Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expansion of extracellular matrix with fibrosis occurs in many tissues as part of the end-organ complications in diabetes, and advanced glycosylation end products (AGE) are implicated as one causative factor in diabetic tissue fibrosis. Connective tissue growth factor (CTGF), also known as insulin-like growth factor-binding protein-related protein-2 (IGFBP-rP2), is a potent inducer of extracellular matrix synthesis and angiogenesis and is increased in tissues from rodent models of diabetes. The aim of this study was to determine whether CTGF is up-regulated by AGE in vitro and to explore the cellular mechanisms involved. AGE treatment of primary cultures of nonfetal human dermal fibroblasts in confluent monolayer increased CTGF steady state messenger RNA (mRNA) levels in a time- and dose-dependent manner. In contrast, mRNAs for other IGFBP superfamily members, IGFBP-rP1 (mac 25) and IGFBP-3, were not up-regulated by AGE. The effect of the AGE BSA reagent on CTGF mRNA was due to nonenzymatic glycosylation of BSA and, using neutralizing antisera to AGE and to the receptor for AGE, termed RAGE, was seen to be due to late products of nonenzymatic glycosylation and was partly mediated by RAGE. Reactive oxygen species as well as endogenous transforming growth factor-beta1 could not explain the AGE effect on CTGF mRNA. AGE also increased CTGF protein in the conditioned medium and cell-associated CTGF. Thus, AGE up-regulates the profibrotic and proangiogenic protein CTGF (IGFBP-rP2), a finding that may have significance in the development of diabetic complications.
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PMID:Advanced glycosylation end products up-regulate connective tissue growth factor (insulin-like growth factor-binding protein-related protein 2) in human fibroblasts: a potential mechanism for expansion of extracellular matrix in diabetes mellitus. 1131 39

Vascular complications arising from multiple environmental and genetic factors are responsible for many of the disabilities and short life expectancy associated with diabetes mellitus. Here we provide the first direct in vivo evidence that interactions between advanced glycation end products (AGEs; nonenzymatically glycosylated protein derivatives formed during prolonged hyperglycemic exposure) and their receptor, RAGE, lead to diabetic vascular derangement. We created transgenic mice that overexpress human RAGE in vascular cells and crossbred them with another transgenic line that develops insulin-dependent diabetes shortly after birth. The resultant double transgenic mice exhibited increased hemoglobin A(1c) and serum AGE levels, as did the diabetic controls. The double transgenic mice demonstrated enlargement of the kidney, glomerular hypertrophy, increased albuminuria, mesangial expansion, advanced glomerulosclerosis, and increased serum creatinine compared with diabetic littermates lacking the RAGE transgene. To our knowledge, the development of this double transgenic mouse provides the first animal model that exhibits the renal changes seen in humans. Furthermore, the phenotypes of advanced diabetic nephropathy were prevented by administering an AGE inhibitor, (+/-)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide (OPB-9195), thus establishing the AGE-RAGE system as a promising target for overcoming this aspect of diabetic pathogenesis.
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PMID:Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice. 1145 79

RAGE (receptor for advanced glycation end products) is a multiligand cell surface molecule of the immunoglobulin superfamily. It was originally described as a receptor for protein adducts formed by glycoxidation (AGEs) that accumulate in diseases such as diabetes and renal failure. Performing RT-PCR and Western blot analysis we intended to determine RAGE expression in the human colon adenocarcinoma cell line Caco-2. Moreover, Caco-2 cells were incubated in the presence of AGEs. Since RAGE ligation triggers the p21(ras) signal transduction pathway the activation state of p44/42 (ERK1/2) MAP kinases was determined. Here we demonstrate for the first time that Caco-2 cells express RAGE and that administration of the food-derived casein-linked AGE N(epsilon)-(carboxymethyl)lysine (Cas-CML) results in Caco-2 p44/42 (ERK1/2) MAP kinase activation.
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PMID:RAGE expression and AGE-induced MAP kinase activation in Caco-2 cells. 1170 25

