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

Diabetic retinopathy is the leading cause of blindness in the under 65s, and with the burden of disease case load expected to exceed 200 million worldwide within 10 years, much effort is being spent on prophylactic interventions. Early work focused on improving glycaemic control; however, with the publication of EURODIAB Controlled trial of Lisinopril in Insulin-dependent Diabetes (EUCLID) and United Kingdom Prospective Diabetes Study (UKPDS), the focus has recently moved to control of blood pressure and specifically the renin-angiotensin system (RAS). There is a large body of evidence for a local RAS within the eye that is activated in diabetes. This appears to be directly responsible, as well as indirectly through other mediators, for an increase in concentration of vascular endothelial growth factor (VEGF), a selective angiogenic and vasopermeability factor that is implicated in the pathogenesis of diabetic retinopathy. Inhibition of angiotensin-converting enzyme appears to reduce concentrations of VEGF, with a concurrent anti-proliferative effect independent of systemic VEGF levels or blood pressure. Angiotensin II (Ang II) Type 1 (AT(1)) receptor blockade has been shown to reduce neovascularisation independent of VEGF levels in animal models. This may be due to antagonism of activation of mitogen-activated protein kinase, which is a potent cellular proliferation stimulator, by Ang II, although this needs further evaluation.
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PMID:The renin-angiotensin-aldosterone system and the eye in diabetes. 1258 67

Increased expression of endothelin-1 (ET-1) is associated with diabetic retinopathy and vasculopathy, although the molecular explanation has not been defined. The effects of high glucose and protein kinase C (PKC) activation on platelet-derived growth factor (PDGF)-BB and of ET-1 expression in the retina of streptozotocin (STZ)-induced diabetic rats and bovine retinal pericytes (BRPC) were examined. In 4-week diabetic rats, PDGF-B and prepro-ET-1 (ppET-1) mRNA levels increased significantly by 2.8- and 1.9-fold, respectively, as quantified by RT-PCR. Treatment with PKC-beta isoform-specific inhibitor (LY333531) or insulin normalized retinal ET-1 and PDGF-B expression. In BRPC, high glucose levels increased ppET-1 and PDGF-B mRNA expression by 1.7- and 1.9-fold, respectively. The addition of PDGF-BB but not PDGF-AA increased expression of ppET-1 and vascular endothelial growth factor mRNA by 1.6- and 2.1-fold, respectively, with both inhibited by AG1296, a selective PDGF receptor kinase inhibitor. A general PKC inhibitor, GF109203X, suppressed PDGF-BB's induction of ET-1 mRNA. Thus, increased ET-1 expression in diabetic retina could be due to increased expression of PDGF-BB, mediated via PDGF-beta receptors in part by PKC activation. The novel demonstration of elevated expression of PDGF-B and its induction by PKC activation identifies a potential new molecular step in the pathogenesis of diabetic retinopathy.
Diabetes 2003 Mar
PMID:Role of protein kinase C on the expression of platelet-derived growth factor and endothelin-1 in the retina of diabetic rats and cultured retinal capillary pericytes. 1260 28

Diabetic retinopathy, one of the most serious complications of long-term diabetes, could clinically be divided into two stages: 1) background retinopathy that does not cause visual impairment and 2) proliferative retinopathy, which is a potentially blinding condition. This study aims to investigate the correlation between enhancement of vascular endothelial growth factor (VEGF) expression and neovascular changes. A binary recombinant adeno-associated virus construct producing green fluorescent protein (GFP) and VEGF under the control of the human cytomegalovirus promoter, recombinant adeno-associated virus (rAAV).VEGF.GFP, was produced and injected into the subretinal space of C57BL mice. GFP expression was tracked by fluorescence fundus photography, and VEGF expression was confirmed by immunohistochemistry and enzyme-linked immunoassay. Neovascular changes were monitored by fluorescein angiography and histology and by quantifying the number of inner retinal vessels. GFP expression was found in 100% of injected eyes, and vascular changes were detected in 9 of 10 rAAV.VEGF.GFP-injected eyes. Of these, four demonstrated microaneurysms and five showed moderate to severe leakage. There was a statistically significant increase in blood vessel number in the inner nuclear layer (P < 0.03) and dilatation of retinal veins (P < or = 0.05). This work has demonstrated that the development of different stages of diabetic retinopathy is closely correlated with an increased VEGF level in the retina.
Diabetes 2003 Mar
PMID:Enhanced recombinant adeno-associated virus-mediated vascular endothelial growth factor expression in the adult mouse retina: a potential model for diabetic retinopathy. 1260 31

