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)

Longstanding diabetes mellitus damages kidney, retina, peripheral nerve and blood vessels, but brain is not usually considered a primary target. We describe direct involvement of the brain, particularly white matter, in long-term (9 months) experimental diabetes of mice, not previously modeled, correlating magnetic resonance (MR) imaging with quantitative histological assessment. Leukoencephalopathy and cerebral atrophy, resembling that encountered in diabetic humans, developed in diabetic mice and was accompanied by time-related development of cognitive changes in behavioural testing. Increased RAGE (receptor for advanced glycation end products) expression, a mediator of widespread diabetic complications, increased dramatically at sites of white matter damage in regions of myelination. RAGE expression was also elevated within neurons, astrocytes and microglia in grey matter and within oligodendrocytes in white matter. RAGE null diabetic mice had significantly less neurodegenerative changes when compared to wild-type diabetic mice. Our findings identify a robust and novel model of cerebral, particularly white matter, involvement with diabetes associated with abnormal RAGE signaling.
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PMID:Diabetes, leukoencephalopathy and rage. 1681 28

Metabolic alterations of diabetes mellitus are not only informative biological signs, but also factors of degenerative complications. Thus, hyperglycaemia increases non enzymatic glycation, characterized by the binding of simple oses (glucose) or by-products to amino groups of proteins. This reaction leads to the formation of complex compounds, advanced glycation end products (AGEs), which alter structure and functions of proteins. Glycation and oxidative stress are closely linked, and both phenomena are referred to as "glycoxidation". All steps of glycoxidation generate oxygen free radical production, some of them being common with lipidic peroxidation pathways. Besides, glycated proteins activate membrane receptors such as RAGE through AGEs, and induce an intracellular oxidative stress and a pro-inflammatory status. So, glycated proteins may modulate functions of cells involved in oxidative metabolism and induce inappropriate responses. Finally, some oxidative products (reactive aldehydes such as methylglyoxal) or lipid peroxidation products (malondialdehyde) may bind to proteins and amplify glycoxidation-generated lesions. The knowledge of glycoxidation mechanisms may lead to new therapeutic approaches.
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PMID:[Oxidative stress and protein glycation in diabetes mellitus]. 1682 72

Features of autoimmunity have been associated with both Alzheimer's disease (AD) and with diabetes. In both diseases high levels of advanced glycation end products (AGEs) and their receptor (RAGE) have been detected in tissues and in the circulation. In addition high titers of antibodies directed against a RAGE-like peptide occur in the circulation. In this study we report the presence of auto-antibodies directed against RAGE and the cytotoxic amyloid peptide Abeta42 in plasma samples derived from four study groups. Anti-RAGE IgG titers were greatest in the AD-diabetic cohort. They were followed in decreasing order by the AD-non-diabetic cohort, the elderly diabetic cohort, and lastly by the control non-diabetic elderly cohort. The same profile of IgG differences was evident for the anti-Abeta42 titers. When all of the data were combined, there was a strong linear correlation between the RAGE and Abeta42 titers suggesting that the two peptides exist as a tight complex in plasma. Plasma IgG titers were not correlated with cognitive status except that AD and AD-diabetic participants were significantly cognitively impaired relative to the two non-AD groups. There also was no significant correlation between IgG titers and subject age, except that there was a trend for a negative slope for the AD participants and a positive slope for the control participants. In keeping with the human data, we also report that chemically-induced diabetes in rats was associated with high levels of AGEs, anti-RAGE-like IgGs, and anti-Abeta42-like IgGs. For non-diabetic rats, there was a clear age-dependency regarding the magnitude of the IgG levels. These data support the concept of an interrelationship between diabetes and AD. For both diseases one underlying contributing factor to cytotoxicity could be the development of an autoimmune response triggered by the presence of AGEs and amyloid peptides.
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PMID:Autoimmunity in Alzheimer's disease as evidenced by plasma immunoreactivity against RAGE and Abeta42: complication of diabetes. 1684

Several epidemiological studies have reported moderately increased risks of Alzheimer's disease (AD) in diabetic patients compared with general population. In diabetes mellitus, the formation and accumulation of advanced glycation end products (AGEs) progress more rapidly. Recent understanding of this process has confirmed that interactions between AGEs and their receptor (RAGE) may play a role in the pathogenesis of diabetic complications and AD. The authors have recently found that glyceraldehyde-derived AGEs (AGE-2), which is predominantly the structure of toxic AGEs (TAGE), show significant toxicity on cortical neuronal cells and that the neurotoxic effect of diabetic serum is completely blocked by neutralizing antibody against the AGE-2 epitope. Moreover, in human AD brains, AGE-2 is distributed in the cytosol of neurons in the hippocampus and parahippocampal gyrus. These results suggest that TAGE is involved in the pathogenesis of AD as well as other age-related diseases. In this review, the authors discuss the molecular mechanisms of AD, especially focusing on TAGE-RAGE system.
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PMID:Toxic advanced glycation end products (TAGE) theory in Alzheimer's disease. 1686 41