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

Nonenzymatic glycation, i.e. binding of monosaccharides to amino groups of proteins, gives rise to complex components called "advanced glycation end-products" (AGEs), which alter protein structure and functions, and participate in diabetic long-term complications. Glycation and oxidative stress are closely linked, and are often referred to as "glycoxidation" processes. Experimental data support these interactions. a) All glycation steps generate oxygen free radicals, some of these steps being common with these of lipid peroxidation. b) AGEs bind to membrane receptors such as RAGE, and induce an oxidative stress and a pro-inflammatory status. c) Glycated proteins modulate cellular oxidative functions: glycated collagens induce an inappropriate oxidative response in PMNs. d) Products of lipid peroxidation (MDA) bind to proteins and amplify glycoxidation-induced damages. Glycoxydation intensity increases in diabetes mellitus, ageing, renal failure and other pathological states with oxidative stress. Therapies aiming at limiting glycoxidation take into account its oxidative part.
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PMID:[Advanced glycation end products (AGEs), free radicals and diabetes]. 1193 55

Diabetes and renal failure have been associated with extremely high restenosis rates following successful angioplasty, resulting in increased morbidity and mortality. Advanced glycosylation end products (AGEs) accumulate in vascular tissues with aging and at an accelerated rate in diabetes and renal failure. AGEs are particularly abundant at sites of atherosclerotic lesions. AGEs interact with specific receptors (RAGE) present on all cells relevant to the restenosis process including inflammatory cells and smooth muscle cells. AGEs-RAGE interaction in vessel wall may lead to inflammation, smooth muscle cell proliferation, and extracellular matrix production, culminating in exaggerated intimal hyperplasia and restenosis. Following arterial injury, the interaction of AGEs with monocytes expressing RAGE can promote migration of inflammatory cells into the lesion and subsequent release of growth factors and cytokines. Binding of AGEs-RAGE on smooth muscle cells increases chemotactic migration and cellular proliferation. AGEs trigger the generation of reactive oxygen species, and upregulate the multifunctional transcription factor NF-kappa B. Finally, AGEs can augment extracellular matrix production by upregulating transforming growth factor-beta. Thus, accumulation of AGEs in vessel wall provides a common mechanism for the high restenosis rates of patients with diabetes and renal failure.
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PMID:Potential role of advanced glycosylation end products in promoting restenosis in diabetes and renal failure. 1220 56

We previously have found that advanced glycation end products (AGE), senescent macroproteins formed at an accelerated rate in diabetes, arise in vivo not only from glucose but also from reducing sugars. Furthermore, we recently have shown that glyceraldehyde- and glycolaldehyde-derived AGE (glycer- and glycol-AGE) are mainly involved in loss of pericytes, the earliest histopathological hallmark of diabetic retinopathy. However, the effects of these AGE proteins on angiogenesis, another vascular derangement in diabetic retinopathy, remain to be elucidated. In this study, we investigated whether these AGE proteins elicit changes in cultured endothelial cells that are associated with angiogenesis. When human skin microvascular endothelial cells (EC) were cultured with glycer-AGE or glycol-AGE, growth and tube formation of EC, the key steps of angiogenesis, were significantly stimulated. The AGE-induced growth stimulation was significantly enhanced in AGE receptor (RAGE)-overexpressed EC. Furthermore, AGE increased transcriptional activity of nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) and then up-regulated mRNA levels of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) in EC. Cerivastatin, a hydroxymethylglutaryl CoA reductase inhibitor; pyrrolidinedithiocarbamate; or curcumin was found to completely prevent the AGE-induced increase in NF-kB and AP-1 activity, VEGF mRNA up-regulation, and the resultant increase in DNA synthesis in microvascular EC. These results suggest that the AGE-RAGE interaction elicited angiogenesis through the transcriptional activation of the VEGF gene via NF-kB and AP-1 factors. By blocking AGE-RAGE signaling pathways, cerivastatin might be a promising remedy for treating patients with proliferative diabetic retinopathy.
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PMID:Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin. 1236 25

