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)

Acrolein (CH2==CH---CHO) is known as a ubiquitous pollutant in the environment. Here we show that this notorious aldehyde is not just a pollutant, but also a lipid peroxidation product that could be ubiquitously generated in biological systems. Upon incubation with BSA, acrolein was rapidly incorporated into the protein and generated the protein-linked carbonyl derivative, a putative marker of oxidatively modified proteins under oxidative stress. To verify the presence of protein-bound acrolein in vivo, the mAb (mAb5F6) against the acrolein-modified keyhole limpet hemocyanin was raised. It was found that the acrolein-lysine adduct, Nepsilon-(3-formyl-3, 4-dehydropiperidino)lysine, constitutes an epitope of the antibody. Immunohistochemical analysis of atherosclerotic lesions from a human aorta demonstrated that antigenic materials recognized by mAb5F6 indeed constituted the lesions, in which intense positivity was associated primarily with macrophage-derived foam cells and the thickening neointima of arterial walls. The observations that (i) oxidative modification of low-density lipoprotein with Cu2+ generated the acrolein-low-density lipoprotein adducts and (ii) the iron-catalyzed oxidation of arachidonate in the presence of protein resulted in the formation of antigenic materials suggested that polyunsaturated fatty acids are sources of acrolein that cause the production of protein-bound acrolein. These data suggest that the protein-bound acrolein represents potential markers of oxidative stress and long-term damage to protein in aging, atherosclerosis, and diabetes.
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PMID:Protein-bound acrolein: potential markers for oxidative stress. 956 Jan 97

Methylglyoxal, a toxic aldehyde, has been reported to be increased in diabetes and has been claimed to be related to diabetic complications. Aminoacetone, an intermediate in the metabolism of threonine and glycine, has been proposed to be an endogenous substrate for semicarbazide-sensitive amine oxidase (SSAO). Methylglyoxal is the product. An HPLC procedure for the determination of SSAO activity toward aminoacetone in vitro is described. It was observed in previous assays that methylglyoxal formed via deamination of aminoacetone was quite unstable and led to erroneous results. o-Phenylenediamine (o-PD) was therefore employed for derivatization of methylglyoxal. o-PD does not affect SSAO activity and can be included in the enzyme reaction mixture for continuous trapping of methylglyoxal. This can avoid the loss of methylglyoxal during incubation. Deamination of aminoacetone by human umbilical artery SSAO was confirmed with this improved assay. The values of Km and Vmax, are 125.9 +/- 20.5 microM and 332.2 +/- 11.7 nmol/h/mg protein, respectively. Deamination of aminoacetone was nearly completely inhibited by 1 mM semicarbazide and 1 microM MDL-72974A, a potent selective SSAO inhibitor, whereas MAO inhibitors clorgyline (1 mM) and deprenyl (1 mM) had no inhibitory effect.
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PMID:Assessment of the deamination of aminoacetone, an endogenous substrate for semicarbazide-sensitive amine oxidase. 1032 70

Production of free radicals from acetaldehyde oxidation by enzymes and cellular fractions is a well-known process. The toxic effects of acetaldehyde, however, are usually attributed to its reactions with biomolecules to produce adducts. Here, we demonstrate that hypothetical adducts produced from attack of acetaldehyde by two important biological oxidants, peroxynitrite and hydrogen peroxide, decompose to produce acetate, formate, and methyl radicals. Acetate, formate, nitrate, and nitrite were characterized and quantified by capillary electrophoresis. Radicals were detected and quantified by the EPR spectra produced in the presence of spin traps 3, 5-dibromo-4-nitrosobenzenesulfonic acid and 5,5-dimethyl-1-pyrroline N-oxide. Kinetic studies and product analysis were performed at different pHs. The results demonstrate that production of methyl radicals during oxidation of acetaldehyde by hydrogen peroxide was strictly dependent on the presence of iron(II) and occurred via two routes. One involved acetaldehyde attack by the hydroxyl radical to produce the acetyl radical that decomposes to methyl radical and carbon monoxide. The other route involved acetaldehyde attack by deprotonated hydrogen peroxide to produce a hypothetical intermediate that reductively cleaves via the action of present iron(II) to produce radicals. The latter mechanism predominates in the case of peroxynitrite, but radical formation does not require metal ions. Most of the hypothetical adduct produced from acetaldehyde and peroxynitrite (k = 680 M(-)(1) s(-)(1) at pH 7.4 and 37 degrees C) decays to nitrate and regenerates the aldehyde [Uppu, R. M., et al. (1997) Chem. Res. Toxicol. 10, 1331], but about 30% of it produces acetate, formate, and methyl radicals. Part of these oxidized products result from beta-scission and 1,2-shift reactions of the 1-hydroxyethoxyl radical which, together with nitrogen dioxide, freely diffuses from the adduct (20% yields). The results provide yet another example of the metal-independent free radical reactivity of peroxynitrite and may be relevant to the toxic effects associated with heavy drinking and diabetes.
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PMID:Oxidation of acetaldehyde by peroxynitrite and hydrogen Peroxide/Iron(II). Production Of acetate, formate, and methyl radicals. 1052 79

