Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein tyrosine phosphatase 1B (PTP1B) plays a key role as a negative regulator of insulin and leptin signalling and is therefore considered to be an important molecular target for the treatment of type 2 diabetes and obesity. Detailed structural information about the structure of PTP1B, including the conformation and flexibility of active-site residues as well as the water-molecule network, is a key issue in understanding ligand binding and enzyme kinetics and in structure-based drug design. A 1.95 A apo PTP1B structure has been obtained, showing four highly coordinated water molecules in the active-site pocket of the enzyme; hence, the active site is highly solvated in the apo state. Three of the water molecules are located at positions that approximately correspond to the positions of the phosphate O atoms of the natural substrate phosphotyrosine and form a similar network of hydrogen bonds. The active-site WPD-loop was found to be in the closed conformation, in contrast to previous observations of wild-type PTPs in the apo state, in which the WPD-loop is open. The closed conformation is stabilized by a network of hydrogen bonds. These results provide new insights into and understanding of the active site of PTP1B and form a novel basis for structure-based inhibitor design.
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PMID:Water-molecule network and active-site flexibility of apo protein tyrosine phosphatase 1B. 1533 22

DNA damage may be associated with type 2 diabetes mellitus (T2DM) and its complications mainly through oxidative stress. Little is known about DNA repair disturbances potentially contributing to the overall extent of DNA damage in T2DM, which, in turn, may be linked with genomic instability resulting in cancer. To assess whether DNA repair may be perturbed in 2DM we determined: (1) the level of endogenous basal DNA damage, this means damage recognized in the alkaline comet assay (DNA strand breaks and alkali labile sites) as well as endogenous oxidative and alkylative DNA damage (2) the sensitivity to DNA-damaging agents hydrogen peroxide and doxorubicin and the efficacy of removing of DNA damage induced by these agents in peripheral blood lymphocytes of T2DM patients and healthy individuals. The level of DNA damage and the kinetics of DNA repair was evaluated by the alkaline single cell gel electrophoresis (comet assay). Oxidative and alkylative DNA damage were assayed with the use of DNA repair enzymes endonuclease III (Endo III) and formamidopyrimidine-DNA glycosylase (Fpg), recognizing oxidized DNA bases and 3-methyladenine-DNA glycosylase II (AlkA) recognizing alkylated bases. The levels of basal endogenous and oxidative DNA damage in diabetes patients were higher than in control subjects. There was no difference between the level of alkylative DNA in the patients and the controls. Diabetes patients displayed higher susceptibility to hydrogen peroxide and doxorubicin and decreased efficacy of repairing DNA damage induced by these agents than healthy controls. Our results suggest that type 2 diabetes mellitus may be associated not only with the elevated level of oxidative DNA damage but also with the increased susceptibility to mutagens and the decreased efficacy of DNA repair. These features may contribute to a link between diabetes and cancer and metrics of DNA damage and repair, measured by the comet assay, may be markers of risk of cancer in diabetes.
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PMID:DNA damage and repair in type 2 diabetes mellitus. 1545 Apr 27

The peroxisome proliferator-activated receptor gamma (PPARgamma) is important to adipocyte differentiation and glucose homeostasis, and mutations in the gene have been observed in type 2 diabetes mellitus. The mutated residues, V290 and P467, bind to neither ligands nor a coactivator peptide in the reported crystal structures of the PPARgamma ligand binding domain. To understand the mechanism of type 2 diabetes mellitus caused by germline mutations in the PPARgamma ligand-binding domain, theoretical models of the PPARgamma-ligand-coactivator complex were built at an atomic resolution. In the models, the secondary coactivator peptide was docked next to the conventional coactivator peptide, which both contain the LXXLL motif. The secondary interface in PPARgamma for the secondary coactivator peptide has not been demonstrated by experiments. Binding energy calculations of the complex, considering the solvent effect, revealed that the secondary coactivator peptide, derived from nuclear receptor box 1 of steroid receptor coactivator 1, can be favorably bound to the secondary interface. The secondary coactivator peptide forms hydrogen bonds and a hydrophobic core with PPARgamma and the primary coactivator peptide. Next, we applied mutations to PPARgamma in silico and found that the V290M mutation, observed in type 2 diabetes mellitus, adversely affected the binding of the secondary peptide. Thus, our model provides structural insight into the impairment of PPARgamma function in type 2 diabetes mellitus.
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PMID:Rational discovery of a novel interface for a coactivator in the peroxisome proliferator-activated receptor gamma: theoretical implications of impairment in type 2 diabetes mellitus. 1555 56