The formation of advanced glycation end products (AGEs) on extracellular matrix components leads to accelerated increases in collagen cross linking that contributes to myocardial stiffness in diabetes. This study determined the effect of the crosslink breaker, ALT-711 on diabetes-induced cardiac disease. Streptozotocin diabetes was induced in Sprague-Dawley rats for 32 weeks. Treatment with ALT-711 (10 mg/kg) was initiated at week 16. Diabetic hearts were characterized by increased left ventricular (LV) mass and brain natriuretic peptide (BNP) expression, decreased LV collagen solubility, and increased collagen III gene and protein expression. Diabetic hearts had significant increases in AGEs and increased expression of the AGE receptors, RAGE and AGE-R3, in association with increases in gene and protein expression of connective tissue growth factor (CTGF). ALT-711 treatment restored LV collagen solubility and cardiac BNP in association with reduced cardiac AGE levels and abrogated the increase in RAGE, AGE-R3, CTGF, and collagen III expression. The present study suggests that AGEs play a central role in many of the alterations observed in the diabetic heart and that cleavage of preformed AGE crosslinks with ALT-711 leads to attenuation of diabetes-associated cardiac abnormalities in rats. This provides a potential new therapeutic approach for cardiovascular disease in human diabetes.
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PMID:A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes. 1270 39

Hyperglycemia derived advanced glycation endproducts (AGE) have been implicated in diabetic atherosclerosis (AS) but the role of exogenous (dietary) AGE in the development of this serious complication is not known. This study evaluates the influence of diet-related AGE on AS in genetically hypercholesterolemic apolipoprotein E-deficient (apoE(-/-)), streptozotocin-induced diabetic mice. Diabetic and non-diabetic apoE(-/-) mice (6-8 weeks old) were randomized into either a standard AIN-93G chow (AGE 12,500+/-700 U/mg, termed high-AGE diet, H-AGE), or the same chow having four to fivefold lower AGE level (L-AGE: 2,700+/-830 U/mg) based on ELISA. After 2 months of diabetes, compared to the diabetic mice fed standard (H-AGE) diet, the AS lesions at the aortic root of the L-AGE group were >50% smaller (0.17+/-0.03 vs. 0.31+/-0.05 mm(2), P<0.05). Serum AGE were lower in the diabetic L-AGE than in the H-AGE mice (by approximately 53%) (P<0.00001), as were in the non-diabetic L-AGE vs. H-AGE groups (P<0.05). No diet-related changes were noted in plasma glucose, triglycerides, or plasma cholesterol. Immunohistochemical comparisons showed markedly suppressed tissue AGE, AGE-Receptor-1, -2 and RAGE expression, reduced numbers of inflammatory cells, tissue factor, vascular cell adhesion molecule-1 and MCP-1 in the L-AGE diabetic group. The findings are supportive of an important link between dietary intake of pre-formed glycoxidation products, tissue-incorporated AGE, and diabetes-accelerated AS. The marked anti-atherogenic effects of an AGE-restricted diet in this model may provide the basis for relevant clinical studies.
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PMID:Dietary glycotoxins promote diabetic atherosclerosis in apolipoprotein E-deficient mice. 1280 3

Advanced glycation end-products (AGEs) are formed during non-enzymatic glycation--the process occurring in vitro and in the organism. The glycation products accumulate in tissues and interact with specific receptors, what induces various cellular responses. Some enzymes important in metabolism can be also glycated. The disturbances of homeostasis, related to the glycation products, are the reason for complications observed in diabetes and aging processes. There are presented in this paper: mechanism of the formation of AGEs, their cellular receptor (RAGE), as well as the effects of glycation in aging, diabetes and Alzheimer disease. Finally, there are described the compounds which could be useful as inhibitors of glycation in clinical practice.
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PMID:[Biochemical properties and clinical significance of protein glycation products]. 1286 52


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