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)

To evaluate whether increased levels of reactive oxygen species (ROS) are involved in the pathogenesis of essential hypertension (EH) and non-insulin-dependent diabetes mellitus (NIDDM), both resting and stimulated levels of intracellular ROS were measured in lymphocytes from patients with EH (n = 10), NIDDM (n = 16) and age-matched healthy individuals (control subjects, n = 19). ROS was monitored with the dye, dihydrorhodamine-123 (DHR; 1 micromol/L) in the presence or absence of superoxide dismutase (superoxide scavenger), sodium azide (singlet oxygen/hydrogen peroxide scavenger), genistein (tyrosine kinase inhibitor), or bisindolylmaleimide (protein kinase C inhibitor). Simultaneous monitoring of cytosolic [Ca2+]i was done with fura-2. Resting ROS levels were significantly higher in NIDDM (4.71+/-0.25 nmol/10(6) cells; mean +/- SEM, P<.05) compared with EH (4.03+/-0.22 nmol/10(6) cells) or controls (4.05+/-0.15 nmol/10(6) cells). The formyl-Met-Leu-Phenylalanine-(fMLP)-induced ROS generation was significantly higher in NIDDM (21.92+/-2.23 nmol/10(6) cells; P<.05) compared with EH (14.58+/-1.90 nmol/10(6) cells) or control (16.06+/-1.22 nmol/10(6) cells). The fMLP-induced ROS increase was significantly reduced in the presence of sodium azide in all groups (P<.01) but was largely unaffected in the presence of SOD. Genistein and bisindolylmaleimide significantly inhibited the fMLP-induced ROS in all groups. The fMLP-induced [Ca2+]i increase was significantly higher in NIDDM (71+/-12 nmol/L, P <.01) compared with EH (42+/-4 nmol/L) and control subjects (35+/-3 nmol/L). Phytohemagglutinin was more effective in increasing [Ca2+]i than ROS. It is concluded that ROS may play a role in the metabolic syndrome of NIDDM but not in EH.
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PMID:Reactive oxygen species in essential hypertension and non-insulin-dependent diabetes mellitus. 1061 78

In the present work the prostaglandin E (PGE) production by ovulated, immature and in vitro matured oocyte-cumulus complexes (OCC) was evaluated in a rat model of type I diabetes induced by streptozotocin (60 mg kg(-1)). A diminished number of ovulated OCC were found in the type I diabetic rat. In contrast to the increment in PGE generation found previously in OCC and embryos from type II diabetic rats, it was found that PGE production by type I diabetic OCC was diminished in comparison with the controls. Nitric oxide synthase (NOS) activity is enhanced in proestrous ovaries from type I diabetic rats, but cGMP levels are diminished. SIN-1 (300 microM), a nitric oxide donor, significantly enhanced PGE generation by control OCC, but was unable to modify the PGE levels in type I diabetic OCC. L-NMMA, a nitric oxide inhibitor that diminished PGE values in type II diabetic OCC, did not modify PGE generation in either control and type I diabetic OCC. Superoxide dismutase (SOD, 1000 U mL(-1)), and SOD (1000 U mL(-1)) plus SIN-1 (300 microM), enhanced PGE generation by both control and diabetic OCC. The present results suggest that even when nitric oxide (NO) is overproduced in diabetic ovaries, the NO-PGE pathway is impaired in type I diabetic OCC. As SOD additions are able to increase PGE generation by diabetic OCC, high concentrations of free oxygen radicals might be quenching the NO, impairing its physiological functions.
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PMID:Diminished levels of prostaglandin E in type I diabetic oocyte-cumulus complexes. Influence of nitric oxide and superoxide dismutase. 1073 54

