascular disease is related to plasma homocysteine, which is correlated with serum folate. The MTHFR genotype does not significantly influence either plasma homocysteine or vascular disease, despite it being a determinant of erythrocyte folate, which reflects its effect on folate metabolism.
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PMID:Homocysteine, folate, methylene tetrahydrofolate reductase genotype and vascular morbidity in diabetic subjects. 1204 16

Endothelial dysfunction occurs early in the development of vascular disease in diabetes. Total plasma homocyst(e)ine (tHcy) is associated with endothelial dysfunction. We therefore aimed to assess endothelial function in children with type 1 diabetes in relation to tHcy and its determinants. Endothelial function was assessed in 36 children with type 1 diabetes aged 13.7 +/- 2.2 years and 20 age- and sex-matched control subjects using ultrasound assessment of flow-mediated dilatation (FMD) and glyceryl trinitrate (GTN)-dependent brachial artery responses. von Willebrand factor (vWF) and thrombomodulin, markers of endothelial activation, were measured in 64 children with type 1 diabetes and 52 control subjects. Fasting glucose, tHcy, serum and red cell folate, vitamin B12, HbA(1c), creatinine, and lipids were also measured. FMD (5.2 +/- 4.7 vs. 9.1 +/- 4.0%, P = 0.002) and the ratio of FMD:GTN-induced dilatation (0.22 +/- 0.39 vs. 0.41 +/- 0.29%, P = 0.008) were significantly lower in diabetic subjects, indicating endothelial dysfunction. In diabetic subjects, red cell folate correlated independently with FMD (beta = 0.42, P = 0.028) and the ratio of FMD:GTN-induced dilatation (beta = 0.59, P < 0.001). Resting vessel diameter correlated independently with tHcy (beta = -0.51, P < 0.001) and height (beta = 0.65, P < 0.001). vWF correlated independently with HbA(1c) (beta = 0.38, P = 0.003), and thrombomodulin correlated independently with red cell folate (beta = -0.38, P = 0.005), tHcy (beta = -0.37, P = 0.004), diastolic blood pressure (beta = -0.28, P = 0.025), and creatinine clearance (beta = 0.26, P = 0.033). Children with type 1 diabetes have early endothelial dysfunction. Better folate status is associated with better endothelial function, as measured by higher FMD, higher FMD:GTN ratio, and lower thrombomodulin. Folate may therefore protect against endothelial dysfunction in children with diabetes.
Diabetes 2002 Jul
PMID:Endothelial dysfunction relates to folate status in children and adolescents with type 1 diabetes. 1208 61

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

Hyperhomocysteinemia (HHCY) is a consequence of disturbed methionine metabolism. It results from enzyme and/or vitamin deficiency. Epidemiological and clinical studies have proven HHCY to be an independent risk factor for atherosclerotic cardiovascular diseases, stroke, peripheral arterial occlusive disease and venous thrombosis. Trials in progress may clarify the "causality" of high homocysteine (HCY) concentrations and will assess the value of HCY lowering therapy. HHCY is also seen as a risk factor for neurodegenerative diseases such as cognitive impairment, dementia, Alzheimer's disease, and also for depression. There is a high prevalence of HHCY as a syndrome of vitamin shortage in elderly subjects, which strongly increases with advancing age. Elderly people have a high frequency of vitamin B12 deficiency which is more reliably diagnosed by measurement of serum methylmalonic acid and holotranscobalamin II, the metabolically active B12 fraction, than by total serum vitamin B12. Subjects who follow a strict vegetarian diet also have a high prevalence of HHCY caused by vitamin B12 deficiency. For prevention of neurological damages an early diagnosis of vitamin B12 deficiency is important. Furthermore, HHCY is a factor in the pathogenesis of neural tube defects and preeclampsia. HCY should be measured in patients with a history of atherothrombotic vessel diseases, in patients with diabetes or hyperlipidemia, in renal patients, in adipose subjects, in elderly people, in vegetarians, in postmenopausal women, and in early pregnancy.
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PMID:Hyperhomocysteinemia: a new risk factor for degenerative diseases. 1238 6

Forty-one unrelated juvenile, insulin-dependent diabetics have been HLA tissue typed for A, B and Dw anitgens and compared with a normal control population. We have found statistically significant increases in the frequencies of B8, B18, and Dw3, and significant decrements in the frequencies of B7, B12 and Dw2. The log-linear modeling technique was used to study the association of JIDD with Dw3 and B8 antigens. We confirmed that the B8 excess seen in diabetics is secondary to the excess of Dw3. The decrements of B7, B12 and Dw2 could reflect an association of these antigens with a protective factor for the disease, or could be due to an artifact. The latter possibility was excluded for B7 and Dw2 by adjusting for the excess antigen frequencies. These findings suggest that the associations between the HLA and diabetes are compatible with the existence of genes which are concerned with the pathogenesis of the disease and are closely associated with the D locus of the major histocompatibility system.
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PMID:HLA-Dw antigens in unrelated juvenile, insulin-dependent diabetics. 1273 74

