UMLS:C0011849 - FACTA Search

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

Protein tyrosine phosphatases (PTPs) are a large family of enzymes that catalyze the hydrolytic removal of the phosphoryl group from phosphotyrosyl (pY) proteins. PTP inhibitors provide potential treatment of human diseases/conditions such as diabetes and obesity as well as useful tools for studying the function of PTPs in signaling pathways. In this work, we have shown that certain aryl-substituted aldehydes act as reversible, slow-binding inhibitors of modest potency against PTP1B, SHP-1, and a dual-specificity phosphatase, VHR. Attachment of the tripeptide Gly-Glu-Glu to the para position of cinnamaldehyde resulted in an inhibitor (Cinn-GEE) of substantially increased potency against all three enzymes (e.g., K(I) = 5.4 microM against PTP1B). The mechanism of inhibition was investigated using Cinn-GEE specifically labeled with (13)C at the aldehyde carbon and (1)H-(13)C heteronuclear single-quantum coherence spectroscopy. While Cinn-GEE alone showed a single cross-peak at delta 9.64 ((1)H) and delta 201 ((13)C), the PTP1B/Cinn-GEE complex showed three distinct cross-peaks at delta 7.6-7.8 ((1)H) and 130-137 ((13)C). Mutation of the catalytic cysteine (Cys-215 in PTP1B) into alanine had no effect on the cross-peaks, whereas mutation of a conserved active-site arginine (Arg-221 in PTP1B) to alanine abolished all three cross-peaks. Similar experiments with Cinn-GEE that had been labeled with (13)C at the benzylic position revealed a change in the hybridization state (from sp(2) to sp(3)) for the benzylic carbon as a result of binding to PTP1B. These results rule out the possibility of a free aldehyde, aldehyde hydrate, or hemithioacetal as the enzyme-bound inhibitor form. Instead, the data are consistent with the formation of an enamine between the aldehyde group of the inhibitor and the guanidine group of Arg-221 in the PTP1B active site. These aldehydes may provide a general core structure that can be further developed into highly potent and specific PTP inhibitors.
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PMID:Peptidyl aldehydes as reversible covalent inhibitors of protein tyrosine phosphatases. 1218 56

Diabetes is associated with ventricular dysfunction. Ethanol consumption increases the risk of cardiovascular disease among diabetics. Acetaldehyde (ACA), the main ethanol metabolite, depresses cardiac contraction and contributes to ethanol-induced cardiac dysfunction. This study examined the influence of gender and diabetes on ACA-induced myocardial dysfunction. Adult male and female rats were made diabetic with streptozotocin (55 mg/kg). Left ventricular papillary muscles were isolated and stimulated to contract at 0.5 Hz. The mechanical parameters measured were peak tension development, time-to-peak tension (TPT), time-to-90% relaxation (RT90), and maximum velocities of tension development and decline (+/-VT). TPT and RT90 were comparably similar between genders. The +/-VT appeared to be slower in myocardium from female rats when compared to that of male counterparts, although the difference was not significant. Experimental diabetes elicited severe hyperglycemia, cardiac hypertrophy, hepatomegaly, and renal hypertrophy in both male and female animals. Myocardial mechanical properties exhibited prolonged TPT and RT90 in diabetic myocardium from both genders. The +/-VT was significantly reduced by diabetes in male but not in female myocardium. Acute ACA exposure decreased myocardial tension development and the +/-VT and shortened TPT and RT90 in myocardium from normal and diabetic rats of both genders. The ACA-induced depressant response on tension development was slightly enhanced by the diabetic state. In conclusion, these data suggest that the development of diabetes-induced myocardial dysfunction is similar between male and female animals and that the ACA-induced myocardial depressant action may be affected by diabetes but not by gender.
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PMID:The influence of gender, diabetes, and acetaldehyde on the intrinsic contractile properties of isolated rat myocardium. 1221 95

