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

Cardiovascular disease is responsible for 70% of the deaths in diabetes mellitus. Endothelial dysfunction occurs early in atherosclerosis and can now be assessed accurately and reproducibly by noninvasive means. Hyperglycemia, insulin resistance, microvascular complications, and coexistent conditions have been shown to impair endothelial function in diabetes. Resistance to insulin's vasodilatory effect and increased free radical generation are probable mechanisms responsible for the endothelial dysfunction in this state. Improvement in glycemic control, insulin and insulin sensitizers, cholesterol lowering, hypolipidemic agents, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers have improved clinical cardiovascular outcomes and have also been shown to improve endothelial function. Strategies designed to assess and improve endothelial function may be further beneficial in terms of cardiovascular outcomes in diabetes mellitus, and need to be tested in a clinical setting.
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PMID:Vascular reactivity in diabetes mellitus. 1264 89

Cardiac allograft vasculopathy is the most aggressive form of atherosclerosis in humans and is the leading cause of death after the first year of heart transplantation. Endothelial dysfunction is a major contributing factor to the acceleration of coronary vascular disease in these individuals. A reflection of this endothelial dysfunction is the severe impairment in endothelium-dependent vasodilation that occurs early after transplantation. The etiology of this allograft endothelial alteration is multifactorial and may include preexisting atherosclerosis of the graft vessels, reperfusion injury during transplantation, denervation, disruption of the lymphatic system, and acute and chronic immune injury, as well as traditional risk factors for coronary artery disease (hyperlipidemia, diabetes, hypertension, or hyperhomocysteinemia) and pathogens, such as cytomegalovirus. The alteration in endothelial function affects vasomotor tone of the coronary arteries. Evidence indicates that there may be an impairment of endothelial production and/or activity of NO. Because NO is a potent vasodilator, its deficiency would explain the abnormal vasomotor tone in these individuals. In addition, because NO inhibits key processes in vascular inflammation and atherosclerosis, its absence may contribute to the acceleration of transplant vascular disease. Recent studies from our group and others have shed light on the mechanisms of endothelial dysfunction and its importance in cardiac allograft vasculopathy. In addition, the alteration in endothelial function contributes to vascular inflammation and progression of the disease.
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PMID:Cardiac allograft vasculopathy and dysregulation of the NO synthase pathway. 1264 81

Endothelial dysfunction is associated with pathological vascular conditions including atherosclerosis, hypertension, and diabetes. The oxidatively modified form of low-density lipoprotein (LDL) is recognized as a major cause of endothelial dysfunction in atherogenesis. As the receptor for oxidized LDL in endothelial cells, we have identified the lectin-like oxidized LDL receptor-1 (LOX-1). LOX-1 is up-regulated by products of oxidative stresses and the molecules that induce oxidative stresses. Activation of LOX-1 induces the generation of reactive oxygen species and decreases NO released from endothelial cells. LOX-1 activation further induces the expression of endothelin-1, AT(1) receptor, and cell adhesion molecules. Together with these properties, LOX-1 works as an adhesion molecule for activated platelets and neutrophils. Thus, LOX-1, within the close relationships between oxidative stress generation and response, enhances functional changes in endothelial cells that are relevant to the disturbed vascular homeostasis under pathological settings.
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PMID:Stress and vascular responses: endothelial dysfunction via lectin-like oxidized low-density lipoprotein receptor-1: close relationships with oxidative stress. 1268 39