Glucagonoma of the pancreas is a rare tumor with distinct clinical manifestations, such as necrolytic migratory erythema,weight loss, anemia, diabetes mellitus, and hypoamino-acidemia. We report the case of a 68-year-old Japanese man who underwent curative resection for malignant glucagonoma of the pancreas diagnosed through anemia and diabetes mellitus. The patient had had diabetes mellitus for 20 years. Anemia was diagnosed in 1998. On admission, the hemoglobin level was 8.3g/dl, but the levels of serum iron, vitamin B12, and erythropoietin and, the number of reticulocytes were within normal limits. The levels of carcinoembryonic antigen (CEA), carbohydrate antigen (CA)19-9, and DUPAN-2 were also within normal limits, and exocrine function of the pancreas (PFD, 75%) was normal. Ultrasonography (US) revealed a hypoechoic tumor in the distal pancreas. Computed tomography (CT) demonstrated a high-density area 4 cm in diameter with calcification. The serum glucagon level was very high (2360 pg/ml), but the levels of other hormones such as somatostatin or gastrin were within normal limits, while insulin was low. Glucagonoma of the pancreas was diagnosed, and distal pancreatectomy with splenectomy was performed. Histological examination revealed a malignant endocrine tumor,which was immunohistochemically positive for chromogranin A and glucagon. Two months after the operation, the serum glucagon level had decreased to within normal limits and the hemoglobin level had increased to 10.4 g/dl. The case of glucagonoma reported here was found through diagnostic examinations of anemia and treated by surgical resection, by which the patient's anemia was largely alleviated. Therefore, we recommend checking patients who have diabetes mellitus and anemia in order to diagnose and treat glucagonoma in its early stage.
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PMID:Malignant glucagonoma of the pancreas diagnoses through anemia and diabetes mellitus. 1291 65

Elevated plasma homocysteine can generate oxygen free radicals and hydrogen peroxide. The enzyme catalase is involved in the protection against hydrogen peroxide. We examined the effect of oxidative stress promoted by homocysteine on erythrocyte metabolism (blood hemoglobin, MCV, folate, B12, serum LDH, LDH isoenzymes, haptoglobin) in the oxidative stress sensitive Hungarian patients with inherited catalase deficiency. The plasma homocysteine (HPLC method, Bio-Rad), folate, B12 (capture binding assay, Abbott), blood hemoglobin concentrations, blood catalase activity (spectrophotometric assay of hydrogen peroxide), and MCV values were determined in 7 hypocatalasemic families including hypocatalasemic (male:12, female:18) patients and their results were compared to those of the normocatalasemic (male:17 female: 12) family members. We found decreased (p <.036) folate (ng/ml) concentrations (male hypocatalasemic 5.44 +/- 2.81 vs. normocatalasemic 7.56 +/- 1.97, female 5.01 +/- 1.93 vs. 6.61 +/- 1.91), blood hemoglobin (p <.010, male:140.2 +/- 11.0 vs. 153.6 +/- 11.6 g/l, female: 128.4 +/- 10.9 vs. 139.6 +/- 9.2 g/l). Increased levels of MCV (p <.001) were detected in hypocatalasemic patients (male: 98.6 +/- 3.4 vs. 90.1 +/- 7.5 fl, female: 95.9 +/- 3.9 vs. 90.1 +/- 2.5 fl), plasma homocysteine (p <.049, male: 9.72 +/- 3.61 vs. 7.36 +/- 2.10 umol/l, female: 9.06 +/- 3.10 vs. 6.84 +/- 2.50 umol/l) and not significant (p >.401) plasma B12 (male: 336 +/- 108 vs. 307 +/- 76 pg/ml, female: 373 +/- 180 vs. 342 +/- 75 pg/ml). The serum markers of hemolysis (LDH, LDH isoenzymes, haptoglobin) did not show significant (p >.228) signs of oxidative erythrocyte damage. We report firstly on increased plasma homocysteine concentrations in inherited catalase deficiency. The increased plasma homocysteine and inherited catalase deficiency together could promote oxidative stress via hydrogen peroxide. The patients with inherited catalase deficiency are more sensitive to oxidative stress of hydrogen peroxide than the normocatalasemic family members. This oxidative stress might be responsible for the decreased concentration of the blood hemoglobin via the oxidation sensitive folate and may contribute to the early development of arteriosclerosis and diabetes in these patients.
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PMID:The effects of hydrogen peroxide promoted by homocysteine and inherited catalase deficiency on human hypocatalasemic patients. 1455 52

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

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.
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PMID:[Hyperhomocysteinemia in patients with dementia]. 1474 46


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