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)

Type 1 diabetes mellitus is known to be associated with reduced bone mass and increased bone fractures. This is thought to be due to a decrease in osteoblastic bone formation rather than an increase in osteoclastic bone resorption, but the precise mechanism is unknown. In this study, we examined whether or not high glucose or advanced glycation end-products (AGEs), which play key roles in the pathogenesis and complications of diabetes, affect the differentiation of osteoblastic MC3T3-E1 cells. First, MC3T3-E1 cells were incubated in media containing either 22 mM glucose, 22 mM mannitol, 300 microg/ml AGE2, or 300 microg/ml AGE3. Each of these agents alone did not affect the mineralization of the cells by von Kossa staining and Alizarin red staining. However, high glucose but not mannitol or AGEs markedly increased mRNA expression of AGE receptor (RAGE) by real-time PCR. Next, we examined the combined effects of high glucose and AGEs on the differentiation of MC3T3-E1 cells. The combination of 22 mM glucose and 300 microg/ml AGE2 significantly inhibited the mineralization of MC3T3-E1 cells, and 22 mM glucose in combination with either 300 microg/ml AGE2 or AGE3 apparently decreased osteocalcin mRNA expression. These results suggest that high glucose or AGEs alone might have no effect on osteoblastic differentiation, but their combination could additionally or synergistically inhibit osteoblastic mineralization through glucose-induced increase in RAGE expression.
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PMID:The combination of high glucose and advanced glycation end-products (AGEs) inhibits the mineralization of osteoblastic MC3T3-E1 cells through glucose-induced increase in the receptor for AGEs. 1796 May 13

Advanced glycation end-products (AGE) are a group of heterogeneous molecules found in higher levels during diabetes, end stage renal failure and aging. Vascular alteration is correlated with their accumulation as during retinopathy or glomerulosclerosis. Glycation of extracellular matrix proteins is associated with diabetic angiopathy. AGE stimulate endothelial cell via the interaction with the receptor RAGE, leading to an inflammatory state with increased adhesion molecule expression, chemoattractant factor and tissue factor production. RAGE activation by AGE triggers reactive oxygen species production by NADPH oxydase. Agents that inhibit AGE formation, stimulate their degradation or neutralize their binding to RAGE represent new approaches to limit the deleterious activities of AGE.
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PMID:[Protein glycation and endothelium dysfunction]. 1797 51

Advanced Glycation End-products (AGE-s) were shown to exhibit a number of potentially harmful properties in contact with cells and tissues. As their concentrations increases with age, faster even in hyperglycemic individuals, they are considered important for aging- and age-associated pathologies, especially for athero-arteriosclerosis and type II diabetes. We describe here the methods used for the demonstration of a direct cytotoxicity of several AGE-products when added to human skin fibroblast cultures. This cytotoxicity was still demonstrable when cells, previously cultured with AGE-s, were transferred to new medium without AGE-s. This effect, the remanence of cytotoxicity in absence of AGE-s, suggests a certain degree of inheritance, possibly by epigenetic mechanisms, of the cytotoxic effect of AGE-s, mediated by the AGE-receptors (RAGE-s) and inhibited by free radical-scavengers, such as L-Carnosine, Catalase and Rhamnose-rich oligo- and polysaccharides. Such cytotoxicity can occur not only on the skin but also in other tissues. It appears thus that besides the crosslinking of collagen and other macromolecules, the products of the Maillard reaction can exert their harmful cytotoxic effects directly on the cells.
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PMID:[Demonstration of the cytotoxic effect of Advanced Glycation Endproducts (AGE-s)]. 1797 52