Recently the AGE-RAGE interaction was identified as a potential mechanism underlying chronic and inflammatory diseases like atherosclerosis, diabetes mellitus and kidney disease. Advanced glycation end products (AGEs) are the derivatives of glucose-protein or glucose-lipid reactions and are mainly generated from the diet (depending on intensity of heating, cooking time and oxygenation). Binding of AGEs or other ligands to the AGE receptor (RAGE) results in cellular activation, i.e. increased expression of inflammatory mediators and oxidative stress. Diet-derived AGEs thus induce deleterious effects on tissues and the cardiovascular system. Recent research also found that other lifestyle factors are associated with pronounced inflammatory activation, e.g. psychosocial stress and smoking. In addition, each intake of meals is associated with proinflammatory cellular changes. The AGE-RAGE model and investigations of the underlying cellular mechanisms thus may lead to a better understanding of the health benefits of diets (Mediterranean diet, uncooked vegetarian diets), caloric restriction and intermittent fasting. The clinical impact of low-AGE diets and fasting and the interaction between stress and food intake should be further investigated in controlled trials.
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PMID:[Glycotoxins and cellular dysfunction. A new mechanism for understanding the preventive effects of lifestyle modifications]. 1689 51

Chemokines mediate the recruitment and activation of blood monocyte/macrophages and lymphocytes to sites of inflammation. Expression of the chemokine IP-10 (interferon-gamma-inducible protein) has been documented in several inflammatory and autoimmune disorders including type 1 diabetes. However, the mechanism of its expression in monocytes or its functional role in diabetes is not known. Advanced glycation end products acting via their receptor, RAGE, play major roles in diabetic complications. In this study, we observed for the first time that S100b, an inflammatory protein as well as a specific RAGE ligand, significantly increased IP-10 mRNA and protein levels in THP-1 monocytes as well as peripheral blood monocytes. Promoter luciferase assays showed that IP-10 mRNA accumulation by S100b was not via increased transcription. On the other hand, S100b significantly increased IP-10 mRNA half-life and stability. This appeared to be mediated by S100b-induced binding of specific RNA-binding protein(s) to a 3'-untranslated region-responsive region of the IP-10 mRNA. Our results demonstrate for the first time that diabetic stimuli such as RAGE ligands can induce inflammatory gene expression in monocytes via increased message stability.
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PMID:Interferon-gamma-inducible protein (IP)-10 mRNA stabilized by RNA-binding proteins in monocytes treated with S100b. 1693 19

Plaque angiogenesis may be associated with the development of unstable and vulnerable plaques. Vascular endothelial growth factors (VEGFs) are potent angiogenic factors that can affect plaque neovascularization. Our objective was to determine the effect of diabetes on atherosclerosis and on the expression of angiogenesis-related genes in atherosclerotic lesions. Alloxan was used to induce diabetes in male Watanabe heritable hyperlipidemic (WHHL) rabbits that were sacrificed 2 and 6 months after the induction of diabetes. Nondiabetic WHHL rabbits served as controls. Blood glucose (Glc), serum-free fatty acids (FFA), and serum triglyceride levels were significantly higher in diabetic rabbits. Accelerated atherogenesis was observed in the diabetic WHHL rabbits together with increased intramyocellular lipids (IMCL), as determined by 1H-NMR spectroscopy. Atherosclerotic lesions in the diabetic rabbits had an increased content of macrophages and showed significant increases in immunostainings for vascular endothelial growth factor (VEGF)-A, VEGF-D, VEGF receptor-1, VEGF receptor-2, RAGE, and NF-kappaB. VEGF-A165 and VEGFR-2 mRNA levels were significantly increased in aortas of the diabetic rabbits, where a trend toward increased plaque vascularization was also observed. These results suggest that diabetes accelerates atherogenesis, up-regulates VEGF-A, VEGF-D, and VEGF receptor-2 expression, and increases NF-kappaB, RAGE, and inflammatory responses in atherosclerotic lesions in WHHL rabbits.
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PMID:VEGF-A, VEGF-D, VEGF receptor-1, VEGF receptor-2, NF-kappaB, and RAGE in atherosclerotic lesions of diabetic Watanabe heritable hyperlipidemic rabbits. 1693 42

