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)

Hyperglycemic conditions of diabetes accelerate protein modifications by glucose leading to the accumulation of advanced glycation end-products (AGEs). We have investigated the conversion of protein-Amadori intermediate to protein-AGE and the mechanism of its inhibition by pyridoxamine (PM), a potent AGE inhibitor that has been shown to prevent diabetic complications in animal models. During incubation of proteins with physiological diabetic concentrations of glucose, PM prevented the degradation of the protein glycation intermediate identified as fructosyllysine (Amadori) by 13C NMR using [2-13C]-enriched glucose. Subsequent removal of glucose and PM led to conversion of protein-Amadori to AGE Nepsilon-carboxymethyllysine (CML). We utilized this inhibition of post-Amadori reactions by PM to isolate protein-Amadori intermediate and to study the inhibitory effect of PM on its degradation to protein-CML. We first tested the hypothesis that PM blocks Amadori-to-CML conversion by interfering with the catalytic role of redox metal ions that are required for this glycoxidative reaction. Support for this hypothesis was obtained by examining structural analogs of PM in which its known bidentate metal ion binding sites were modified and by determining the effect of endogenous metal ions on PM inhibition. We also tested the alternative hypothesis that the inhibitory mechanism involves formation of covalent adducts between PM and protein-Amadori. However, our 13C NMR studies demonstrated that PM does not react with the Amadori. Because the mechanism of interference with redox metal catalysis is operative under the conditions closely mimicking the diabetic state, it may contribute significantly to PM efficacy in preventing diabetic complications in vivo. Inhibition of protein-Amadori degradation by PM also provides a simple procedure for the isolation of protein-Amadori intermediate, prepared at physiological levels of glucose for relevancy, to study both the biological effects and the chemistry of post-Amadori pathways of AGE formation.
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PMID:Modification of proteins in vitro by physiological levels of glucose: pyridoxamine inhibits conversion of Amadori intermediate to advanced glycation end-products through binding of redox metal ions. 1297 71

The T-box transcription factor T-bet is known to control lineage commitment and interferon-gamma production by T helper 1 (Th1) CD4 lymphocytes. We report here that T-bet is essential for development of CD8 lymphocyte-dependent autoimmune diabetes (type 1 diabetes [T1D]) in the rat insulin promoter-lymphocytic choriomeningitis virus (LCMV) transgenic model for virally induced T1D. In the absence of T-bet, autoaggressive (anti-LCMV) CD8 lymphocytes were reduced in number and produced less IFN-gamma, but increased IL-2 compared with controls. Further analysis showed that T-bet intrinsically controls the generation, but not apoptosis, maintenance, or secondary expansion of antiviral effector/memory CD8 lymphocytes. This observation points toward a therapeutic opportunity for the treatment of T1D and other autoimmune disorders.
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PMID:T-bet controls autoaggressive CD8 lymphocyte responses in type 1 diabetes. 1509 40

Pterospartum tridentatum is a Leguminosae that grows spontaneously in Portugal. The flowers are used in popular medicine for the treatment of throat irritation conditions and in herbal mixtures for diabetes. Diabetic vascular complications are due, among other reasons, to increased oxidative stress and for that reason antioxidants are believed to be beneficial for the diabetic patient. The flower water extract of this herbal drug showed dose-dependent protective effect of cultured human endothelial cells against oxidative injury induced by H2O2, at concentrations > or =0.3 mg/ml. This water extract, after liquid-liquid and chromatographic fractionation afforded one new isoflavone (5,5'-dihydroxy-3'-metoxi-isoflavone-7-O-beta-glucoside) and three other known isoflavones (prunetin, genistin and sissotrin). The structural characterisation of isolated compounds was achieved by UV, NMR and MS analysis. The flavonol glycoside isoquercitrin was also identified in the extract by HPLC analysis. Isoquercitrin is one of the active antioxidant principles of the extract since it showed dose-dependent protective effect against oxidative injury at concentrations > or =0.3 mM. Isoflavones were inactive at the same concentrations. The results suggest that the water extract of this herbal drug may prevent or reduce the development of diabetic vascular complications.
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PMID:Flavonoids of an extract of Pterospartum tridentatum showing endothelial protection against oxidative injury. 1523 78