The study addressed the role for aldose reductase (AR) in 1) retinal oxidative stress and vascular endothelial growth factor (VEGF) overexpression in early diabetes, and 2) high glucose-induced oxidative stress in retinal endothelial cells. In vivo experiments were performed on control rats and diabetic rats treated with or without low or high dose of the AR inhibitor (ARI) fidarestat (2 or 16 mg. kg(-1). day(-1)). In vitro studies were performed on bovine retinal endothelial cells (BREC) cultured in either 5 or 30 mmol/l glucose with or without 1 micro mol/l fidarestat. Intracellular reactive oxygen species were assessed using the 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (H(2)DCFDA) probe and flow cytometry. Both low and high doses of fidarestat (i.e., the doses that partially and completely inhibited sorbitol pathway hyperactivity) arrested diabetes-induced retinal lipid peroxidation. This was achieved due to upregulation of the key antioxidative defense enzyme activities rather than changes in reduced glutathione, oxidized glutathione, ascorbate and dehydroascorbate concentrations, and the glutathione and ascorbate redox states. Diabetes-associated 2.1-fold VEGF protein overexpression (enzyme-linked immunosorbent assay; ELISA) was dose-dependently prevented by fidarestat, whereas total VEGF mRNA and VEGF-164 mRNA (RT-PCR) abundance were not affected by either diabetes or the ARI. In BREC, fidarestat corrected hyperglycemia-induced increase in H(2)DCFDA fluorescence but not oxidative stress caused by three different pro-oxidants in normoglycemic conditions. In conclusion, increased AR activity contributes to retinal oxidative stress and VEGF protein overexpression in early diabetes. The findings justify the rationale for evaluation of fidarestat on diabetic retinopathy.
Diabetes 2003 Mar
PMID:Aldose reductase inhibitor fidarestat prevents retinal oxidative stress and vascular endothelial growth factor overexpression in streptozotocin-diabetic rats. 1260 32

Diabetes mellitus is associated with an increased risk of cardiovascular disease (CVD), even in the presence of intensive glycemic control. Substantial clinical and experimental evidence suggests that both diabetes and insulin resistance cause a combination of endothelial dysfunctions, which may diminish the anti-atherogenic role of the vascular endothelium. Endothelial dysfunctions that have been described include decreased endothelium-dependent vasorelaxation, increased leukocyte-endothelial cell adhesion and vascular permeability, and the altered production of a variety of vasoactive substances, which affect coagulation, extracellular matrix homeostasis, and smooth muscle physiology. The primary mechanisms that contribute to these endothelial dysfunctions in diabetes appear to involve the activation of protein kinase C (PKC) pathways, increased non-enzymatic glycation, increased oxidant stress, and reduced endothelial insulin action. In addition, many of the adverse effects of these abnormalities associated with hyperglycemia and insulin resistance are mediated and amplified by potent vasoactive hormones including angiotensin II, transforming growth factor-beta, and vascular endothelial growth factor. Multiple interventions have been shown to improve endothelial dysfunction in diabetes, including PKC inhibition, infusion of soluble receptors for advanced glycation end-products, antioxidant and insulin supplementation, and angiotensin-converting enzyme inhibition. These findings are consistent with a model involving a combination of factors contributing to the etiology of the endothelial dysfunctions in diabetes. Further work is needed to determine whether endothelial function can be used as a therapeutic target to reduce CVD and improve clinical outcomes.
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PMID:Endothelial dysfunction in diabetes mellitus: role in cardiovascular disease. 1263 71

A 62-year-old man with well-controlled diabetes mellitus developed numbness of the bilateral feet and hands, followed by subacutely progressive weakness and amyotrophy of extremities. He became bed-ridden state, and dyspnea also appeared, so he was referred to our hospital. Physical examination revealed a lean man, with dark-reddish skin pigmentation, crabbed fingers, bilateral pretibial pitting edema, and bristles in extremities. Thoracoabdominal paradoxical respiration was observed and pulmonary vesicular sounds was decreased markedly in the both lungs. Laboratory data revealed hypoproteinemia, abnormalities of endocrine system, but M-protein was not detected. Serum vascular endothelial growth factor level was quite high. Chest radiography revealed elevation of the bilateral diaphragm, the % vital capacity (%VC) was 24%, and arterial blood gas analysis showed marked hypoxia with hypercapnia. These findings suggested that his respiratory failure was induced by bilateral diaphragmatic paralysis caused by bilateral phrenic nerve palsy due to Crow-Fukase syndrome. He became somnolent because of hypercapnic narcosis, so non-invasive positive pressure ventilation (NIPPV) was started. We treated him with intravenous immunoglobulin and oral corticosteroids therapies, and after these therapies, his symptoms were remarkably recovered and NIPPV became unnecessary soon. The most frequent causes of respiratory failure in Crow-Fukase syndrome are pleural effusion and pulmonary hypertension, and only two cases of this syndrome with respiratory failure caused by bilateral diaphragmatic paralysis were reported until now. When the patients with Crow-Fukase syndrome complain of dyspnea, we should take the diaphragmatic paralysis into consideration, which may be improved by appropriate therapies.
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PMID:[A case of Crow-Fukase syndrome with respiratory failure due to bilateral diaphragmatic paralysis]. 1266 Nov 11