The vascular endothelium influences not only the three classically interacting components of hemostasis: the vessel, the blood platelets and the clotting and fibrinolytic systems of plasma, but also the natural sequelae: inflammation and tissue repair. Two principal modes of endothelial behaviour may be differentiated, best defined as an anti- and a prothrombotic state. Under physiological conditions endothelium mediates vascular dilatation (formation of NO, PGI2, adenosine, hyperpolarizing factor), prevents platelet adhesion and activation (production of adenosine, NO and PGI2, removal of ADP), blocks thrombin formation (tissue factor pathway inhibitor, activation of protein C via thrombomodulin, activation of antithrombin III) and mitigates fibrin deposition (t- and scuplasminogen activator production). Adhesion and transmigration of inflammatory leukocytes are attenuated, e.g. by NO and IL-10, and oxygen radicals are efficiently scavenged (urate, NO, glutathione, SOD). When the endothelium is physically disrupted or functionally perturbed by postischemic reperfusion, acute and chronic inflammation, atherosclerosis, diabetes and chronic arterial hypertension, then completely opposing actions pertain. This prothrombotic, proinflammatory state is characterised by vaso-constriction, platelet and leukocyte activation and adhesion (externalization, expression and upregulation of von Willebrand factor, platelet activating factor, P-selectin, ICAM-1, IL-8, MCP-1, TNF alpha, etc.), promotion of thrombin formation, coagulation and fibrin deposition at the vascular wall (expression of tissue factor, PAI-1, phosphatidyl serine, etc.) and, in platelet-leukocyte coaggregates, additional inflammatory interactions via attachment of platelet CD40-ligand to endothelial, monocyte and B-cell CD40. Since thrombin formation and inflammatory stimulation set the stage for later tissue repair, complete abolition of such endothelial responses cannot be the goal of clinical interventions aimed at limiting procoagulatory, prothrombotic actions of a dysfunctional vascular endothelium.
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PMID:Endothelial function and hemostasis. 1079 71

The effect of sulfur dioxide (SO(2) ) on red cell antioxidant status and lipid peroxidation was examined in this research. Forty healthy male albino rats, aged three months, were divided into four equal groups: Control (C), SO(2) +C (CSO(2) ), diabetic (D) and SO(2) +D (DSO(2) ). Experimental diabetes mellitus was induced by i.v injection of alloxan with a dose of 50 mg/kg body weight. Ten ppm SO(2) was administered to the animals of SO(2) exposed groups in an exposure chamber for one hr/day x 7 days/wk x 6wks while other groups were exposed to filtered air in the same condition. SO(2) exposure, while markedly decreasing Cu, Zn-Superoxide dismutase (Cu, Zn-SOD) activity, significantly increased glutathione peroxidase (GSH-Px), catalase (CAT), glutathione (GSH) and glutathione-s-transferase (GST) activities and TBARS values in CSO(2) and DSO(2) groups compared with their respective control groups. From these results, it could be concluded that adaptative changes occurred in antioxidant systems that may counteract the free radical effect of SO(2) in the experimental groups.
Diabetes Metab 2000 Apr
PMID:Effect of sulfur dioxide inhalation on erythrocyte antioxidant status and lipid peroxidation in experimental diabetes. 1080 29

Glycated lipoproteins, which elevate the blood in diabetic patients, cause direct attenuation of endothelial function. Increased glycation of apolipoproteins may play a trigger role in the accelerated development of atherosclerosis in the patient with diabetes. Here we assessed whether glycated lipoproteins affect on the endothelial function with particular emphasis on the role of reactive oxygen species in vitro. Incubation of human aortic endothelial cells(HAEC) with glycated LDL had little influence on the expression of antioxidant enzymes such as nitric oxide synthase(NOS), Cu2+Zn(2+)-superoxide dismutase (Cu2+Zn(2+)-SOD), catalase, and p22 phox in the cells. In contrast, exposure of glycated HDL induced a marked decrease of Cu2+Zn(2+)-SOD, catalase, and endothelial NOS as well as a slight increase of p22 phox in HAEC in term of both protein and mRNA expression, suggesting that increased formation of reactive oxygen species such as O2- and OH radical participate in the deterioration for the function of vascular endothelial cells in diabetic patients.
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PMID:[Expression of reactive oxygen-species related enzymes in endothelial cells stimulated with glycated lipoproteins]. 1081 Aug 80