Endothelial dysfunction is recognized as an early event in the pathogenesis of atherosclerosis. Many risk factors cause endothelial dysfunction, such as hypercholesterolemia, hypertension, cigarette smoking, and diabetes mellitus. The precise steps leading to endothelial dysfunction are still being elucidated. Increasing evidence indicates that oxidized low-density lipoprotein (LDL) cholesterol (ox-LDL) plays an important role in endothelial dysfunction. Ox-LDL induces endothelial injury; inhibits apoptosis, monocyte adhesion, and platelet aggregation; and inhibits endothelial nitric oxide synthase (eNOS) expression/activity, all of which contribute to atherosclerotic process. Several pharmacologic agents, such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), have been shown to provide endothelial stabilization through mechanisms that go beyond their primary therapeutic effect. Alteration in the endothelial function might result from increase in eNOS activity, reduction in the production of free radicals, inhibition of ox-LDL action, or other undefined mechanisms. This review will focus on the protective role and some of the mechanisms of statins in ox-LDL-induced endothelial dysfunction.
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PMID:3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors protect against oxidized low-density lipoprotein-induced endothelial dysfunction. 1269 73

Endothelial dysfunction is a multifactorial term in that it encompasses a number of complex biochemical alterations in the ability of endothelial cells to perform their normal physiological function. These alterations are generally initiated by increased oxidative stress leading to pathological alterations in the cellular balance of mediators produced by endothelial cells. The key mediators include nitric oxide (NO), superoxide and endothelin. This review presents the current status of our knowledge of endothelial dysfunction in diabetes and in glaucoma and presents the case for evaluation of multifunctional drugs in these diseases.
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PMID:Multifunctional drugs for endothelial dysfunction in diabetes and glaucoma. 1278 7

Endothelial dysfunction is an early and key determinant of diabetic vascular complications that is elicited at least in part by oxidized LDL (oxLDL). The recent observation that lectin-like oxLDL receptor-1 (LOX-1) expression is increased in the vascular endothelium of diabetic rats suggests a role for LOX-1 in the pathogenesis of diabetic vascular dysfunction. Because postprandial plasma glucose has been recently proposed as an independent risk factor for cardiovascular diseases in patients with diabetes, we evaluated, in the current study, the in vitro effect of high glucose on LOX-1 expression by human aortic endothelial cells (HAECs) and the role of this receptor in glucose-induced human monocyte adhesion to endothelium. Exposure of HAECs to high D-glucose concentrations (5.6-30 mmol/l) enhanced, in a dose- and time-dependent manner, LOX-1 expression, both at the gene and protein levels. The stimulatory effect of glucose on LOX-1 gene expression in HAECs was abolished by antioxidants and inhibitors of nuclear factor (NF)-kappaB, protein kinase C (PKC), and mitogen-activated protein kinases (MAPKs). Electrophoretic mobility shift assay data demonstrated that high glucose enhanced, in HAECs, the nuclear protein binding to the NF-kappaB regulatory element of the LOX-1 gene. Finally, our results showed that incubation of HAECs with high glucose increased human monocyte adhesion to endothelium through a LOX-1-dependent signaling mechanism. Overall, these results demonstrate that high glucose induces endothelial LOX-1 expression. This effect appears to be exerted at the transcriptional level through increased oxidant stress and NF-kappaB, PKC, and MAPK activation. The study also suggests a role for LOX-1 as mediator of the stimulatory effect of high glucose on monocyte adhesion.
Diabetes 2003 Jul
PMID:Glucose enhances endothelial LOX-1 expression: role for LOX-1 in glucose-induced human monocyte adhesion to endothelium. 1282 55

Morbidity and mortality from diabetes mellitus remain high despite managing the traditional risk factors. Recent data imply that the pathophysiology of macrovascular and microvascular complications involve other factors. The metabolic syndrome precedes the onset of type 2 diabetes by many years. Early treatment of individuals with this syndrome might delay the onset of diabetes and its complications. Endothelial dysfunction, subclinical inflammation and impaired fibrinolysis may contribute to progression of macrovascular as well as microvascular complications. The roles of infection and hyperhomocysteinemia are less clear but may be significant. This review discusses the current knowledge on these "non-traditional" risk factors and therapies to improve them.
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PMID:Novel cardiovascular risk factors and macrovascular and microvascular complications of diabetes. 1286 62