Degradation of a novel insulin sensitizer in aqueous solutions was studied using high pressure liquid chromatography/mass spectrometry (LC/MS). The insulin sensitizer, containing a thiazolidine-2,4-dione (TZD), was a new class of antidiabetic agent for the treatment of type II diabetes. Chemical stability of the insulin sensitizer was evaluated by stressing its aqueous solutions at 40 degrees C for 24 h. Oxygen was removed from one of the solutions by bubbling pure nitrogen through to identify non-oxidative pathways. LC/MS analyses of the stressed solutions revealed that hydrolysis and oxidation are the primary degradation pathways for the studied compound. A alpha-thiol acetic acid, acyl amide, and two dimeric diastereomers were the main degradates of the insulin sensitizer. The alpha-thiol acetic acid served as an intermediate-like species, and oxidized to two dimeric degradates upon exposing to air. All of them were identified as ring-opening products of the TZD. The entities of the acyl amide and dimeric degradates were respectively verified by a synthetic standard or NMR following isolation of a diastereomeric degradate. Characterization using MS in both positive and negative ion scans were discussed for an isolated diastereomeric degradate. Mechanisms of fragmentation and formation for those degradates are presented based on the MS result.
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PMID:Application of liquid chromatography/mass spectrometry and nuclear magnetic resonance to the identification of degradates of a novel insulin sensitizer in aqueous solutions. 1538 Jul 17

Exenatide, synthetic exendin-4, is the first member of the incretin mimetic class of potential therapeutic agents. It has been the subject of extensive clinical trials in people with Type 2 diabetes. Results to date indicate that exenatide decreases postmeal blood glucose concentrations and that this effect is associated with weight loss. Prior NMR studies of exendin-4 utilized 30% trifluoroethanol because this medium affords sharp, high-resolution NMR spectra. These studies defined its three-dimensional structure in this medium. The NMR-derived ensemble included a novel tertiary structure motif that has subsequently been optimized, yielding water-soluble Trp-cage miniproteins. Prior to the present study, the structuring propensities (and aggregation/association state) of exendin-4 in strictly aqueous media had not been established. Studies of exendin-4 and N-terminally truncated analogs of exendin have established that the structuring propensities of these species are highly medium dependent. This study extends knowledge of the medium dependence of exendin structure to DMSO-water mixtures and to aqueous media mimicking the formulation conditions for this investigational drug. Exenatide retains a substantial helical propensity from residues 9-27 even in 98% DMSO. The addition of water leads to the appearance of NMR diagnostics of the Trp-cage formation. In strictly aqueous media (pH 4-4.4), exenatide is monomeric only at <10 microM peptide concentrations. Under these conditions the Trp cage is partially formed. NMR and CD data indicate that higher concentrations lead to helix bundle formation and that the helix/helix interactions involve residues 11-26. Both the N- and C-termini of the helix bundle state display rapid segmental motion.
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PMID:Exenatide: NMR/CD evaluation of the medium dependence of conformation and aggregation state. 1538 69

Localized in vivo 1H magnetic resonance spectroscopy (MRS) was used to investigate metabolite levels in the brain of adult Zucker Diabetic Fatty (ZDF) rats, an animal model for type 2 diabetes mellitus. This study focussed on the hippocampus, assumed to be one of the main brain areas affected by this disease. Together with an almost 5-fold increase in blood glucose concentration measured by glucose oxidation, significant increases were found in the hippocampal concentrations of glucose (4.93 vs 1.66 mM p < 0.001), myo-inositol (6.52 vs 4.30 mM; p < 0.05), and total creatine (12.71 vs 10.50 mM; p < 0.05) in ZDF rats (n = 5) compared with littermates (n = 5). Although no obvious alterations were detected in the hippocampal levels of other metabolites, including NAA + NAAG and choline-containing compounds in the ZDF rats, the increase in Glc and Ins levels is in line with elevated brain tissue contents of these metabolites in patients with diabetes mellitus.
NMR Biomed 2004 Oct
PMID:Metabolic profile of the hippocampus of Zucker Diabetic Fatty rats assessed by in vivo 1H magnetic resonance spectroscopy. 1538 26