Glycation (nonenzymatic glycosylation of proteins) is known to be increased as a result of hyperglycaemia in diabetes. Moreover, cell glutathione concentration has been found to be lower in diabetics and such depletion may impair the cell defence against toxic radical species. Ribose being a potent reducing sugar expected to be increased in cells of diabetics where the pentose phosphate pathway is enhanced, its putative condensation with glutathione was investigated. Reduced glutathione (GSH) was incubated with ribose and the structure of the resultant product was assessed by mass spectrometry, as well as the measurement of its remaining thiol group. A covalent reaction clearly occurred between the reducing sugar and GSH, to give an adduct named N-ribosyl-1-glutathione. This adduct appears to be the Amadori product resulting from the condensation of the primary amine group of GSH with the aldehyde group of ribose. Interestingly, the adduct could not be used as a proper substrate by glutathione peroxidase although it keeps its thiol group. We conclude that the coupling of GSH with a monosaccharide such as ribose might contribute to the decreased cell GSH and glutathione peroxidase activity observed in diabetics.
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PMID:Covalent coupling of reduced glutathione with ribose: loss of cosubstrate ability to glutathione peroxidase. 1259 81

The 2-oxoaldehyde methylglyoxal (MeG) is the precursor to a number of the known advanced glycation endproducts (AGE) implicated in the development of diabetic complications. Other 2-oxoaldehydes that are important in AGE formation, such as glyoxal, glucosone, deoxyglucosone, xylosone and deoxyxylosone, are produced by nonenzymatic reactions. By contrast, MeG is produced by both enzymatic and nonenzymatic processes, most of which appear to be enhanced in diabetes. MeG may be a major precursor to formation of AGE, and rates of production of MeG depend upon physiological conditions such as hyperglycemia and ketoacidosis. MeG is also unique compared to the other 2-oxoaldehydes in its complex metabolism. At least four pathways contribute to detoxification of MeG: (1) aldose reductase, a member of the aldo-keto reductase superfamily, catalyzes the NADPH-dependent reduction of a wide range of aldehydes. MeG is the best of the known physiological aldehyde substrates of aldose reductase. The distribution of aldose reductase in human tissue is restricted; there is little expression in liver; (2) the ubiquitous and highly active glyoxalase system converts MeG into D-lactate. However, this system depends upon the availability of glutathione; activity is severely limited by conditions of oxidative stress that impact levels of glutathione; (3) betaine aldehyde dehydrogenase, also known as ALDH9, is able to catalyze the oxidation of MeG to pyruvate, although less efficiently than with its substrate betaine aldehyde; (4) the long-known but not widely studied 2-oxoaldehyde dehydrogenases (2-ODHs) catalyze the oxidation of MeG to pyruvate, primarily in liver. There are two NADP-dependent 2-ODHs in human liver. Both of these require an activating amine. The physiological activator is unknown.
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PMID:Methylglyoxal metabolism and diabetic complications: roles of aldose reductase, glyoxalase-I, betaine aldehyde dehydrogenase and 2-oxoaldehyde dehydrogenase. 1260 21

Apoptosis of vascular endothelial cells (VECs) and concomitant proliferation of the underlying vascular smooth muscle cells (VSMCs) in large arteries are the key features of atherosclerosis and restenosis. However, the mechanisms underlying endothelial cell death and abnormal smooth muscle cell proliferation during the development of vascular lesions remain unclear. We have previously demonstrated that treatment with inhibitors of the aldehyde-metabolizing enzyme and aldose reductase (AR) attenuates restenosis of balloon-injured rat carotid arteries. The inhibition of AR also prevents the apoptosis of VECs induced by the tumor necrosis factor-alpha (TNF-alpha). Apoptosis of the VECs was determined by the incorporation of [3H]-thymidine and the activation of caspase-3. Stimulation of the VECs with TNF-alpha led to an increase in the DNA-binding activity of the transcription factor, nuclear factor-kappa binding protein (NF-kappaB) and the induction of the adhesion molecule (ICAM)-1. Treatment of VECs with the AR inhibitor, tolrestat, prevented the activation of NF-kappaB and diminished ICAM-1 induction stimulated by TNF-alpha. These results indicate an obligatory requirement of AR activity in the transduction of intracellular signaling initiated by the ligation of the TNF-alpha receptors leading to the activation of NF-kappaB. Although the specific signaling events interrupted by AR inhibition remain unknown, our results suggest that product(s) of AR catalysis may be essential for NF-kappaB activation. These observations could form the basis of future investigations into the therapeutic utility of AR inhibitors in preserving endothelial function and integrity during atherosclerosis and diabetes.
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PMID:Role of aldose reductase in TNF-alpha-induced apoptosis of vascular endothelial cells. 1260 46

