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

There are reports that lung function is altered in diabetes mellitus. Since data are limited concerning the structural--functional correlates in hyperglycemic animals, we designed experiments to assess: (i) whether hyperglycemia induces changes in the structure of the lung capillary endothelial cells (EC), and (ii) the effect of advanced glycation endproducts of albumin (AGE-Alb) on EC. Experiments were conducted on mice and hamsters rendered diabetics by streptozotocin (D-STZ) injection; age-matched animals were used as controls (C). The structure of EC, and the interaction of EC with AGE-Alb adsorbed to 5 nm colloidal gold (AGE-Alb.Au) were examined by electron microscopy; the uptake and cellular distribution of [125I]-AGE-Alb were investigated by spectrometry and autoradiography. The results showed that, compared to C group, in D-STZ animals the alveolar capillary EC exhibited: (i) an uneven distribution of the anionic sites exposed by the luminal plasmalemma, (ii) a metabolicaly active phenotype, (iii) a thickened basal lamina provided with focal nodules, similar in density and distribution to those found in the glomerular basal lamina in diabetes; in addition, (iv) a narrowed or collapsed lumen was found in approximately 30% of the capillaries. The functional alterations of lung EC in diabetes consisted in increased uptake of intravascularly infused [125I]-AGE-Alb and enhanced transcytosis and endocytosis of AGE-Alb.Au. The fusion of plasmalemmal vesicles, and opening of the interendothelial junctions observed, may account for the increased permeability of the alveolar capillary EC. This study asserts that hyperglycemia affects the structure and functional properties of the alveolar capillary EC, and suggests the existence of microangiopathic alterations in diabetic lung.
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PMID:Structural and transport property alterations of the lung capillary endothelium in diabetes. 1172 83

Native glucose-derived glycation derivatives (advanced glycation end products, AGE) in vascular, renal and neuronal tissues contribute to organ damage. Glycation derivatives include a number of chemically and cell-reactive substances, also termed glycoxidation products or glycotoxins (GT). Cell-associated AGE-specific receptors (AGE-Rs), AGE-R1-3, RAGE, as well as the scavenger receptors ScR-II and CD-36 that are present on vascular, renal, hemopoietic, and neuronal/glial cells, serve in the regulation of AGE uptake and removal. AGE-Rs also modulate cell activation, growth-related mediators, and cell proliferation, consequently influencing organ structure/function. This occurs via oxidant stress triggered via receptor-dependent or -independent pathways, and leads to signal activation pathways, resulting in pro-inflammatory responses. In susceptible individuals, the AGE-R expression/function may be subject to environmental or gene-related modulation, which in turn may influence tissue-specific gene functions. In this context, altered expression and activity of AGE-R components has recently been found in both mouse diabetes models and humans with diabetic complications. Although several gene polymorphisms are detected in most AGE-R components, no significant correlation to diabetic complications has as yet been found. Further investigation is underway to define whether primary or secondary genetic links of pathogenic significance exist in this system. Various AGE-binding peptides or soluble receptors have emerged as potential sequestering agents for toxic AGEs as potential therapies for diabetic complications.
Diabetes Metab Res Rev
PMID:The AGE-receptor in the pathogenesis of diabetic complications. 1175 79

Hypertension and diabetes mellitus represent increasing threats to the health of many populations. For reasons not completely understood, the prevalence of these diseases is higher in some ethnic groups than in others. The key to this puzzle may rest with the interplay of a defect of an enzyme-mediated process and the environment. Oxidative stress and impairment of synthesis or release of nitric oxide (NO) are being regarded as causative factors in the pathogenesis of hypertension, diabetes mellitus and atherosclerosis, among other conditions. Glucose-6-phosphate dehydrogenase (G6PD) deficiency has been overlooked as a cause of both oxidative stress and a decrease in the generation of nitric oxide (NO). G6PD generates nicotinamide adenine dinucleotide phosphate (NADPH), a co-factor in the synthesis of nitric oxide. There is impairment of the production of nitric oxide superoxide and hydrogen peroxide in G6PD-deficient granulocytes. In the polyol pathway, G6PD deficiency causes hyperglycemia, making more glucose available for the non-enzymatic production of advanced glycosylation end products (AGE's), which also causes an increase in superoxide anions and a quenching of nitric oxide. Currently, there are 200 million people worldwide with red cell x-linked chromosome defects who, with the persistent ingestion of refined carbohydrates, are at greater risk of developing hypertension or diabetes mellitus than those racial groups without the defect.
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PMID:G6PD deficiency: its role in the high prevalence of hypertension and diabetes mellitus. 1176 98