Cardiovascular disease is a leading cause of death and disability in patients with diabetes or metabolic syndrome (MS). The available data suggest that many patients with diabetes or MS already have vascular abnormalities by the time they are diagnosed with their metabolic disorder. Endothelial dysfunction (ED), which is one of the initial steps in the process of vascular disease, is often present in patients with diabetes or MS. Although the precise mechanism(s) by which diabetes or MS causes ED remains to be elucidated, several possibilities exist. Hyperglycemia, hyperinsulinemia, increased oxidative stress, and diabetic dyslipidemia can all contribute to ED individually or in concert with one another. ED in the setting of diabetes or MS can subsequently result in the activation of a variety of pathways that alter vascular function and participate in the process of vascular remodeling and atherosclerosis. Because insulin resistance is the predominant mechanism responsible for various perturbations seen in MS or diabetes, it is essential to develop a therapeutic strategy that can improve insulin sensitivity with the hope that such interventions would reduce the risk of future cardiovascular events.
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PMID:Mechanisms of endothelial dysfunction in the metabolic syndrome. 1286 90

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of micro- and macrovascular complications, causing considerable morbidity and mortality. Endothelial dysfunction and insulin resistance have been strongly associated with reduced vascular reactivity in T2DM. We investigated the effect of the insulin-sensitizing antidiabetic agent rosiglitazone at a dose level of 8 mg/day on in vivo skin nitric oxide (NO) production and blood flow in the foot in a 16-week, randomized, double-blind, placebo-controlled crossover to open-label, single-blind study in patients with T2DM. NO production was assessed using an amperometric meter inserted directly into the skin. Skin perfusion was studied using laser Doppler techniques in response to local warming. Ten patients completed the study. NO production was significantly increased by rosiglitazone compared with baseline after 8-16 weeks of treatment (from 61.6+/-13.5 to 85.3+/-6.4 nM, P<.05 in response to warming). Fasting serum C-peptide levels were significantly reduced (P<.05) compared with baseline following rosiglitazone (4.78+/-1.19 ng/dl at Week 2 compared with 3.63+/-0.72 ng/dl after rosiglitazone treatment at Week 16), correlating inversely (r=-.65, P=.08) with the increase in NO production. Skin perfusion increased after 16 weeks of rosiglitazone treatment (P=ns). This is the first study to show that rosiglitazone attenuates the effects of T2DM on NO production, a marker of endothelial function, in vivo. This provides further evidence for the beneficial effects of rosiglitazone on nontraditional cardiovascular risk factors associated with T2DM.
J Diabetes Complications
PMID:Rosiglitazone treatment increases nitric oxide production in human peripheral skin: a controlled clinical trial in patients with type 2 diabetes mellitus. 1295 57

Endothelial dysfunction is a critical factor in the development of vascular disease in patients with diabetes mellitus. Maintenance of the vascular tone and luminal diameter of a blood vessel is dependent on the net balance of vasoconstrictor and vasodilator forces. In both diabetes and obesity, vascular reactivity is abnormal. After ischemia, carbon dioxide challenge, thermal challenge, or exercise, individuals with diabetes do not exhibit the increase in blood flow or vasodilation observed in persons without diabetes. The mechanisms involved in abnormal reactivity may include both the endothelium and vascular smooth muscle. Major vasodilator factors that act on vascular smooth muscle cells are nitric oxide, prostacyclin, and hyperpolarizing factor. The main vasoconstrictors are endothelin, angiotensin II, norepinephrine, serotonin, and thromboxane A(2). In patients with diabetes, there is an increase in vasoconstrictors and a decrease in vasodilators. Thiazolidinediones (TZDs) improve vasodilative responses, which may be of importance in the treatment of vascular disease. The TZDs have anti-inflammatory effects and suppress free fatty acids and reactive oxygen species at the endothelial level, which may contribute to the improved vascular reactivity observed in patients treated with these agents. In addition, these effects of TZDs may have implications for reducing the incidence and severity of atherosclerosis in the long term.
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PMID:Vascular reactivity and thiazolidinediones. 1467 71


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