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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial dysfunction accompanies suboptimal glucose control in patients with diabetes mellitus. A hallmark of endothelial dysfunction is a deficiency in production or bioavailability of vascular nitric oxide (NO). Here we demonstrate that acute exposure of human endothelial cells to glucose, at levels found in plasma of diabetic patients, results in a significant blunting of NO responses to the endothelial nitric oxide synthase (eNOS) agonists bradykinin and A-23187. Monitoring of NO generation by purified recombinant bovine eNOS in vitro, using amperometric electrochemical detection and an NO-selective porphyrinic microelectrode, showed that glucose causes a progressive and concentration-dependent attenuation of detectable NO. Addition of glucose to pure NO solutions similarly elicited a sharp decrease in NO concentration, indicating that glucose promotes NO loss. Electrospray ionization-tandem mass spectrometry, using negative ion monitoring, directly demonstrated the occurrence of a covalent reaction involving unitary addition of NO (or a derived species) to glucose. Collectively, our findings reveal that hyperglycemia promotes the chemical inactivation of NO; this glucose-mediated NO loss may directly contribute to hypertension and endothelial dysfunction in diabetic patients.
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PMID:Glucose scavenging of nitric oxide. 1118 10

Vascular endothelium is involved in the regulation of vascular tone, vessel permeability, and angiogenesis. Vessel tone is determined by the balance of various paracrine vasodilatory and vasoconstrictor factors, most notably nitric oxide (NO) and endothelin-1. Not surprisingly, endothelial dysfunction is believed to be crucial in the development of the chronic vascular complications of diabetes. Endothelial dysfunction, which may be examined by studying endothelial-dependent vasodilatation in humans, is also disturbed by many of the individual features of the insulin resistance syndrome including hypertension, dyslipidaemia, and hyperglycaemia. Therefore, it may be possible that endothelial dysfunction could be closely associated with, or even a common antecedent of, the insulin resistance syndrome (IRS). There is emerging evidence that impaired endothelial-dependent vasodilatation is present in populations at future risk of diabetes and even in children of low birth weight, who may exhibit features of the insulin resistance syndrome in later life. Endothelial dysfunction is an obvious therapeutic target if the vascular pathology associated with insulin resistance and type 2 diabetes is to be ameliorated.
Diabetes Obes Metab 1999 May
PMID:The association between insulin resistance and endotheliopathy. 1122 Feb 84

Endothelial dysfunction is generally believed to be the inciting event in atherosclerosis, and is probably important in ischemic manifestations as well. The release of endothelium-derived vasoactive substances is not only triggered by acetylcholine, but also controlled by a host of neuromediators and by shear forces exerted by the blood flowing through the blood vessel. However, this balance is altered in disease states such as atherosclerosis, diabetes, chronic heart failure, coronary artery disease, or hypertension. The most important mechanism in the decrease in endothelium-dependent relaxation appears to be a reduced release of nitric oxide. In healthy people, the predominant effect of stimulation of the endothelium is vasodilation. It is tempting to hypothesize that endothelial dysfunction is one of the initial steps involved in the development of atherosclerosis, but also in peripheral artery atherosclerosis. Impairment of endothelium-dependent vasodilation in the coronary arteries has been demonstrated not only in patients with documented atherosclerosis and/or established cardiovascular risk factors. Noninvasive evaluation of brachial artery vasoactivity using high resolution B-mode ultrasound is currently being established to evaluate endothelial function. We studied the endothelial function in 50 normal volunteers, 28 hypertensive subjects, and 31 hypercholesterolemia subjects. The diameter of the target artery was measured from two-dimensional ultrasound images with 10 MHz linear transducer. The results suggested that antihypertensive therapy with a certain calcium antagonist did not have a favorable effect on endothelial function and after cessation of cholesterol lowering therapy, the endothelial dysfunction developed again. The endothelial function can now be readily measured in humans and is very useful research tool to assess the effect of risk factors and their treatment on vascular function. Endothelial function testing will assume a prominent role in the evaluation and treatment of patients at risk of developing coronary atherosclerosis and its sequelae.
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PMID:Noninvasive evaluation of endothelial function. 1143 34