It is well established that cardiomyopathy is a consistent feature of diabetes and that alcohol consumption increases the risk of cardiovascular disease among diabetic subjects. Acetaldehyde (ACA), the main ethanol metabolite, is considered to play a role in the ethanol-induced cardiac dysfunction. It has been reported recently that the negative inotropic effect of ACA was more potent in the diabetic myocardium. To determine whether the disparate ACA-induced myocardial depression in diabetes is due to intrinsic alterations at the cellular level, mechanical properties in response to ACA were evaluated in ventricular myocytes from both normal and streptozotocin-induced diabetic rat hearts. Myocytes were electrically stimulated to contract at 0.5 Hz and contractile properties analyzed included peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90)) and maximal velocities of shortening and relengthening (+/-dL/dt). Ca(2+) transients were measured as fura-2 fluorescence intensity (DeltaFFI) changes. ACA (0. 1-30 mM) disproportionately depressed PS in a dose-dependent manner, in myocytes from diabetic hearts compared to normal hearts. Interestingly, the degree of inhibition in DeltaFFI was similar in both groups. Neither the duration nor maximal velocities of shortening and relengthening were affected by ACA in either group. These results are the first to suggest that enhanced ACA-induced myocardial depression in diabetes is due to disparate intrinsic actions on individual myocytes. The mechanism underlying the alteration of ACA-induced myocardial depression may be due, in part, to depressed Ca(2+) responsiveness in diabetic hearts.
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PMID:Diabetes enhances acetaldehyde-induced depression of cardiac myocyte contraction. 1072 Apr 79

We previously reported that brain-derived neurotrophic factor (BDNF) regulates both food intake and blood glucose metabolism in rodent obese diabetic models such as C57BL/KsJ-lepr(db)/lepr(db) (db/db) mice. To elucidate the effect of BDNF on glucose metabolism, we designed a novel pellet pair-feeding apparatus to eliminate the effect of appetite alteration on glucose metabolism. The apparatus was used to synchronize food intake precisely between BDNF-treated and vehicle-treated db/db mice. It was shown using this pellet pair-feeding apparatus that BDNF administered daily (20 mg x kg(-1) x day(-1)) to db/db mice significantly lowered blood glucose compared with pellet pair-fed db/db mice. To evaluate the effect of BDNF on insulin action, we used streptozotocin-induced type 1 diabetic mice. In this case, BDNF did not lower blood glucose concentration but rather enhanced the hypoglycemic action of insulin. In hyperglycemic db/db mice, pancreatic insulin content was reduced and glucagon content was increased compared with normoglycemic db/m mice. BDNF administered to db/db mice significantly restored both pancreatic insulin and glucagon content. Histological observations of aldehyde-fuchsin staining and immunostaining with anti-insulin indicated that insulin-positive pancreatic beta-cells were extensively regranulated by BDNF administration. We also studied the effect of BDNF on KK mice, normoglycemic animals with impaired glucose tolerance. In these mice, BDNF administration improved insulin resistance in the oral glucose tolerance test. To elucidate how blood glucose was metabolized in BDNF-treated animals, we investigated the effect of BDNF on the energy metabolism of db/db mice. Body temperature and oxygen consumption of the pellet pair-fed vehicle-treated mice were remarkably lower than the ad libitum-fed vehicle-treated mice. Daily BDNF administration for 3 weeks completely ameliorated both of the reductions. Finally, to clarify its action mechanism, the effect of intracerebroventricular administration of BDNF on db/db mice was examined. Here, a small dose of BDNF was found to be effective in lowering blood glucose concentration. This indicates that BDNF regulates glucose metabolism by acting directly on the brain.
Diabetes 2000 Mar
PMID:Brain-derived neurotrophic factor regulates glucose metabolism by modulating energy balance in diabetic mice. 1086 66