Many lines of evidences indicate that increased flux of glucose through the pathway, in which glutamine:fructose-6-phosphate amidotransferase (GFPT or GFAT) is a key catalyst while uridine-5'-diphosphate-N-acetylglucosamine (UDP-GlcNAc) functions as an energy sensor, can lead to the insulin resistance that is characteristic of Type-2 diabetes. In view of this, GFAT and its interaction mechanism with UDP-GlcNAc may become a novel therapeutic target for the treatment of type 2 diabetes. To stimulate the structure-based drug design, the three-dimensional structures of human GFAT1 monomer and dimer have been developed. It has been found by docking UDP-GlcNAc to the dimer (the smallest unit for catalyzing the substrate) that UDP-GlcNAc is bound to the interface of the dimer by 12 hydrogen bonds. On the basis of the docking results, a binding pocket of human GFAT1 dimer for UDP-GlcNAc is defined. All of these findings can serve as a reference or footing in developing new therapeutic strategy for the treatment of type-2 diabetes.
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PMID:Molecular therapeutic target for type-2 diabetes. 1559 39

Metformin (1,1-dimethylbiguanide) is an antihyperglycaemic drug used to normalize glucose concentrations in type 2 diabetes. Furthermore, antioxidant benefits have been reported in diabetic patients treated with metformin. This work was aimed at studying the scavenging capacity of this drug against reactive oxygen species (ROS) like *OH and (O2*-)-free radicals. ROS were produced by gamma radiolysis of water. The irradiated solutions of metformin were analyzed by UV/visible absorption spectrophotometry. It has been shown that hydroxyl free radicals react with metformin in a concentration-dependent way. The maximum scavenging activity was obtained for concentrations of metformin > or = 200 micromol.L(-1), under our experimental conditions. An estimated value of 10(7) L.mol(-1).s(-1) has been determined for the second order rate constant k(*OH + metformin). Superoxide free radicals and hydrogen peroxide do not initiate any oxidation on metformin in our in vitro experiments.
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PMID:Radical-induced oxidation of metformin. 1560 61

Frank metabolic acidosis is known to promote renal excretion of hydrogen ion by induction of glutaminase and other enzymes in the renal tubules. This induction, at least in part, reflects an increase in pituitary output of ACTH and a consequent increased production of cortisol and aldosterone; these latter hormones act on the renal tubules to promote generation of ammonia, which expedites renal acid excretion. Recent evidence suggests that the moderate metabolic acidosis associated with a protein-rich diet low in organic potassium salts - quantifiable by net acid output in daily urine - can likewise evoke a modest increase in cortisol production. Since cortisol promotes development of visceral obesity, and has a direct negative impact on insulin function throughout the body, even a modest sustained up-regulation of cortisol production may have the potential to increase risk for insulin resistance syndrome and type 2 diabetes. This thesis appears to be consistent with previous epidemiological reports correlating high potassium consumption, or a high intake of fruits and vegetables, with reduced risk for diabetes and coronary disease. Future prospective epidemiology should assess whether the estimated acid-base balance of habitual diets - calculated from the ratio of dietary protein and potassium - correlates with risk for insulin resistance syndrome and diabetes.
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PMID:Acid-base balance may influence risk for insulin resistance syndrome by modulating cortisol output. 1560 73

To determine the role of the endoplasmic reticulum (ER) in diabetes, Akita mice, a mouse model of type 2 diabetes, were mated with either heterozygous knockout mice or two types of transgenic mice of 150-kDa oxygen-regulated protein (ORP150), a molecular chaperone located in the ER. Systemic expression of ORP150 in Akita mice improves insulin intolerance, whereas the exclusive overexpression of ORP150 in pancreatic beta-cells of Akita mice did not change their glucose tolerance. Both an insulin tolerance test and hyperinsulinemic-euglycemic clamp revealed that ORP150 enhanced glucose uptake, accompanied by suppression of oxidized protein. Furthermore, ORP150 enhanced the insulin sensitivity of myoblast cells treated with hydrogen peroxide. These data suggest that ORP150 plays an important role in insulin sensitivity and is a potential target for the treatment of diabetes.
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PMID:The endoplasmic reticulum chaperone improves insulin resistance in type 2 diabetes. 1573 40