Endothelial dysfunction plays a pivotal role in the initial stage of atherosclerosis. Insulin resistance is associated with accelerated atherosclerosis, especially coronary heart disease. To elucidate the relationship between endothelial dysfunction and insulin resistance or insulin resistance syndrome in patients with type 2 diabetes, we investigated the correlation between plasma soluble thrombomodulin (TM) and von Willebrand factor (vWF), measures of endothelial dysfunction, and the degree of insulin resistance evaluated by homeostasis assessment models of insulin resistance (HOMA-IR), or variables of insulin resistance syndrome. We studied 53 patients with type 2 diabetes, 23 treated with diet alone and 30 treated with sulfonylureas, who had normal renal function. The plasma soluble TM concentrations were highly correlated with HOMA-IR (r=0.64, p<0.0001), the plasma insulin (r=0.72, p<0.0001), the systolic blood pressure (r=0.45, p=0.0005), and the plasma fibrinogen (r=0.43, p=0.0018), while they were inversely correlated with the serum HDL cholesterol concentrations (r=-0.27, p=0.0344). The plasma vWF concentrations were positively correlated with HOMA-IR (r=0.35, p=0.0151) and the plasma fibrinogen (r=0.32, p=0.0203), but not with the plasma insulin, the systolic blood pressure or the HDL cholesterol concentrations. Furthermore, plasma TM, but not vWF, was positively correlated with total number of variables of insulin resistance syndrome (r=0.45, p=0.0005). These results indicate that endothelial dysfunction may be associated with the pathogenesis of insulin resistance syndrome as well as insulin resistance, and that the plasma TM might reflect endothelial damage better than the plasma vWF in the state of insulin resistance in patients with type 2 diabetes.
Exp Clin Endocrinol Diabetes 2001
PMID:Relationship between plasma soluble thrombomodulin levels and insulin resistance syndrome in type 2 diabetes: a comparison with von Willebrand factor. 1145 33

Diabetic Nephropathy (DN) is the commonest cause of end-stage renal failure (ESRF) in the Western world. Diabetic nephropathy follows a well outline clinical course, starting with microalbuminuria through proteinuria, azotaemia and culminating in ESRF. Before the onset of overt proteinuria, there are various renal functional changes including renal hyperfiltration, hyperperfusion, and increasing capillary permeability to macromolecules. Basement-membrane thickening and mesangial expansion have long been recognized as pathological hallmark of diabetes. It has been postulated that DN occurs as a result of the interplay of metabolic and hemodynamic factors in the renal microcirculation. There is no doubt that there is a positive relationship between hyperglycaemia, which is necessary but not sufficient, and microvascular complications. The accumulation of advanced glycosylated end-products (AGEs), the activation of isoform(s) of protein kinase C (PKC) and the acceleration of the aldose reductase pathway may explain how hyperglycemia damages tissue. PKC is one of the key signaling molecules in the induction of the vascular pathology of diabetes. The balance between extracellular matrix production and degradation is important in this context. Transforming growth factor-beta (TGF-beta) appears to play a pivotal role in accumulation in the diabetic kidney. Hemodynamic disturbances are believed to be directly responsible for the development of glomerulosclerosis and its attendant proteinuria. There is familial clustering of diabetic kidney disease. A number of gene loci have been investigated to try to explain the genetic susceptibility to diabetic nephropathy. The genes coding for components of renin-angiotensin system have drawn special attention, due to the central role that this system plays in the regulation of blood pressure, sodium metabolism, and renal hemodynamics. Endothelial dysfunction is closely associated with the development of diabetic retinopathy, nephropathy and atherosclerosis, both in IDDM and in NIDDM. The pathogenesis of diabetic nephropathy is not clarified completely yet.
Exp Clin Endocrinol Diabetes 2001
PMID:Pathogenesis of diabetic nephropathy. 1146 May 89

Vascular structure, function, and mechanics are altered in hypertension, which contributes to an important degree to complications of elevated blood pressure. Vascular hypertrophy with collagen deposition and increased stiffness is found in large arteries, whereas in small arteries, smooth muscle cells are restructured around a smaller lumen, and there is no net growth of the vascular wall, particularly in milder forms of hypertension. Hypertrophic remodeling and increased small artery stiffness may be found in more severe hypertension. Endothelial dysfunction occurs in large or smaller vessels in a variable percentage of patients, particularly in presence of other risk factors such as diabetes, smoking, dyslipidemia, and advanced atherosclerosis. In clinical trials, 1-year treatment with angiotensin-converting enzyme inhibitors, angiotensin AT1 receptor antagonists, and long-acting calcium channel blockers corrected small artery structure and endothelial dysfunction in hypertensive patients, whereas beta-adrenergic receptor blockers did not. Improved outcomes in hypertensive patients demonstrated in recent trials with some but not others of these agents could be a consequence, at least in part, of vascular protection offered by some antihypertensive agents.
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PMID:Small artery remodeling in hypertension: can it be corrected? 1146 50

The focus of attention in preventing and treating cardiovascular (CV) disease today is shifting toward the arterial wall. Evidence has been accumulating for several years that protecting the endothelium is key to reducing CV risk. Endothelial dysfunction results in reduced compliance, or increased arterial stiffness, particularly in the smaller arteries. This abnormality is characteristic of patients with hypertension but may also be seen in normotensive patients before the appearance of clinical disease. Reduced arterial compliance is also seen in patients with diabetes and in smokers, and is part of a vicious cycle that further elevates blood pressure, aggravates atherosclerosis, and leads to increased CV risk. Although other factors are involved, the damage to the endothelium results in reduced secretion of nitric oxide, which influences smooth muscle growth, migration, and contraction, as well as influencing inflammation and clotting. Arterial compliance can be measured by several techniques, most of which are invasive or otherwise not clinically appropriate. Pulse contour analysis is a newly developed noninvasive method that allows for easy, in-office measurement of arterial elasticity to identify patients at risk for CV events before disease becomes clinically apparent. Further research is needed to confirm whether this method offers a means of improving risk stratification and therapeutic decision making.
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PMID:Arterial compliance to stratify cardiovascular risk: more precision in therapeutic decision making. 1149 6