Glycation, one of the post-translational modifications of proteins, is a nonenzymatic reaction initiated by the primary addition of a sugar aldehyde or ketone to the amino groups of proteins. In the early stage of glycation, the synthesis of intermediates leading to the formation of Amadori compounds occurs. In the late stage, advanced glycation end products (AGE) are irreversibly formed after a complex cascade of reactions. Several AGEs have been characterized chemically, while other new compounds remain to be identified. To date, studies of the contribution of glycation to diseases have been primarily focused on its relationship to diabetes and diabetes-related complications. However, glucose-induced damage is not limited to diabetic patients. Although it does not cause rapid or remarkable cell damage, glycation advances slowly and accompanies every fundamental process of cellular metabolism. It has recently become clear that glycation also affects physiological aging and neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. Glycation alters the biological activity of proteins and their degradation processes. Protein cross-linking by AGE results in the formation of detergent-insoluble and protease-resistant aggregates. Such aggregates may interfere with both axonal transport and intracellular protein traffic in neurons. In addition, glycation reactions lead to the production of reactive oxygen species. Conversely, glycation is promoted by oxidative stress. We speculate on the presence of synergism between glycation and oxidative stress. In this review, we provide an outline of glycation and propose some possible mechanisms of its cytotoxicity and defense systems against it.
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PMID:Glycation--a sweet tempter for neuronal death. 1266 85

Aldose-, aldehyde and renal specific oxido reductase (RSOR) belong to the family of aldo-keto reductases (AKRs). They are monomeric (alpha/beta)8-barrel proteins with a molecular weight ranging from 30 to 40 kDa, and at present include more than 60 members. Except for RSOR, they are expressed in a wide variety of animal and plant species and in various tissues. They catalyze NADPH-dependent reduction of various aliphatic and aromatic aldehyde and ketones. During the past three decades aldehyde reductase (AKR1A) and aldose reductase (AKR1B) have been extensively investigated, and the gene regulation of AKR1B has been noted to be heavily influenced by hyperglycemic state and high glucose ambience in various culture systems. AKR1B catalyzes the conversion of glucose to sorbitol in concert with a coenzyme, NADPH. The newly discovered RSOR has certain structural and functional similarities to AKR1B and seems to be relevant to the renal complications of diabetes mellitus. Like other AKRs, it has a NADPH binding motif, however, it is located at the N-terminus and it probably undergoes N-linked glycosylation in order to achieve functional substrate specificity. Besides the AKR3 motif, it has very little nucleotide or protein sequence homology with other members of the AKR family. Nevertheless, gene regulation of RSOR, like AKR1B, is heavily modulated by carbonyl, oxidative and osmotic stresses, and thus it is anticipated that its discovery would lead to the development of new inhibitors as well as gene therapy targets to alleviate the complications of diabetes mellitus in the future.
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PMID:Gene regulation of aldose-, aldehyde- and a renal specific oxido reductase (RSOR) in the pathobiology of diabetes mellitus. 1287 Nov 37

Glycation of nucleotides in DNA forms AGEs (advanced glycation end-products). Nucleotide AGEs are: the imidazopurinone derivative dG-G [3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxyimidazo[2,3-b]purin-9(8)one], CMdG ( N (2)-carboxymethyldeoxyguanosine) and gdC (5-glycolyldeoxycytidine) derived from glyoxal, dG-MG [6,7-dihydro-6,7-dihydroxy-6-methylimidazo-[2,3-b]purine-9(8)one], dG-MG(2) [ N (2),7-bis-(1-hydroxy-2-oxopropyl)deoxyguanosine] and CEdG [ N (2)-(1-carboxyethyl)deoxyguanosine] derived from methylglyoxal, and dG-3DG [ N (2)-(1-oxo-2,4,5,6-tetrahydroxyhexyl)deoxyguanosine] derived from 3-deoxyglucosone and others. Glyoxal and methylglyoxal induce multi-base deletions, and base-pair substitutions - mostly occurring at G:C sites with G:C-->C:G and G:C-->T:A transversions. Suppression of nucleotide glycation by glyoxalase I and aldehyde reductases and dehydrogenases, and base excision repair, protects and recovers DNA from damaging glycation. The effects of DNA glycation may be most marked in diabetes and uraemia. Mutations arising from DNA glycation may explain the link of non-dietary carbohydrate intake to incidence of colorectal cancer. Overexpression of glyoxalase I was found in drug-resistant tumour cells and may be an example of an undesirable effect of the enzymatic protection against DNA glycation. Experimental overexpression of glyoxalase I conferred resistance to drug-induced apoptosis. Glyoxalase I-mediated drug resistance was found in human leukaemia and lung carcinoma cells. Methylglyoxal-mediated glycation of DNA may contribute to the cytotoxicity of some antitumour agents as a consequence of depletion of NAD(+) by poly(ADP-ribose) polymerase, marked increases in triosephosphate concentration and increased formation of methylglyoxal. S - p -Bromobenzylglutathione cyclopentyl diester is a cell-permeable glyoxalase I inhibitor. It countered drug resistance and was a potent antitumour agent against lung and prostate carcinoma. Glyoxalase I overexpression was also found in invasive ovarian cancer and breast cancer.
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PMID:Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy. 1464 Oct 66