We have previously shown that diabetes significantly enhances apoptosis of osteoblastic cells in vivo and that the enhanced apoptosis contributes to diabetes impaired new bone formation. A potential mechanism is enhanced apoptosis stimulated by advanced glycation end products (AGEs). To investigate this further, an advanced glycation product, carboxymethyl lysine modified collagen (CML-collagen), was injected in vivo and stimulated a 5-fold increase in calvarial periosteal cell apoptosis compared to unmodified collagen. It also induced apoptosis in primary cultures of human or neonatal rat osteoblastic cells or MC3T3-E1 cells in vitro. Moreover, the apoptotic effect was largely mediated through RAGE receptor. CML-collagen increased p38 and JNK activity 3.2- and 4.4-fold, respectively. Inhibition of p38 and JNK reduced CML-collagen stimulated apoptosis by 45% and 59% and by 90% when used together (P<0.05). The predominant apoptotic pathway induced by CML-collagen involved caspase-8 activation of caspase-3 and was independent of NF-kappaB activation. When osteoblastic cells were exposed to a long-term low dose incubation with CML-collagen, there was a higher degree of apoptosis compared to short-term incubation. In more differentiated osteoblastic cultures, apoptosis was enhanced even further. These results indicate that advanced glycation end products, which accumulate in diabetic and aged individuals, may promote apoptosis of osteoblastic cells and contribute to deficient bone formation.
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PMID:Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways. 1706 73

Mammalian Toll-like receptors (TLRs) are cellular pattern-recognizing receptors (PRRs) that recognize the molecular patterns of pathogens. After engaging the pathogenic patterned ligands, the cytosolic portion of the TLRs in monocytes and macrophages, recruits adaptor proteins, via a receptor-driven signaling cascade, activates the transcription factor NF-kappaB, leading to the expression of proinflammatory cytokines, which trigger inflammation. Such rapid, innate cellular responses serve as the first line of host defense against infection by pathogens, and also stimulate the adaptive immune system to clear the invading microbes. Increasing evidence suggests that TLRs also recognize host-derived ligands, linking this group of PRRs to diseases that may not have an etiology that is associated directly with infections. Advanced glycation end products (AGEs) are nonenzymatically glycated or oxidated proteins, lipids and nucleic acids that are formed in the environment of oxidant stress and hyperglycemia. Binding of AGEs to their receptor RAGE initiates cellular signals that activate NF-kappaB, which results in transcription of proinflammatory factors. RAGE can also interact with other endogenous ligands generated by cell death and tissue injuries. RAGE has been implicated in chronic diseases such as diabetes, atherosclerosis, neurodisorders, cancers, as well as aging. This review discusses the possible role of RAGE as a PRR that may use signaling mechanisms parallel to TLRs', to solicit inflammatory reactions. Thus, in this scenario, RAGE may play a prominent role in the regulation of cellular homeostasis in the context of complex disease progression.
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PMID:RAGE on the Toll Road? 1709 32

Vascular calcification is a common feature in advanced atherosclerosis and also a predictor of future cardiovascular events such as unstable angina and myocardial infarction, especially in diabetes. There is a growing body of evidence that advanced glycation end products (AGEs), senescent macroprotein derivatives formed at an accelerated rate in diabetes, exist within atherosclerotic lesions, thereby being implicated in the pathogenesis of accelerated atherosclerosis in diabetes. Indeed, we have previously shown that AGE - their receptor (RAGE) interaction could induce angiogenesis through autocrine production of vascular endothelial growth factor, suggesting its role for plaque formation and enlargement in diabetes. Furthermore, we have found that AGEs have the ability to induce the osteoblatic differentiation of pericytes, thus contributing to the development of vascular calcification as well. These observations suggest that the inhibition of AGE formation or blockade of the downstream signaling of RAGE may be a novel therapeutic target for the inhibition of vascular calcification in diabetic atherosclerosis. Since we, along with others, have shown that nifedipine inhibits glycation of low-density lipoprotein in vitro and blocks the AGE-induced RAGE expression in endothelial cells through its anti-oxidative properties, nifedipine could inhibit vascular calcification by blocking the AGE formation or the downstream signaling in diabetes. In this paper, we would like to propose the possible ways of testing our hypothesis. Does nifedipine treatment slow down the progression of coronary calcification in diabetic patients? If the answer is yes, is this beneficial effect of nifedipine superior to that of other DHPs with equihypotensive properties? Does nifedipine treatment decrease expression levels of AGEs and RAGE in diabetic atherosclerosis? Is the unique effect of nifedipine on vascular calcification correlated with its AGE or RAGE-suppressing properties? These prospective studies will provide further valuable information whether nifedipine could prevent vascular calcification in diabetic atherosclerosis by blockade the AGE-RAGE signaling in vascular wall cells.
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PMID:Prevention of diabetic vascular calcification by nifedipine, a dihydropyridine-based calcium channel blocker. 1709 22


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