The SOX (sex-determining region [SRY]-type high mobility group [HMG] box) family of transcription factors play key roles in determining cell fate during organ development. In this study, we have identified a new human SOX gene, SOX13, as encoding the type 1 diabetes autoantigen, islet cell antigen 12 (ICA12). Sequence analysis showed that SOX13 belongs to the class D subgroup of SOX transcription factors, which contain a leucine zipper motif and a region rich in glutamine. SOX13 autoantibodies occurred at a significantly higher frequency among 188 people with type 1 diabetes (18%) than among 88 with type 2 diabetes (6%) or 175 healthy control subjects (4%). Deletion mapping of the antibody epitopes showed that the autoantibodies were primarily directed against an epitope requiring the majority of the protein. SOX13 RNA was detected in most human tissues, with the highest levels in the pancreas, placenta, and kidney. Immunohistochemistry on sections of human pancreas identified SOX13 in the islets of Langerhans, where staining was mostly cytoplasmic. In mouse pancreas, Sox13 was present in the nucleus and cytoplasm of beta-cells as well as other islet cell types. Recombinant SOX13 protein bound to the SOX consensus DNA motif AACAAT, and binding was inhibited by homodimer formation. These observations-along with the known molecular interactions of the closely related protein, rainbow trout Sox23-suggest that SOX13 may be activated for nuclear import and DNA binding through heterodimer formation. In conclusion, we have identified ICA12 as the putative transcription factor SOX13 and demonstrated an increased frequency of autoantibody reactivity in sera from type 1 diabetic subjects compared with type 2 diabetic and healthy control subjects.
Diabetes 2000 Apr
PMID:Sex-determining region Y-related protein SOX13 is a diabetes autoantigen expressed in pancreatic islets. 1087 Nov 92

Hepatocyte nuclear factor 4alpha (HNF4alpha) (NR2A1), an orphan member of the nuclear receptor superfamily, binds DNA exclusively as a homodimer even though it is very similar in amino acid sequence to retinoid X receptor alpha (RXRalpha), which heterodimerizes readily with other receptors. Here, experimental analysis of residues involved in protein dimerization and studies on a reported ligand for HNF4alpha are combined with a structural model of the HNF4alpha ligand-binding domain (LBD) (residues 137 to 384). When K300 (in helix 9) and E327 (in helix 10) of HNF4alpha1 were converted to the analogous residues in RXRalpha (E390 and K417, respectively) the resulting construct did not heterodimerize with the wild-type HNF4alpha, although it was still able to form homodimers and bind DNA. Furthermore, the double mutant did not heterodimerize with RXR or RAR but was still able to dimerize in solution with an HNF4alpha construct truncated at amino acid residue 268. This suggests that the charge compatibility between helices 9 and 10 is necessary, but not sufficient, to determine dimerization partners, and that additional residues in the HNF4alpha LBD are also important in dimerization. The structural model of the HNF4alpha LBD and an amino acid sequence alignment of helices 9 and 10 in various HNF4 and other receptor genes indicates that a K(X)(26)E motif can be used to identify HNF4 genes from other organisms and that a (E/D(X)(26-29)K/R) motif can be used to predict heterodimerization of many, but not all, receptors with RXR. In vitro analysis of another HNF4alpha mutant construct indicates that helix 10 also plays a structural role in the conformational integrity of HNF4alpha. The structural model and experimental analysis indicate that fatty acyl CoA thioesters, the proposed HNF4alpha ligands, are not good candidates for a traditional ligand for HNF4alpha. Finally, these results provide insight into the mechanism of action of naturally occurring mutations in the human HNF4alpha gene found in patients with maturity onset diabetes of the young 1 (MODY1).
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PMID:Analysis of protein dimerization and ligand binding of orphan receptor HNF4alpha. 1099 27