Reducing sugars can react non-enzymatically with amino groups of protein to form Amadori products. These early glycation products undergo further complex reaction such as rearrangement, dehydration, and condensation to become irreversibly cross-linked, heterogeneous fluorescent derivatives, termed advanced glycation end products (AGEs). The formation and accumulation of AGEs have been known to progress at an accelerated rate in diabetes. There is a growing body of evidence that AGEs and their receptor (RAGE) axis is implicated in the pathogenesis of diabetic vascular complications. Indeed, the engagement of RAGE with AGEs is shown to elicit oxidative stress generation and subsequently evoke inflammatory responses in various types of cells, thus playing an important role in the development and progression of diabetic micro- and macroangiopathy. Moreover, administration of a recombinant soluble form of RAGE (sRAGE), has been shown to suppress the development of accelerated atherosclerosis in diabetic apolipoprotein E-null mice. These observations suggest that exogenously administered sRAGE may capture and eliminate circulating AGEs, thus protecting against the AGEs-elicited tissue damage by acting as a decoy receptor. Recently, endogenous sRAGE has been identified in humans. However, there is few comprehensive review about the regulation and role of endogenous sRAGE in diabetes. In the former part of this paper, we review the role of the AGE-RAGE system in the pathogenesis of diabetic vascular complications. Then we summarize in the latter part of this review the kinetics and pathophysiological role of endogenous sRAGE in diabetes. We also discuss the possibility that endogenous sRAGE may be a therapeutic target for the prevention of diabetic vascular complications.
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PMID:Kinetics, role and therapeutic implications of endogenous soluble form of receptor for advanced glycation end products (sRAGE) in diabetes. 1797 74

Functional polymorphisms of two MHC genes (DRB1 and RAGE) were analysed in Italian pediatric patients with Type 1 diabetes and in a control group. The diabetic condition is related positively to the positive electric charge of the pocket 4 of pro-inflammatory DRB1 alleles (R = 0.5072, P = 0.0001) and negatively to at least one anti-inflammatory RAGE allele (R = -0.2200, P = 0.0106). The association DRB1-disease decreases from high risk positively charged alleles to low risk negatively ones. A multiple regression model including the effect of electric charges at positions 70 and 74 of the DRB1 explains more than 31% of the variability of our data. The addition of the RAGE dependent variables does not increase the significance of the model. Our results confirm that the interaction between a negatively charged amino acid of insulin autoantigenic peptides and a positively charged DRB1 is the key event triggering the autoimmune process. The linkage disequilibrium between RAGE and DRB1 is the main cause of the association between the variants of RAGE and the initial outcome of the disease. However, since RAGE ligands increase during the disease progression, the observed association suggests that the proinflammatory RAGE and DRB1 polymorphisms synergize to activate the immune response which leads to the complications of diabetes. These evidences support a new hypothesis that considers the largely unexplored role of the MHC genes in genetic adaptation to a variable environment and in the maintenance of the metabolic biodiversity. A mechanism based on the maternal immunization against the negatively charged autoantigens, such as the insulin peptide B9-23, and on the fetal-maternal interaction might transform the physiological adaptation into adaptive changes of the genetic population structure. According to the "thrifty-genotype" hypothesis, "thrifty DRB alleles" with a positive charge are responsible for the susceptibility to diabetes and for an efficient storage of caloric intake in arctic climates with scarce food availability while "non-thrifty DRB alleles" with a negative or neutral charge are advantaged in tropical climates with constant food supply.
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PMID:Pro-inflammatory variants of DRB1 and RAGE genes are associated with susceptibility to pediatric type 1 diabetes: a new hypothesis on the adaptive role of autoimmunity. 1798 63

Chronic diseases (CD) represent the main cause of mortality in developed countries. The increase in the prevalence of of CD is associated with changes in lifestyle habits, including those related to the consumption of processed foodstuffs. In these foods advanced glycation end products (AGE) and advanced lipoperoxydation products (ALE) are formed as a consequence of the reactivity of proteins, carbohydrates, lipid and other components. The aim of the present review is to offer a perspective of how AGE and ALE affect the physiology and development of CD. Continous intake of AGE and ALE contributes to the exccesive accumulation of these products into body tissues, which in turn negatively influence the innate immune system, inflammatory responses, and resistance to diseases. This is achieved by direct interaction of AGE and ALE with specific cell AGE receptors (RAGE) that have a key role as master switches regulating the development of CD. Long-life molecules, namely collagen and myelin, and low-turnover tissues, e.g. connective, bone and neural tissues, are the main targets of AGE and ALE. In these tissues, AGE and ALE lead to the synthesis of insoluble compounds that severely alter cellular functionality. It has been reported associations of AGE and ALE with allergic and autoimmune diseases, Alzheimer disease and other degenerative disorders, catarats, atherosclerosis, cancer, and diabetes mellitus type 2, as well as a number of endocrine, gastrointestinal, skeleton-muscle, and urogenital alterations. Controlling all those pathologies would need further dietary recommendations aiming to limit the intake of processed foods rich in AGE and ALE, as well as to reduce the formation of those products by improving technological processes applicable to foods.
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PMID:[Advanced glycation and lipoxidation end products--amplifiers of inflammation: the role of food]. 1805 88

