Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0011860 (type 2 diabetes)
57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 2 diabetes mellitus induces a characteristic platelet hyperactivity that might be due to several factors including oxidative stress and abnormal intracellular Ca2+ homeostasis. Hyperhomocysteinaemia is considered a risk factor in the development of thrombosis although its effect on platelet function and the mechanisms involved are still poorly understood. Here we show that homocysteine (Hcy) induce a concentration-dependent increase in endogenous production of reactive oxygen species (ROS), which was significantly greater in platelets from diabetic patients than in controls. Platelet treatment with Hcy resulted in Ca2+ release from the dense tubular system and the acidic stores. Ca2+ mobilisation-induced by Hcy consisted in two components, an initial slow increase in intracellular free Ca2+ concentration ([Ca2+]i) and a rapid and marked increase in [Ca2+]i, the second leading to the activation of platelet aggregation. As well as ROS generation, Ca2+ mobilization and platelet aggregation were significantly greater in platelets from diabetic donors than in controls, which indicate that platelets from diabetic donors are more sensitive to Hcy. These findings, together with the hyperhomocysteinaemia reported in diabetic patients, strongly suggest that Hcy might be considered a risk factor in the development of cardiovascular complications associated to type 2 diabetes mellitus.
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PMID:Effect of homocysteine on calcium mobilization and platelet function in type 2 diabetes mellitus. 1808 91

The presence of white matter lesions (WML) is an important prognostic factor for the development of stroke. Plasma total homocysteine (tHcy), which increases with diabetes, has been flagged as a novel predictor for cerebrovascular events. We tested the hypothesis that the presence of WML correlates with tHcy and insulin resistance in type 2 diabetic patients not receiving insulin treatment. Based on brain magnetic resonance imaging findings, 81 type 2 diabetic patients were divided into two groups, with-WML group (57 +/- 8 years, mean +/- standard deviation, n = 31) and without-WML group (57 +/- 6 years, n = 50). The blood glucose level was assessed by fasting plasma glucose (FPG), fasting immunoreactive insulin, Homeostasis Model Assessment (HOMA) Index and hemoglobin A1c. The body mass index was higher in the with-WML group than in the without-WML group (P < 0.05). Plasma levels of triglyceride were higher whilst high-density lipoprotein cholesterol was lower in the with-WML group than in the without-WML group (P < 0.05 and P < 0.0001 respectively). FPG (P < 0.005), insulin concentrations (P < 0.0001), HOMA Index (P < 0.0001) and tHcy (<0.0001) levels were higher in the with-WML group than in the without-WML group. Multivariate logistic analysis revealed that WML was independently predicted by the high tHcy and insulin resistance. Our findings indicate that the presence of WML was associated with the high tHcy and insulin resistance in these Japanese patients with type 2 diabetes mellitus.
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PMID:Hyperhomocysteinaemia is a significant risk factor for white matter lesions in Japanese type 2 diabetic patients. 1829 Aug 50

Patients with diabetes mellitus are prone to cardiovascular disease, and risk factors presumably unrelated to diabetes, such as hyperhomocysteinemia, may be involved in the atherothrombotic process in these subjects. Plasma homocysteine levels are usually normal in diabetes, although both lower and higher levels have been reported. This has been ascribed to hyperfiltration and renal dysfunction or low folate status, respectively. Insulin resistance does not appear to be a major determinant of plasma homocysteine level. Hyperhomocysteinemia has been associated with microalbuminuria and retinopathy in type 1 and type 2 diabetes. In patients with type 2 diabetes, plasma homocysteine concentration has also been shown to be related to macrovascular disease 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 relate to worsening of endothelial dysfunction or structural vessel properties. Because homocysteine and diabetes have an apparent synergistic detrimental vascular effect, patients with diabetes are good candidates for screening and treatment with folic acid until the results of ongoing clinical trials are available.
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PMID:Epidemiology of homocysteine as a risk factor in diabetes. 1837 Jun 32

Hyperhomocysteinemia is a well-established risk factor for cardiovascular disease. The association of hyperhomocysteinemia with diabetes mellitus is complex and may explain some of the risk of CVD in diabetics not explained by traditional risk factors. Both modifiable and non-modifiable factors interact with homocysteine metabolism and determine the plasma homocysteine concentrations. These include genetic abnormalities, age, sex, and various nutritional and hormonal determinants, all of which play a role in atherosclerosis and accelerated peripheral and cardio-vascular disease (CVD). Several medications modulate homocysteine metabolism and hence may play a role in the pathogenesis of CVD. Changes in renal function and interference with the homocysteine metabolism account for some of these drug effects. While a few of these drugs raise plasma homocysteine concentrations, others are beneficial and may counter some of the deleterious effects of hyperhomocysteinemia. Treatment of hyperhomocysteinemia with vitamins lowers plasma homocysteine concentrations and also reverses many of these drug effects. Little data is available on the effect of this intervention on cardiovascular outcomes. This review briefly outlines the effect of various medications used in the management of type 2 diabetes mellitus and metabolic syndrome.
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PMID:Effect of pharmacological treatments for diabetes on homocysteine. 1837 Jun 36