In Japanese type 2 diabetes, which occupies more than 95%, it is an increasingly important problem as a life-style related disease. The total diabetic population is estimated as approximately 7 million with a prevalence of approximately 6%. Along with genetically low postprandial insulin secretion, they are found to be less tolerable to being overweight to develop insulin resistance. The body weight change in the prediabetic era consisting of 508 male patients treated on their diet alone was reviewed and it was found that a few kilograms of weight gain could be a cause of insulin resistance. Moreover, inactive aldehyde dehydrogenese 2 (ALDH2), which is common in Japanese, is found to be a factor in the development of hyperglycemia. In 163 diabetics, HbAlc of the inactive ALDH2 group was 8.1+/-1.3, while that of active ALDH2 was 7.5+/-0.9% (P<0.05) in a light, social drinking group. However, Japanese type 2 diabetes is also changing. In recent years, the data from a 75-g oral glucose tolerance test of 2121 clients showed that insulinogenic index of clients with impaired glucose tolerance was similar to that of a normal glucose tolerance group and that the area under the insulin curve (AUC) was high in younger diabetics. From a life-style modification perspective, the importance of body weight control by diet and exercise as well as refraining from excessive drinking should be emphasized.
Diabetes Res Clin Pract 2000 Oct
PMID:Genetic and environmental interaction in Japanese type 2 diabetics. 1102 79

We studied a new family of aldose-reductase inhibitors with an imidazolidine arylmethylene and thiazolidine-acetate structure susceptible to prevent ocular, renal and vascular complications of insulin-dependent diabetes mellitus. We examined the role of the enzyme in the pathological processes involved and reviewed knowledge of known aldose reductase inhibitors leading to the development of the basic structure modulated to have insight into the different elements of the structure-quantitative activity relationship. Potential inhibitors are synthesized by condensation of heterocyclic rings and aldehyde aromatic rings. Their identity and structure were established by magnetic resonance spectroscopy (MRS) based on proton-carbon couplage constants and the homonuclear NOE effect. The structure-activity correlations were analyzed on the basis of the IC50 using a structural model and a physicAL model which showed the importance of the sulfur atom in the heterocyclic ring due to its important lipophilic contribution. Finally, a molecular modeling approach led to a provisional descriptive model of the inhibitor-enzyme interaction.
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PMID:[Imidazolidine/thiazolidine-acetate aldose reductase inhibitors]. 1114 74

Many clinical and experimental studies have established the beneficial effect of kinins in hypertension, heart failure and ischaemia-reperfusion syndrome, but little attention has been given to the role of kinins in hyperglycaemic conditions. The purpose of the present study was to determine the influence of bradykinin on the levels of glucose, insulin, malondialdehyde and hydrogen peroxide, as well as antioxidative enzyme activity in rats with streptozotocin (STZ)-induced acute hyperglycaemia. In STZ-induced hyperglycaemic rats the levels of glucose, hydrogen peroxide and malondialdehyde were increased by 256% (from 6.0+/-0.3 to 21.4+/-1.3 mmol/l, P<0.001), 33% (from 1.9+/-0.1 to 5.6+/-0.3 mmol H(2)O(2)/ml, P<0.001) and 19% (from 3.7+/-0.3 to 4.9+/-0.2 nmol/l, P<0.001) respectively. The activity of superoxide dismutase, catalase and glutathione peroxidase and the level of insulin were decreased by 46% (from 1367+/-73 to 737+/-59 U/g Hb, P<0.001), 36% (from 2.3+/-0.3 to 1.4+/-0.1 U Bergmayera/g Hb, P<0.001), 31% (from 236+/-19 to 163+/-24 U/g Hb, P<0.001) and 91% (from 47.5+/-1.7 to 2.4+/-0.5 mU/l, P<0.001) respectively in rats treated with streptozotocin. The administration of bradykinin caused the decrease in glucose, hydrogen peroxide and malondi-aldehyde levels by 38% (from 21.4+/-1.3 to 13.3+/-1.0 mmol/l, P<0.001), 37% (from 5.6+/-0.3 to 4.3+/-0.2 mmol H2O2/ml, P<0.001), 39% (from 4.9+/-0.2 to 3.0+/-0.2 nmol/l, P<0.001) respectively and the increase in insulin level and superoxide dismutase, catalase and glutathione peroxidase activity by 62% (from 2.4+/-0.5 to 4.0+/-0.4 mU/l, P<0.001), 23% (from 736.8+/-58.5 to 906.7+/-47.8 U/g Hb, P<0.001), 23% (from 1.4+/-0.1 to 1.9+/-0.1 U Bergmayera/g Hb, P<0.01) and 19% (from 163.1+/-23.6 to 202.3+/-11.7 U/g Hb, P<0.001) respectively in rats with hyperglycaemia. Thus, bradykinin is able to reduce oxidative stress in hyperglycaemic conditions.
Diabetes Res Clin Pract 2001 Feb
PMID:The effect of bradykinin on the oxidative state of rats with acute hyperglycaemia. 1116 87