Growth hormone (GH) deficiency decreases left ventricular (LV) contractility, induces LV chamber dilatation and promotes progression to congestive heart failure. It is, however, controversial, whether GH replacement therapy in addition to standard medical heart failure therapy should be considered as routine treatment in GH deficient patients with heart failure. In the present report of a 64-year-old GH deficient patient with heart failure, we demonstrate by using Doppler echocardiography, magnetic resonance imaging and 31P NMR spectroscopy that even a 12 month period of GH replacement therapy had no sustained effect on morphometric or functional parameters of LV performance nor on clinical signs or symptoms of heart failure. It is concluded that GH replacement therapy should currently not be regarded as standard heart failure therapy in patients with GH deficiency and should only be employed under careful monitoring including close follow-up in a standardized way.
Exp Clin Endocrinol Diabetes 2004 Oct
PMID:Failure of recombinant human growth hormone treatment to improve congestive heart failure in hypopituitarism. 1550 63

Methylglyoxal is a highly reactive dicarbonyl compound, which reacts in vivo with biological macromolecules and thereby affects their structure and function. These changes are associated with complications during aging, diabetes and Alzheimer's disease as well as with growth inhibition in different tumors. Many enzymes are involved in the metabolism of methylglyoxal, but its true physiological role in metabolism and chemical properties are still obscure. In this study it was shown that methylglyoxal, during the freeze-drying of aqueous solutions, polymerizes into small polymeric structures which are stable in organic media such as dimethylsulfoxide. When re-exposed to water, the polymers are immediately transformed into the monomeric mono- and dihydrate forms of methylglyoxal. By NMR and UV spectroscopy, it was shown that solvent, temperature, and the amount of available water strongly influence the equilibrium of the different forms of methylglyoxal and thereby change its reactivity. 1H and 13C NMR spectroscopy were used to determine the structures of the different monomeric and oligomeric structures of methylglyoxal.
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PMID:Spectroscopic studies of methylglyoxal in water and dimethylsulfoxide. 1553 Sep 96

Protein tyrosine phosphatases (PTPs) catalyze the hydrolysis of phosphotyrosyl (pY) proteins to produce tyrosyl proteins and inorganic phosphate. Specific PTPs inhibitors provide useful tools for studying PTP function in signal transduction processes and potential treatment for human diseases such as diabetes, inflammation, and cancer. In this work, trans-beta-nitrostyrene (TBNS) and its derivatives are found to be slow-binding inhibitors against protein tyrosine phosphatases PTP1B, SHP-1, and Yop with moderate potencies (K(I*) = 1-10 microM). Competition experiments with a substrate (pNPP) and iodoacetate indicate that TBNS is active site-directed. The mechanism of inhibition was investigated by UV-vis absorption spectroscopy, (1)H-(13)C heteronuclear single-quantum correlation NMR spectroscopy, and site-directed mutagenesis. These studies suggested a mechanism in which TBNS acts a pY mimetic and binds to the PTP active site to form an initial noncovalent E.I complex, followed by nucleophilic attack on the TBNS nitro group by Cys-215 of PTP1B to form a reversible, covalent adduct as the tighter E.I* complex. TBNS derivatives represent a new class of neutral pY mimetic inhibitors of PTPs.
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PMID:trans-Beta-nitrostyrene derivatives as slow-binding inhibitors of protein tyrosine phosphatases. 1555 9

Expression of the agouti signaling protein (ASIP) during hair growth produces the red/yellow pigment pheomelanin. ASIP, and its neuropeptide homolog the agouti-related protein (AgRP) involved in energy balance, are novel, paracrine signaling molecules that act as inverse agonists at distinct subsets of melanocortin receptors. Ubiquitous ASIP expression in mice gives rise to a pleiotropic phenotype characterized by a uniform yellow coat color, obesity, overgrowth, and metabolic derangements similar to type II diabetes in humans. Here we report the synthesis and NMR structure of ASIP's active, cysteine-rich, C-terminal domain. ASIP adopts the inhibitor cystine knot fold and, along with AgRP, are the only known mammalian proteins in this structure class. Moreover, ASIP populates two distinct conformers resulting from a cis peptide bond at Pro102-Pro103 and a coexistence of cis/trans isomers of Ala104-Pro105. Pharmacologic studies of Pro-->Ala mutants demonstrate that the minor conformation with two cis peptide bonds is responsible for activity at all MCRs. The loop containing the heterogeneous Ala-Pro peptide bond is conserved in mammals, and suggests that ASIP is either trapped by evolution in this unusual configuration or possesses function outside of strict MCR antagonism.
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PMID:Structures of the agouti signaling protein. 1570 17


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