Alzheimer's disease, AD, is the most common form of dementia. AD initially targets memory and progressively destroys the mind. The brain atrophies as the neocortex suffers neuronal, synaptic, and dendritic losses, and the hallmark amyloid plaques and neurofibrillary tangles proliferate. Pharmacological management, at best, is palliative and transiently effective, with marked adverse effects. Certain nutrients intrinsic to human biochemistry (orthomolecules) match or exceed pharmacological drug benefits in double-blind, randomized, controlled trials, with superior safety. Early intervention is feasible because its heritability is typically minimal and pathological deterioration is detectable years prior to diagnosis. The syndrome amnestic mild cognitive impairment exhibits AD pathology and to date has frustrated attempts at intervention. The condition age-associated memory impairment is a nonpathological extreme of normal brain aging, but with less severe cognitive impairment than amnestic mild cognitive impairment. Age-associated memory impairment is a feasible target for early intervention against AD, beginning with the modifiable AD risk factors - smoking, hypertension, homocysteine, type 2 diabetes, insulin resistance, and obesity. Stress reduction, avoidance of toxins, and mental and physical exercise are important aspects of prevention. The diet should emphasize omega-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid; flavonoids and other antioxidant nutrients; and B vitamins, especially folate, B6 and B12. Dietary supplementation is best focused on those proven from randomized, controlled trials: the phospholipids phosphatidylserine and glycerophosphocholine, the energy nutrient acetyl-L-carnitine, vitamins C and E, and other antioxidants. A comprehensive integrative strategy initiated early in cognitive decline is the most pragmatic approach to controlling progression to Alzheimer's disease.
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PMID:Alzheimer's disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention. 1859 Mar 47

The weak peroxisome proliferator activated receptor-alpha (PPAR-alpha) agonists gemfibrozil and fenofibrate achieve only small increases in high-density lipoprotein (HDL) cholesterol. CP-778,875 is a more potent PPAR-alpha agonist developed to produce greater HDL cholesterol increases. This randomized, multicenter, double-blinded, placebo-controlled study evaluated the efficacy and safety of CP-778,875 in subjects with mixed dyslipidemia and type 2 diabetes. Eight-six subjects with low HDL cholesterol (< or =45 mg/dl for men and < or =55 mg/dl for women) and increased triglycerides (150 to 500 mg/dl) who had coexisting type 2 diabetes were randomized. Subjects received CP-778,875 doses of 0.5, 2, or 6 mg/day or placebo for 6 weeks. Any other lipid-altering therapy was stopped at screening. The primary end point was percent change in HDL cholesterol from baseline. The 2-mg/day dose of CP-778,875 significantly increased HDL cholesterol by 14%. The 2-mg dose also increased concentrations of apolipoprotein (apo) A-I, HDL(2) cholesterol, and HDL(3) cholesterol by 13%, 12%, and 19%, respectively. An unusual dose-response pattern was observed in that at 6 mg/day CP-778,875 only increased HDL cholesterol by 3% and decreased HDL(2) cholesterol by 24%. Fasting triglyceride levels were significantly decreased to a similar extent (26%) by all 3 doses of CP-778,875. CP-778,875 significantly increased homocysteine levels. There was no significant relation between change in homocysteine and change in apoA-I or HDL cholesterol. No subjects developed myopathy. In conclusion, CP-778,875 2 mg/day significantly increased HDL cholesterol, significantly lowered fasting triglycerides, and increased apoA-I and HDL subfractions. The clinical relevance of the increase in homocysteine levels is unknown.
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PMID:Efficacy and safety of a potent and selective peroxisome proliferator activated receptor alpha agonist in subjects with dyslipidemia and type 2 diabetes mellitus. 1867 1

Type 2 diabetes mellitus induces a characteristic platelet hyperactivity that might be due to several factors including oxidative stress and abnormal intracellular Ca(2+) homeostasis. Hyperhomocysteinaemia is considered a risk factor in the development of thrombosis although its effect on platelet function and the mechanisms involved are still poorly understood. Here we show that homocysteine induce a concentration-dependent increase in endogenous production of reactive oxygen species (ROS), which was significantly greater in platelets from diabetic patients than in controls. Platelet treatment with homocysteine resulted in Ca2+ release from the dense tubular system and the acidic stores. Ca2+ mobilization-induced by homocysteine consisted in two components, an initial slow increase in intracellular free Ca (+) concentration ([Ca2+]i) and a rapid and marked increase in [Ca2+]i, th second leading to the activation of platelet aggregation. As well as ROS generation, Ca2+ mobilization and platelet aggregation were significantly greater in platelets from diabetic donors than in controls, which indicate that platelets from diabetic donors are more sensitive to homocysteine. These findings, together with the hyperhomocysteinaemia reported in diabetic patients, strongly suggest that homocysteine might be considered a risk factor in the development of cardiovascular complications associated to type 2 diabetes mellitus.
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PMID:Effect of homocysteine on calcium mobilization and platelet function in type 2 diabetes mellitus. 1901 28