Semicarbazide-sensitive amine oxidase (SSAO) catalyzes the deamination of methylamine and aminoacetone to produce toxic aldehydes, i.e. formaldehyde and methylglyoxal, as well as hydrogen peroxide and ammonia. An increase of SSAO activity was detected by different laboratories in patients suffering from vascular disorders, i.e. diabetes and myocardial infarction. The enzyme has been suggested to play a role in vascular endothelial damage and atherogenesis. To date, there are no selective SSAO inhibitors. In the present study, 2-bromoethylamine (2-BrEA) was found to be a highly effective and selective inhibitor of SSAO obtained from different sources. The inhibition was irreversible and time dependent. It was competitive when the enzyme was not preincubated with the inhibitor, but became noncompetitive after incubation of the enzyme with 2-BrEA. The aldehyde trapping agent o-phenylenediamine was capable of preventing 2-BrEA-induced inhibition of SSAO activity. An aldehyde product was detected to be an initial product of 2-BrEA after it was incubated with SSAO. The inhibition, therefore, is mechanism-based. The SSAO inhibitory effects of eight structural analogues of 2-BrEA were assessed. It was concluded that a bromine atom at the beta position is quite important for exerting high potency of SSAO inhibition. The inhibition of SSAO activity by 2-BrEA was also demonstrated in vivo. It increased the urinary excretion of methylamine, an endogenous substrate for SSAO, in mice. 2-BrEA can be employed as a very useful tool in the investigation of SSAO.
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PMID:2-Bromoethylamine as a potent selective suicide inhibitor for semicarbazide-sensitive amine oxidase. 1126 60

Plasma activity of the enzyme semicarbazide-sensitive amine oxidase (SSAO) is high in diabetes. Production of angiotoxic substances (an aldehyde, hydrogen peroxide, and ammonia) in vessel walls is catalysed by SSAO, suggesting a role for SSAO in the development of complications of diabetes. The objective of the present study was to follow up plasma SSAO activity (measured radiometrically), HbA(1c) (using ion exchange chromatography), and retinopathy (by fundus photography) after 2.8 years, in 34 patients with Type 2 diabetes. We also measured urinary levels of an SSAO substrate, methylamine, by fluorometric high-performance liquid chromatography (HPLC). As at baseline, plasma SSAO activity was now higher in subjects with retinopathy (mean 19.5) than in subjects without retinopathy (mean 16.0), 95% confidence interval (CI) for difference 0.6-6.3 nmol benzylamine ml(-1) plasma h(-1). SSAO activity had not changed significantly since baseline, mean difference -1.65 and 95% CI for difference -3.76 to 0.46 nmol benzylamine ml(-1) plasma h(-1). Mean HbA(1c) level remained higher for patients with retinopathy (now 7.9%) compared to those without retinopathy (6.1%), 95% CI for difference 0.6-3.0%. Comparing baseline and the present study, retinopathy was nonproliferative; level had worsened for five and improved for two patients. Urinary methylamine/creatinine ratio was lower in the group of patients with retinopathy (mean 0.99) than in those without retinopathy (mean 1.78), 95% CI for difference 0.1-1.5 microg mg(-1). The results of the present study are compatible with a role for SSAO in the development of diabetic retinopathy.
J Diabetes Complications
PMID:Follow-up of plasma semicarbazide-sensitive amine oxidase activity and retinopathy in Type 2 diabetes mellitus. 1152 99


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