Several interacting and mutually perpetuating biochemical pathways or systems, such as the polyol pathway, nonenzymatic glycation, oxidative stress, protein kinase Cbeta and the reninangiotensin system, may be activated as a result of sustained hyperglycemia in diabetes. These abnormally activated pathways may in turn influence several vasoactive factors and cytokines, such as vascular endothelial growth factor, interleukin-6, pigment epithelium-derived factor and endostatin, which are important in mediating the functional and structural changes of diabetic retinopathy. Intricate and interacting regulatory mechanisms involving these factors may control their ultimate ability to produce biologically significant effects. A better understanding of these factors and their interactions may assist in the development of adjuvant therapies for the treatment of diabetic retinopathy. (c) 2002 Prous Science. All rights reserved.
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PMID:Pathophysiology of Diabetic Retinopathy. 1267 48

Increased vascular permeability is one of the first stages in both physiological and pathological angiogenesis-the generation of new blood vessels from preexisting vasculature. Although this has been hypothesised to be true in physiological angiogenesis, it is clearly a mark of blood vessel growth in disease. Normal, healthy blood vessel growth (physiological angiogenesis) occurs throughout development as well as during tissue repair and growth in adult tissues. Angiogenesis is also seen in a wide variety of diseases, which include all the major causes of mortality in the West-heart disease, cancer, stroke, vascular disease, and diabetes. Much of this angiogenesis is significantly different from normal blood vessel growth and is termed pathological angiogenesis. Angiogenesis is regulated by vascular growth factors, the most notable being the vascular endothelial growth factor family of proteins (VEGF). These act on specific receptors in the vascular system to stimulate new vessel growth by a number of mechanisms. VEGFs also directly stimulate increased vascular permeability to water and large molecular weight proteins and vasodilatation. These two effects result in a large flux of water and macromolecules from the vasculature to the interstitium, often resulting in oedema. This review will outline the mechanisms by which VEGFs do this and discuss some of the difficulties in interpreting data from VEGF studies due to the conflicting and synergistic effects of these actions.
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PMID:Regulation of vascular permeability by vascular endothelial growth factors. 1274 62

The purpose of these experiments was to determine the specific role of reactive oxygen species (ROS) in the blood-retinal barrier (BRB) breakdown that characterizes the early stages of vascular dysfunction in diabetes. Based on our data showing that high glucose increases nitric oxide, superoxide, and nitrotyrosine formation in retinal endothelial cells, we hypothesized that excess formation of ROS causes BRB breakdown in diabetes. Because ROS are known to induce increases in expression of the well-known endothelial mitogen and permeability factor vascular endothelial growth factor (VEGF) we also examined their influence on the expression of VEGF and its downstream target urokinase plasminogen activator receptor (uPAR). After 2 weeks of streptozotocin-induced diabetes, analysis of albumin leakage confirmed a prominent breakdown of the BRB. This permeability defect was correlated with significant increases in the formation of nitric oxide, lipid peroxides, and the peroxynitrite biomarker nitrotyrosine as well as with increases in the expression of VEGF and uPAR. Treatment with a nitric oxide synthase inhibitor (N-omega-nitro-L-arginine methyl ester, 50 mg/kg/day) or peroxynitrite scavenger (uric acid, 160 mg/kg/day) blocked the breakdown in the BRB and prevented the increases in formation of lipid peroxides and tyrosine nitration as well as the increases in expression of VEGF and uPAR. Taken together, these data indicate that early diabetes causes breakdown of the BRB by a mechanism involving the action of reactive nitrogen species in promoting expression of VEGF and uPAR.
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PMID:Experimental diabetes causes breakdown of the blood-retina barrier by a mechanism involving tyrosine nitration and increases in expression of vascular endothelial growth factor and urokinase plasminogen activator receptor. 1275 55

Angiopoietins are a recently discovered family of growth factors which act on endothelial cells via Tie receptors. They are widely expressed and have essential roles in regulating vascular growth, development, maturation and permeability. Disturbances in microvascular regulation play an important part in a number of diseases prominent in the developed world including diabetes, ischemic heart disease and cancer. It is the interplay between angiopoietins and other factors including vascular endothelial growth factor (VEGF) which determines endothelial behavior both in health and in these diseases. Angiopoietin-1 is unique in its ability to reduce endothelial permeability and it antagonises the effects of VEGF in its permeability and angiogenesis-inducing actions. The renal glomerulus constitutes a highly specialized microcirculation in which the permeability characteristics of the capillary wall allow its unique filtration function. Disturbance of this function may cause a reduction in glomerular filtration rate or proteinuria. Understanding of the regulation of the filtration barrier is incomplete but the expression of angiopoietins in the glomerulus suggests a mechanism for maintenance of the glomerular endothelium and modulation of the actions of glomerular VEGF. As has been clearly shown for VEGF, angiopoietins are likely to be involved in glomerular disease and recovery from it. Manipulation of angiopoietins has a wide range of potential therapeutic applications from inhibition of diabetic retinal neovascularisation to promotion of glomerular repair.
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PMID:Angiopoietins: microvascular modulators with potential roles in glomerular pathophysiology. 1276 63


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