Despite decades of research, the question as to whether coffee intake increases the risk of coronary heart disease (CHD) remains controversial. In the current paper, we discuss the acute and long-term cardiovascular effects of coffee, and its major constituents, which could underlie such an association. Experimental studies have shown that administration of coffee or caffeine acutely raises blood pressure, circulating concentrations of (nor)epinephrine, increases arterial stiffness, impairs endothelium dependent vasodilation and inhibits ischemic preconditioning. The adverse effects of chronic coffee consumption on traditional risk factors for CHD are less consistent: although coffee intake slightly increases blood pressure, and plasma concentrations of homocysteine and cholesterol, there is no association with the incidence of hypertension, and a strong negative association with the incidence of type 2 diabetes mellitus. Moreover, common polymorphisms in genes involved in the metabolism of caffeine, catecholamines, homocysteine, and cholesterol can modulate the effect of coffee intake on cardiovascular parameters. Many epidemiological studies have explored the association between coffee drinking and CHD. Most prospective studies have not shown a positive association, whereas case-control studies in general have reported such an association. This discrepancy could be explained by an acute adverse effect of coffee, rather than a long-term adverse effect. We postulate that coffee drinking may have an acute detrimental effect in triggering coronary events and increasing infarct size in selected patient groups, rather than promoting the development of atherosclerosis in the general population, and we propose an alternative approach to explore such an effect in epidemiological studies.
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PMID:Acute and long-term cardiovascular effects of coffee: implications for coronary heart disease. 1904 13

The study included 105 patients (63 men and 42 women) aged 34-84 (mean 63.8 +/- 5.1) years with ischemic renal disease (IRD). All of them underwent routine medical examination, blood homocysteine was measured in 30 patients. IRD was always associated with other manifestations of disseminated atherosclerosis and cardiovascular risk factors. Plasma homocysteine increased with decreasing glomerular filtration rate (GFR) that was especially low in patients with isolated systolic arterial hypertension, smoking, and type 2 diabetes. In 34.3% of the patients, IRD associated with other chronic conditions and in 49% with cardiovascular complications and/or the development of terminal renal insufficiency. It is concluded that IRD is characterized by a large number of concomitant manifestations of disseminated atherosclerosis and a high probability of irreversible deterioration of renal functions related to cardiovascular risk factors. IRD may be associated with other chronic renal diseases and a high risk of cardiovascular complications and terminal renal insufficiency.
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PMID:[Ischemic renal disease (atherosclerotic renovascular hypertension), a clinical variant of disseminated atherosclerosis and a cause of chronic renal insufficiency]. 1914 Apr 63

Recent studies suggest that serum cystatin C level is not only a sensitive marker for renal dysfunction but also a predictive marker for cardiovascular disease (CVD). However, the mechanism of this connection is not fully understood. We aimed to determine whether insulin resistance or various biomarkers of cardiovascular risk have a role in the link between cystatin C and CVD in type 2 diabetes mellitus patients. Anthropometric measurements and biochemical studies including inflammatory biomarkers were performed in 478 patients with type 2 diabetes mellitus. The degree of insulin resistance was assessed by homeostasis model assessment (HOMA-IR) and indicators of metabolic syndrome. Estimated glomerular filtration rate (eGFR) was derived from the Modification of Diet in Renal Disease study equation. After adjusting for age, sex, body mass index, and eGFR, the cystatin C level increased significantly in proportion to the number of metabolic syndrome components present (1.08 +/- 0.06, 1.19 +/- 0.04, 1.20 +/- 0.04, 1.23 +/- 0.04, and 1.37 +/- 0.06 mg/L; P < .0001); and HOMA-IR increased significantly in proportion to cystatin C quartiles (1.16 +/- 0.15, 1.40 +/- 0.13, 1.49 +/- 0.13, and 2.00 +/- 0.17; P < .0001) (means +/- SE). Albumin-creatinine ratio, fibrinogen, uric acid, homocysteine, high-sensitivity C-reactive protein, and lipoprotein(a) all showed significant correlations with cystatin C that were generally higher than those with eGFR. Cystatin C level was independently associated with HOMA-IR (beta = 0.0380, P = .0082), albumin-creatinine ratio (beta = 0.0004, P < .0001), uric acid (beta = 0.0666, P < .0001), and homocysteine (beta = 0.0087, P = .0004). In conclusion, cystatin C level was significantly associated with insulin resistance and biomarkers reflecting inflammation independent of renal function. These components may have a role in addition to that of eGFR in explaining the link between cystatin C and CVD in type 2 diabetes mellitus patients.
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PMID:Insulin resistance and inflammation may have an additional role in the link between cystatin C and cardiovascular disease in type 2 diabetes mellitus patients. 1976 73


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