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)

Recently, human endogenous retrovirus type K (HERV-K [IDDMK(1,2)22]) was isolated from an IDDM patient's beta-cell supernatant and shown to be implicated in expression as a superantigen. Furthermore, HERV-K RNA was found in plasma samples from newly diagnosed patients but not in those from healthy control subjects. We had earlier identified the presence of a HERV-K long terminal repeat element of the HLA DQ gene (DQ-LTR) to be positively associated with IDDM, which led us to investigate whether DQ-LTR is related to transcription of the putative retroviral superantigen. Additionally, we sought immunological evidence to determine whether those retroviral antigens could evoke an antibody response. Patients with IDDM (n = 14), Hashimoto's thyroiditits (n = 5), and Graves' disease (n = 12), as well as healthy control subjects (n = 12), were investigated, as were four nuclear families of Graves' disease patients and two of IDDM patients. RNA was isolated from plasma and peripheral blood lymphocytes and subjected to reverse transcription-polymerase chain reaction for transcripts of the env region of the HERV-K (IDDMK(1,2)22) sequence. We identified env transcripts in both plasma and peripheral blood lymphocytes in all individuals studied: patients with recent-onset or long-standing IDDM, their relatives, and healthy control subjects, as well as patients with thyroid autoimmune disorders. Furthermore, we screened the sera of patients (n = 62) and control subjects (n = 35) for evidence of humoral immunity against HERV-K by Western blot specific for the ENV protein. Similar frequencies of antibody-positives were observed both in patients with IDDM (29%) and in healthy control subjects (26%). We conclude that neither the ubiquitous HERV-K transcripts nor the comparable percentage of ENV protein antibodies are associated with IDDM. An earlier, presymptomatic antibody response against HERV-K (IDDMK(1,22)22) ENV cannot be ruled out. However, the superantigen hypothesis of an endogenous retrovirus in beta-cell autoimmunity awaits confirmation.
Diabetes 1999 Jan
PMID:IDDM patients neither show humoral reactivities against endogenous retroviral envelope protein nor do they differ in retroviral mRNA expression from healthy relatives or normal individuals. 989 47

Epidemiological data consistently show that reduced levels of serum albumin, which is the most abundant protein in plasma, are associated with an increased mortality risk. Various biological properties evidenced by direct effects of the albumin molecule may explain its beneficial effects. The present work aimed to investigate in vitro whether glycation or free radicals or both factors would affect the antioxidant properties of bovine serum albumin (BSA). Glycation was performed by long-term incubations (60 days) of BSA with increasing concentrations of glucose (up to 500 mmol/l) at 37 degreesC. Minimally oxidized BSA was obtained after controlled incubations of dialyzed BSA samples with a water-soluble free radical generator [2,2' azo-bis(2-amidinopropane) HCl]. The glycation-mediated modifications and the free radical-induced conformational changes of BSA were monitored using intrinsic fluorescence measurements of the tryptophan residues and acrylamide as a quenching agent. Thiol groups, Amadori glycophore contents, and boronate binding were also measured. We found that the changes observed in the conformation of the BSA molecule were associated with modifications of its antioxidant properties. The latter were studied by the copper-mediated oxidation of human low density lipoproteins and the free radical-induced blood hemolysis test. Our data support the concept that oxidative-induced BSA modifications are important determinants in the antioxidant properties of BSA. Glycated BSA still behaved as an antioxidant but became pro-oxidant in the presence of copper, probably by generating oxygenated species. These data confirm the key role of metals ions in this process. Although these results warrant further in vivo investigations, we propose that, considering the poor glucose control found in diabetics as well as the key role of oxidative stress in vascular complications, glycation-mediated and free radical-induced impairment of the antioxidant properties of albumin might be important parameters in vascular complications encountered in diabetes.
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PMID:Glucose and free radicals impair the antioxidant properties of serum albumin. 997 11