Diabetic vascular complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Chronic hyperglycemia is essentially involved in the development and progression of diabetic micro- and macroangiopathy. Among various metabolic derangements implicated in the pathogenesis of diabetic vascular complication, advanced glycation end product (AGE) hypothesis is most compatible with the theory of 'hyperglycemic memory'. In this review, we discuss the molecular mechanisms of diabetic vascular complication, specially focusing on AGEs and their receptor (RAGE) system. Several types of AGE inhibitors and their therapeutic implications in this devastating disorder are also discussed here.
Curr Diabetes Rev 2005 Feb
PMID:Advanced glycation end products (AGEs) and diabetic vascular complications. 1822 May 86

Atherosclerosis is a major global cause of morbidity and mortality, and diabetes patients are at increased risk of coronary heart disease development. Advanced glycation of proteins occurs in the body due to raised concentrations of reducing sugars and reactive oxygen species, and is a causal factor behind complications of diabetes. Glycated proteins, through alteration of protein structure and function, and from ligation with their receptors, lead to widespread vascular damage. The alpha-oxoaldehyde, methylglyoxal (MG) is the most reactive glycation precursor, and is increased in the blood of diabetes patients. There is debate about the triggering events leading to atherosclerosis, but the inflammatory action of glycated proteins, including those with MG adducts, through their receptor, RAGE, is a major candidate for initiating plaque formation. In addition glycation may cause cross-links on proteins of the extracellular matrix, stiffening arteries and 'trapping' other macromolecules. MG is also likely to form adducts on many other proteins, enzymes, lipids, DNA or RNA, changing their structure, and may disrupt enzyme activity, hormone regulation and immune function. In the latter context, MG disrupts function of the potent antigen presenting cells, dendritic cells. This effect may be a double edged sword: Poor control of infections may contribute to persistent inflammation, whilst inhibition of immune activation by dendritic cells may inhibit plaque progression. This review aims to present these ideas as a novel slant on the role of the glycation process in atherosclerosis.
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PMID:Advanced glycation: a novel outlook on atherosclerosis. 1822 Aug 6

Advanced glycation endproducts (AGEs) are implicated in the complications of diabetes and ageing, affecting several tissues, including bone. Metformin, an insulin-sensitizer drug, reduces the risk of life-threatening macrovascular complications. We have evaluated the hypothesis that metformin can abrogate AGE-induced deleterious effects in osteoblastic cells in culture. In two osteoblast-like cell lines (UMR106 and MC3T3E1), AGE-modified albumin induced cell death, caspase-3 activity, altered intracellular oxidative stress and inhibited alkaline phosphatase activity. Metformin-treatment of osteoblastic cells prevented these AGE-induced alterations. We also assessed the expression of AGE receptors as a possible mechanism by which metformin could modulate the action of AGEs. AGEs-treatment of osteoblast-like cells enhanced RAGE protein expression, and this up-regulation was prevented in the presence of metformin. Although the precise mechanisms involved in metformin signaling are still elusive, our data implicate the AGE-RAGE interaction in the modulation of growth and differentiation of osteoblastic cells.
Exp Clin Endocrinol Diabetes 2008 Jun
PMID:Metformin reverts deleterious effects of advanced glycation end-products (AGEs) on osteoblastic cells. 1827 53

Diabetic vascular complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Although several hyperglycemia-elicited metabolic and hemodynamic derangements have been implicated in the pathogenesis of diabetic vascular complication, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory 'hyperglycemic memory'. Further, there is a growing body of evidence that AGEs and their receptor (RAGE) axis is involved in the pathogenesis of diabetic vascular complication. Indeed, the engagement of RAGE with AGEs is shown to elicit oxidative stress generation and subsequently evoke inflammatory responses in various types of cells, thus playing an important role in the development and progression of diabetic micro- and macroangiopathy. These observations suggest that down-regulation of RAGE expression or blockade of the RAGE downstream signaling may be a promising target for therapeutic intervention in diabetic vascular complication. In this review, we discuss several types of agents that could potentially inhibit RAGE expression or its downstream pathways and their therapeutic implications in diabetic vascular complication.
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PMID:Receptor for advanced glycation end products (RAGE): a novel therapeutic target for diabetic vascular complication. 1828 75


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