Diabetes is a state of increased oxidant stress and there is evidence that oxidation may play a role in the genesis of complications. Gliclazide, a sulfonylurea hypoglycemic drug, has been shown to possess free radical scavenging properties. This study examined the effects of in vitro supplementation with gliclazide and other sulfonylureas as on low-density lipoprotein (LDL) oxidation and the total plasma antioxidant capacity (TPAC). In a separate study, the effects of 10 months of oral gliclazide therapy on oxidative parameters were assessed in 44 type 2 diabetic patients. Gliclazide, but not glibenclamide, glimepiride, glipizide or tolbutamide, inhibited LDL oxidation and enhanced TPAC. With the addition of 1 microM gliclazide, oxidation lag time increased from 53.6+/-2.6 to 113.6+/-5.1 min (p<0.001), and TPAC increased from 1. 09+/-0.11 to 1.23+/-0.11 mM (p<0.01). Administration of either modified release or standard gliclazide to type 2 diabetic patients resulted in a fall in 8-isoprostanes, a marker of lipid oxidation, and an increase in the antioxidant parameters TPAC, SOD and thiols. These studies show that gliclazide possesses antioxidant properties that produce measurable clinical effects at therapeutic doses.
J Diabetes Complications
PMID:In vitro and in vivo antioxidant properties of gliclazide. 1100 29

Lipid peroxidation is thought to be one of the major factors involved in atherogenesis. There is an increasing evidence is increasing that oxidation of LDL cholesterol may be instrumental in atherogenesis. Diabetics are known to be at increased risk of cardiovascular diseases, a phenomenon which has previously been linked to the lipid peroxidation process. As a result, a number of studies have been undertaken to evaluate the effects of antioxidant vitamins on coronary heart disease and risks factors of ischaemic heart disease such as diabetes mellitus. Lipid peroxidation and antioxidant status were studied in 51 patients with ischaemic heart disease and some of with having diabetes mellitus (18%). Results were compared before and after supplementation of 450 mg of tocopherol acetate for three months. SOD were found to be elevated in patients with diabetes and in whole groups of patients after supplementation of tocopherol acetate. Also, TAS was found to be elevated in a subgroup of patients without diabetes and no significant changes were found in glutathion-peroxidase after supplementation. We found statistically significantly decreased mean values of glucose after supplementation in all groups of patients. The monitoring of antioxidant parameters in diabetic patients could be of vital importance in the study of the disease.
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PMID:[Effect of vitamin E on erythrocyte enzymes and total antioxidant status in diabetic patients with ischemic heart disease]. 1108 30

-Oxygen free radicals are believed to play a key role in cellular proliferation, and increased concentrations of these molecules have been implicated in the pathogenesis of endothelial dysfunction in diabetes mellitus. Our aim was to study the role of superoxide anions in endothelial cell proliferation under conditions of normoglycemia and hyperglycemia. Human aortic endothelial cells (HAECs) and human umbilical vein endothelial cells (HUVECs) exposed to adenoviral vectors encoding CuZnSOD (AdCuZnSOD), ss-galactosidase (Adssgal), or diluent (control) were cultured in normal glucose (NG, 5.5 mmol/L) or high glucose (HG, 28 mmol/L) medium. Cell proliferation was compared by use of [(3)H]thymidine incorporation and cell count in transduced and control cells in the setting of NG and HG. Transgene expression was detected in transduced cells by X-gal staining and by Western analysis and SOD activity assay in AdCuZnSOD-transduced cells. Superoxide production was significantly (P:<0.05) decreased in AdCuZnSOD-transduced cells cultured in both NG and HG medium. In NG, AdCuZnSOD-transduced endothelial cells had decreased proliferation compared with control cells. After 48 hours in HG, superoxide levels were increased and DNA synthesis was decreased (P:<0.05) in control and Adssgal-transduced but were not affected in AdCuZnSOD-transduced cells. In addition, after 7 days in HG, cell counts were reduced (P:<0.05) in control (73+/-2.5%) and Adssgal-transduced (75+/-3.4%) but not in AdCuZnSOD-transduced cells (89+/-3.4%). These results suggest that either a deficiency or an excess of superoxide anions inhibits endothelial cell proliferation, and the inhibitory effect of increased superoxide due to hyperglycemia can be reversed by CuZnSOD overexpression.
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PMID:Superoxide anions and endothelial cell proliferation in normoglycemia and hyperglycemia. 1115 52


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