Dehydroascorbic acid, the oxidized form of vitamin C, is transported into mammalian cells via facilitative glucose transporters and hyperglycemia inhibits this process by competitive inhibition. This inhibited transport may promote oxidative stress and contribute to the increase in atherosclerotic cardiovascular disease observed in patients with diabetes mellitus. This review explores the importance of this proposed mechanism in light of current research. For example, recent reports suggest that administration of antioxidants, such as vitamin C, may slow atherogenesis by improving endothelium-dependent vasodilation in individuals with abnormal glucose and lipid metabolism, perhaps by preventing the oxidation of nitric oxide, an important regulator of vasomotor tone. Endothelial dysfunction plays a key role in the development of atherosclerosis and endothelial cells may be particularly affected by hyperglycemia-induced ascorbic acid deficiency as they line the interior of blood vessels. In addition, we discuss evidence of several other mechanisms by which vitamin C status may affect the development of atherosclerotic cardiovascular disease, particularly its inverse relationship to multiple cardiovascular disease risk factors and indicators. Given these factors, vitamin C administration is recommended during periods of both acute and chronic hyperglycemia to help preserve endothelial function.
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PMID:Hyperglycemia-induced ascorbic acid deficiency promotes endothelial dysfunction and the development of atherosclerosis. 1150 Jan 68

Angiotensin-converting enzyme (ACE) is primarily localized (>90%) in various tissues and organs, most notably on the endothelium but also within parenchyma and inflammatory cells. Tissue ACE is now recognized as a key factor in cardiovascular and renal diseases. Endothelial dysfunction, in response to a number of risk factors or injury such as hypertension, diabetes mellitus, hypercholesteremia, and cigarette smoking, disrupts the balance of vasodilation and vasoconstriction, vascular smooth muscle cell growth, the inflammatory and oxidative state of the vessel wall, and is associated with activation of tissue ACE. Pathologic activation of local ACE can have deleterious effects on the heart, vasculature, and the kidneys. The imbalance resulting from increased local formation of angiotensin II and increased bradykinin degradation favors cardiovascular disease. Indeed, ACE inhibitors effectively reduce high blood pressure and exert cardio- and renoprotective actions. Recent evidence suggests that a principal target of ACE inhibitor action is at the tissue sites. Pharmacokinetic properties of various ACE inhibitors indicate that there are differences in their binding characteristics for tissue ACE. Clinical studies comparing the effects of antihypertensives (especially ACE inhibitors) on endothelial function suggest differences. More comparative experimental and clinical studies should address the significance of these drug differences and their impact on clinical events.
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PMID:The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data. 1169 20

Cardiovascular disease has a multifactorial aetiology that is influenced by both genetic and environmental factors. Endothelial dysfunction is a key event in the pathogenesis of vascular disease that occurs before structural vascular changes or clinical symptoms are evident. Conventional risk factors, for example hypertension and diabetes mellitus, are associated with endothelial dysfunction, but the influence of other putative risk factors is not clear. The methylenetetrahydrofolate reductase (MTHFR) C677T genotype, a common polymorphism that induces hyperhomocysteinaemia, has been proposed as being a genetic risk factor for cardiovascular disease. A total of 126 healthy adults recruited by MTHFR C677T genotype (42 of each genotype, i.e. CC, CT and TT) underwent assessment of endothelial function. Brachial artery endothelium-dependent flow-mediated dilatation (FMD) was measured using high-resolution ultrasonic vessel "wall-tracking". Using multiple regression analysis, MTHFR genotype and 21 other subject and subject-lifestyle variables were investigated as potential predictors of endothelial function. FMD was influenced positively by frequency of aerobic exercise and by hormone replacement therapy, and negatively by increases in systolic blood pressure. MTHFR C677T genotype and the associated variation in plasma homocysteine levels did not influence FMD. Additionally, other factors, including plasma cholesterol and self-supplementation with either antioxidant vitamins or cod liver oil, showed no significant relationship with FMD, although these findings are compromised by the narrow range studied for cholesterol and the small number of subjects taking supplements. These observations have implications for risk factor management in the primary prevention of cardiovascular disease in healthy individuals.
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PMID:Influence of methylenetetrahydrofolate reductase genotype, exercise and other risk factors on endothelial function in healthy individuals. 1174 60


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