Our observations show that long term hyperglycaemia by the formation of AGE, but also short term hyperglycaemic periods ("glucose spikes") damage the endothelium of the heart in diabetes. The endothelium is exposed to oxidative stress. The simultaneous generation of NO and superoxide anions enables the reaction of both species to form peroxynitrite which has been identified as an important mediator for the transformation of endothelium from an anticoagulant to a procoagulant state. Together with a functional loss of endothelium these processes are assumed to impair the coronary perfusion and to provoke adaptive processes which finally lead to cardiac dysfunction and remodelling of cardiac structure (Figure 6) as it has been described for the heart in diabetes.
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PMID:Molecular mechanisms of endothelial dysfunction in the diabetic heart. 1190 Apr 5

Receptor for AGE (RAGE) is a member of the immunoglobulin superfamily that engages distinct classes of ligands. The biology of RAGE is driven by the settings in which these ligands accumulate, such as diabetes, inflammation, neurodegenerative disorders and tumors. In this review, we discuss the context of each of these classes of ligands, including advance glycation end-products, amyloid beta peptide and the family of beta sheet fibrils, S100/calgranulins and amphoterin. Implications for the role of these ligands interacting with RAGE in homeostasis and disease will be considered.
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PMID:RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease. 1222 59

Semicarbazide-sensitive amine oxidase (SSAO) catalyzes formation of methylglyoxal (MG) from aminoacetone; MG then reacts with proteins to form advanced glycation end products or AGEs. Because of its potential to generate MG, SSAO may contribute to AGE-associated vascular complications of aging and diabetes. We developed a method to measure SSAO activity in bovine aortic smooth muscle cells (BASMC) based on the oxidation of 2',7'-dichlorofluorescin by hydrogen peroxide and horseradish peroxidase. The SSAO activity was completely inhibited by 10 mM semicarbazide. Argpyrimidine is a readily detectable fluorescent product of the reaction between MG and arginine. Cell lysates incubated with aminoacetone formed argpyrimidine in a reaction that was inhibited by 20 mM semicarbazide. Immunostaining of tissue sections showed that aminoacetone-treated rats (normal as well as diabetic) formed more argpyrimidine in aortic smooth muscle than untreated controls. We believe that SSAO can enhance AGE synthesis in the macrovasculature of diabetic individuals by production of MG.
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PMID:Semicarbazide-sensitive amine oxidase in aortic smooth muscle cells mediates synthesis of a methylglyoxal-AGE: implications for vascular complications in diabetes. 1235 32

Thickening of basement membrane in capillaries and small vessels is a well-known finding and important in the progression of diabetic microangiopathy. To monitor the metabolism of the basement membrane protein collagen type IV (CIV) in diabetes mellitus, serum levels of IgG, IgM and IgA to CIV were measured using an ELISA method in 28 children with Type 1 diabetes mellitus over a period of 6 years. These values were compared to serum antibodies to CIV in 24 age- and sex-matched controls. At the end of the study, 11 children had diabetic microangiopathy. IgG to CIV was associated with age (r = .33, P = .026), diabetes duration (r = .32, P = .021), HbA1c (r = .31, P = .019), microalbuminuria (r = .32, P = .022) and anti-AGE antibodies (r = .47, P = .0007). IgM to CIV correlated with age (r = .46, P = .001), diabetes duration (r = .45, P = .001), HbA1c (r = .26, P = .038) and anti-AGE antibodies (r = .26, P = .038) and IgA to CIV with triglycerides (r = .29, P = .038) and anti-AGE antibodies (r = .44, P = .0025). We suggest that serum levels of IgG to CIV can be used as a marker for the development of diabetic microalbuminuria.
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PMID:Serum antibodies to collagen type IV and development of diabetic vascular complications in children with type 1 (insulin-dependent) diabetes mellitus. A longitudinal study. 1240 12

Diet is a major environmental source of proinflammatory AGEs (heat-generated advanced glycation end products); its impact in humans remains unclear. We explored the effects of two equivalent diets, one regular (high AGE, H-AGE) and the other with 5-fold lower AGE (L-AGE) content on inflammatory mediators of 24 diabetic subjects: 11 in a 2-week crossover and 13 in a 6-week study. After 2 weeks on H-AGE, serum AGEs increased by 64.5% (P = 0.02) and on L-AGE decreased by 30% (P = 0.02). The mononuclear cell tumor necrosis factor-alphabeta-actin mRNA ratio was 1.4 +/- 0.5 on H-AGE and 0.9 +/- 0.5 on L-AGE (P = 0.05), whereas serum vascular adhesion molecule-1 was 1,108 +/- 429 and 698 +/- 347 ngml (P = 0.01) on L- and H-AGE, respectively. After 6 weeks, peripheral blood mononuclear cell tumor necrosis factor-alpha rose by 86.3% (P = 0.006) and declined by 20% (P, not significant) on H- or L-AGE diet, respectively; C-reactive protein increased by 35% on H-AGE and decreased by 20% on L-AGE (P = 0.014), and vascular adhesion molecule-1 declined by 20% on L-AGE (P < 0.01) and increased by 4% on H-AGE. Serum AGEs were increased by 28.2% on H-AGE (P = 0.06) and reduced by 40% on L-AGE (P = 0.02), whereas AGE low density lipoprotein was increased by 32% on H-AGE and reduced by 33% on L-AGE diet (P < 0.05). Thus in diabetes, environmental (dietary) AGEs promote inflammatory mediators, leading to tissue injury. Restriction of dietary AGEs suppresses these effects.
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PMID:Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. 1242 56