The enzyme catalase is the main regulator of hydrogen peroxide metabolism. Recent findings suggest that a low concentration of hydrogen peroxide may act as a messenger in some signalling pathways whereas high concentrations are toxic for many cells and cell components. Acatalasemia is a genetically heterogeneous condition with a worldwide distribution. Yet only two Japanese and three Hungarian syndrome-causing mutations have been reported. A large-scale (23 130 subjects) catalase screening program in Hungary yielded 12 hypocatalasemic families. The V family with four hypocatalasemics (60.6 +/- 7.6 MU/L) and six normocatalasemic (103.6 +/- 23.5 MU/L) members was examined to define the mutation causing the syndrome. Mutation screening yielded four novel polymorphisms. Of these, three intron sequence variations, namely G-->A at the nucleotide 60 position in intron 1, T-->A at position 11 in intron 2, and G-->T at position 31 in intron 12, are unlikely to be responsible for the decreased blood catalase activity. However, the novel G-->A mutation in exon 9 changes the essential amino acid Arg 354 to Cys 354 and may indeed be responsible for the decreased catalase activity. This inherited catalase deficiency, by inducing an increased hydrogen peroxide steady-state concentration in vivo, may be involved in the early manifestation of type 2 diabetes mellitus for the 35-year old proband.
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PMID:Detection of a novel familial catalase mutation (Hungarian type D) and the possible risk of inherited catalase deficiency for diabetes mellitus. 1580 Sep 61

Reactive oxygen and nitrogen molecules have been typically viewed as the toxic by-products of metabolism. However, accumulating evidence has revealed that reactive species, including hydrogen peroxide, serve as signaling molecules that are involved in the regulation of cellular function. The chronic and/or increased production of these reactive molecules or a reduced capacity for their elimination, termed oxidative stress, can lead to abnormal changes in intracellular signaling and result in chronic inflammation and insulin resistance. Inflammation and oxidative stress have been linked to insulin resistance in vivo. Recent studies have found that this association is not restricted to insulin resistance in type 2 diabetes, but is also evident in obese, nondiabetic individuals, and in those patients with the metabolic syndrome. An increased concentration of reactive molecules triggers the activation of serine/threonine kinase cascades such as c-Jun N-terminal kinase, nuclear factor-kappaB, and others that in turn phosphorylate multiple targets, including the insulin receptor and the insulin receptor substrate (IRS) proteins. Increased serine phosphorylation of IRS reduces its ability to undergo tyrosine phosphorylation and may accelerate the degradation of IRS-1, offering an attractive explanation for the molecular basis of oxidative stress-induced insulin resistance. Consistent with this idea, studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine indicate a beneficial impact on insulin sensitivity, and offer the possibility for new treatment approaches for insulin resistance.
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PMID:The molecular basis for oxidative stress-induced insulin resistance. 1599 59

Protein tyrosine phosphatase activity depends on a catalytic thiolate group on an acidic cysteine residue that is sensitive to reactive oxygen species. Representative of this family of enzymes is protein tyrosine phosphatase 1B (PTP1B), a major target for type 2 diabetes therapy. PTP1B is sensitive to hydrogen peroxide (H2O2) in vitro and in cells. It is also sensitive to glutathionylation by glutathione disulfide (GSSG). The sensitivity of PTP1B to the redox state of its environment was partially characterized in vitro by examination of phosphatase activity in the presence of various concentrations of glutathione (GSH) and GSSG. Enzyme sensitivity to glutathionylation was dependent on the amount of available thiol groups and increased as GSH concentration was increased. The half-inhibitory concentration for H2O2 was much less than that of GSSG in the presence of low concentrations of GSH, indicating that reaction with H2O2 is much more likely than is glutathionylation by GSSG. PTP1B and a related oxidant-sensitive phosphatase, PTEN, were also sensitive to the lipid peroxidation by-product 4-hydroxynonenal. Furthermore, PTP1B was inhibited by cytochrome c and microperoxidase. Taken together, these data suggest that not only H2O2, but also a variety of redox-active metabolites and hemes can oxidatively inactivate PTPs with potentially profound implications for signal transduction.
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PMID:Sensitivity of protein tyrosine phosphatase activity to the redox environment, cytochrome C, and microperoxidase. 1599 63


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