Semicarbazide-sensitive amine oxidases (SSAO) are enzymes that are capable of deaminating primary amines to produce aldehyde, ammonia, and hydrogen peroxide. This activity has been associated with vascular adhesion protein-1 (VAP-1) and is found in the serum, endothelium, adipose, and smooth muscle of mammals. Circulating SSAO activity is increased in congestive heart failure, diabetes, and inflammatory liver diseases. To investigate the origin of circulating SSAO activity, two transgenic mouse models were created with full-length human VAP-1 (hVAP-1) expressed on either endothelial (mTIEhVAP-1) or adipose tissues (aP2hVAP-1), with tie-1 and adipocyte P2 promoters, respectively. Under normal conditions a circulating form of hVAP-1 was found at high levels in the serum of mice with endothelium-specific expression and at low levels in the serum of mice with adipose specific expression. The level of circulating hVAP-1 in the transgenic mice varied with gender, transgene zygosity, diabetes, and fasting. Serum SSAO activity was absent from VAP-1 knockout mice and endothelial cell-specific expression of human VAP-1 restored SSAO activity to the serum of VAP-1 knockout mice. Together, these experiments show that in the mouse VAP-1 is the only source of serum SSAO, that under physiological conditions vascular endothelial cells can be a major source of circulating VAP-1 protein and SSAO, and that serum VAP-1 can originate from both endothelial cells and adipocytes during experimental diabetes. An increased endothelial cell capacity for lymphocyte binding and altered expression of redox-sensitive proteins was also associated with the mTIEhVAP-1 transgene.
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PMID:Origins of serum semicarbazide-sensitive amine oxidase. 1517 39

In the history of diabetes, chlorpropamide alcohol flushing test (CPAF) was a big topic in the 1970s to 1980s. Alcohol tolerance after chlorpropamide has prognostic significance, with the intolerant group (CPAF-positive group) being less prone to develop vascular complication than the tolerant group (CPAF-negative group). A mechanism of CPAF has been regarded as the inhibition of aldehyde dehydrogenase 2 (ALDH2) by an N-alkyl-substituted derivative of chlorpropamide, and the expression of these mutations of ALDH2 and alcohol dehydrogenase 2 (ADH2) could determine the alcohol tolerance among the Japanese population. Therefore, we hypothesized that expression of different ALDH2 and ADH2 polymorphisms may induce differences in vascular complications in diabetes and conducted two studies. The first study (study 1) was to determine the association of ALDH2/AHD2 polymorphism with diabetic complications. To know the association of ALDH2/AHD2 polymorphism with diabetic vasculopathy and neuropathy, a total of 158 patients with type 2 diabetes were divided into four groups on the basis of ALDH2 "activity" and ADH2 "superactivity." The frequency of proteinuria and the percentage of proliferative retinopathy among the patients with retinopathy was higher in those with active ALDH2 and superactive ADH2. We speculated that protein kinase C isoforms up-regulated by 4-hydroxynonenal that was detoxified by ALDH2 and ADH2 may account for the long-term development of diabetic nephropathy and severe retinopathy. As for neuropathy, the frequency of symptomatic neuropathy was higher in patients with inactive ALDH2 and usual ADH2. We speculate that increased tissue levels of toxic aldehyde could result from inactive ALDH2 and usual ADH2 expression, which results in the increased level of reactive aldehyde in sensory neuron pathway, thereby causing symptomatic polyneuropathy.
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PMID:ALDH2/ADH2 polymorphism associated with vasculopathy and neuropathy in type 2 diabetes. 1531 96

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