Previous studies have shown that renal function in type 2 diabetes correlates better with tubular changes than with glomerular pathology. Since advanced glycation end products (AGEs; AGE-albumin) and in particular carboxymethyllysine (CML) are known to play a central role in diabetic nephropathy, we studied the activation of nuclear factor kappaB (NF-kappaB) in tubular epithelial cells in vivo and in vitro by AGE-albumin and CML. Urine samples from healthy control subjects (n = 50) and type 2 diabetic patients (n = 100) were collected and tested for excretion of CML and the presence of proximal tubular epithelial cells (pTECs). CML excretion was significantly higher in diabetic patients than in healthy control subjects (P < 0.0001) and correlated with the degree of albuminuria (r = 0.7, P < 0.0001), while there was no correlation between CML excretion and HbA(1c) (r = 0.03, P = 0.76). Urine sediments from 20 of 100 patients contained pTECs, evidenced by cytokeratin 18 positivity, while healthy control subjects (n = 50) showed none (P < 0.0001). Activated NF-kappaB could be detected in the nuclear region of excreted pTECs in 8 of 20 patients with pTECs in the urine sediment (40%). Five of eight NF-kappaBp65 antigen-positive cells stained positive for interleukin-6 (IL-6) antigen (62%), while only one of the NF-kappaB-negative cells showed IL-6 positivity. pTECs in the urine sediment correlated positively with albuminuria (r = 0.57, P < 0.0001) and CML excretion (r = 0.55, P < 0.0001). Immunohistochemistry in diabetic rat kidneys and a human diabetic kidney confirmed strong expression of NF-kappaB in tubular cells. To further prove an AGE/CML-induced NF-kappaB activation in pTECs, NF-kappaB activation was studied in cultured human pTECs by electrophoretic mobility shift assays (EMSAs) and Western blot. Stimulation of NF-kappaB binding activity was dose dependent and was one-half maximal at 250 nmol/l AGE-albumin or CML and time dependent at a maximum of activation after 4 days. Functional relevance of the observed NF-kappaB activation was demonstrated in pTECs transfected with a NF-kappaB-driven luciferase reporter plasmid and was associated with an increased release of IL-6 into the supernatant. The AGE- and CML-dependent activation of NF-kappaBp65 and NF-kappaB-dependent IL-6 expression could be inhibited using the soluble form of the receptor for AGEs (RAGE) (soluble RAGE [sRAGE]), RAGE-specific antibody, or the antioxidant thioctic acid. In addition transcriptional activity and IL-6 release from transfected cells could be inhibited by overexpression of the NF-kappaB-specific inhibitor kappaBalpha. The findings that excreted pTECs demonstrate activated NF-kappaB and IL-6 antigen and that AGE-albumin and CML lead to a perpetuated activation of NF-kappaB in vitro infer that a perpetuated increase in proinflammtory gene products, such as IL-6, plays a role in damaging the renal tubule.
Diabetes 2002 Dec
PMID:Activation of tubular epithelial cells in diabetic nephropathy. 1245 11

Arteriosclerosis, atherosclerosis and vascular calcification are causally related to the high morbidity and mortality of patients with chronic renal failure. Oxidative stress and carbonyl stress of uremia, dialysis procedure and/or intravenous iron therapy result in AGE (advanced glycation end-product), ALE (advanced lipoxidation end-product) and AOPP (advanced oxidation protein product) formation, favouring together with elevated CRP (C-reactive protein) levels the development of cardiovascular and cerebrovascular complications. Enhanced plasma levels of homocysteine and ADMA (asymmetric dimethylarginine) contribute to this process. In addition, in chronic renal insufficiency hyperphosphatemia and an enhanced calcium x phosphorus ion product are associated with the morbidity and mortality of the patients, particularly in the presence of fetuin deficiency. Phosphorus, AGEs and AOPPs, beside other factors, catalyze the conversion of vascular smooth muscle cells to osteoblast--like cells (particularly in the presence of monocytes/macrophages), resulting in bone matrix protein formation. Other risk factors, such as age, male sex, smoking, hypertension, diabetes, chronic inflammation, insulin resistance or dyslipidemia (enhanced non-HDL-cholesterol) also contribute to the atherosclerotic risk profile of the patient with chronic renal insufficiency. While there is growing understanding of the mechanisms involved in arteriosclerosis, atherosclerosis and vascular calcification in uremia, we are still missing effective therapeutic maneuvers for reduction of excess mortality in uremic patients.
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PMID:[Atherosclerosis and uremia: signifance of non-traditional risk factors]. 1277 74


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