Recent studies have suggested an association between Type II (non-insulin-dependent) diabetes mellitus-related phenotypes and a cytosine-to-thymidine substitution that results in the replacement of tryptophan by arginine at codon 64 (Trp64Arg or W64R) of the beta3-adrenergic receptor gene. Here, we present the results of possibly the largest association study to date on the variant in a sample of 526 families with a total of 1725 subjects, 1053 of whom had Type II diabetes. Preliminary calculations suggested that we had excellent power to detect the moderate associations which were reported in previous studies. No associations were found between the W64R variant and the following phenotypes in our sample: Type II diabetes, age at diagnosis for Type II diabetes, measures of obesity, fasting glucose, fasting insulin, minimal model variables, and systolic and diastolic blood pressures. In the analysis of plasma lipids, we detected an association between the variant and HDL ratios (HDL cholesterol/total cholesterol) (p = 0.013), which remained significant even after adjusting for sex, affection status and age. Since W64R homozygotes (n = 11) had the highest HDL ratios, however, heterozygotes had the lowest and the wild-type subjects had intermediate values, we conclude that the W64R variant is unlikely to reduce HDL ratios in a dose-dependent, pathogenic manner.
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PMID:The W64R variant of the beta3-adrenergic receptor is not associated with type II diabetes or obesity in a large Finnish sample. 1006 5

The brain stems (BS) of streptozotocin (STZ)-diabetic rats were studied to see the changes in neurotransmitter content and their receptor regulation. The norepinephrine (NE) content determined in the diabetic brain stems did not show an increase, while epinephrine (EPI) content increased significantly compared with control. The NE to EPI turnover showed a significant increase. The alpha2 adrenergic receptor kinetics revealed that the receptor affinity was significantly reduced during diabetes. In insulin treated rats the NE content decreased while EPI content remained increased as in the diabetic state. Insulin treatment increased the Bmax for alpha2 adrenergic receptors significantly while the increase in Kd reversed to normal. Unlabelled clonidine inhibited [3H]NE binding in BS of control diabetic and insulin treated diabetic rats showed that alpha2 adrenergic receptors consisted of two populations of binding sites with Hill slopes significantly away from unity. In diabetic animals the ligand bound weaker to the low affinity site than in controls. Insulin treatment reversed this alteration to control levels. The displacement analysis using (-)-epinephrine against [3H]yohimbine in control and diabetic animals revealed two populations of receptor affinity states. In control animals, when GTP analogue added with epinephrine, the curve fitted for a single affinity model; but in the diabetic BS this effect was not observed. In both the diabetic and control BS the effects of monovalent cations on affinity alterations were intact. Our data thus show that alpha2 adrenergic receptors have a reduced affinity due to an altered post receptor affinity regulation The serotonin (5-HT) content in the brain stem increased. Its precursor (5-hydroxy) tryptophan (5-HTP) showed an increase and its breakdown metabolite (5-hydroxy) indoleacetic acid (5-HIAA) showed a significant decrease. This showed that in serotonergic nerves there is a disturbance in both synthetic and breakdown pathways which lead to an increased 5-HT. The high affinity serotonin receptor numbers remained unaltered with a decrease in the receptor affinity. The insulin treatment reversed these altered serotonergic receptor kinetic parameters to control level. Thus our study shows a decreased serotonergic receptor function. These changes in adrenergic and serotonergic receptor function were suggested to be important in insulin function during STZ diabetes.
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PMID:Alpha2 adrenergic and high affinity serotonergic receptor changes in the brain stem of streptozotocin-induced diabetic rats. 1042 26

We intended to confirm genetically the involvement of the IDDMK1,2-22 gene in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). For this purpose, we isolated a human endogenous retrovirus gene, possibly corresponding to IDDMK1,2-22. The isolated gene showed 99.8% and 99.7% homologies in nucleotide sequences to a part of the env region and of the 3'-LTR region, respectively, compared to those of IDDMK1,2-22 deposited in GenBank. The gene also showed a close relation to HERV-K18, of which the 3'-LTR sequence gave 99.5% homology. It seemed likely that these genes represented the same single gene. The newly isolated gene was present in the first intron of the CD48 gene and was located on chromosome 1q21.2-q22. A CA repeat marker was found approximately 20 kb upstream from the 5'-end of the 5'-LTR of the gene.
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PMID:Isolation and localization of an IDDMK1,2-22-related human endogenous retroviral gene, and identification of a CA repeat marker at its locus. 1049 80

The effect of methylglyoxal on the plasminogen-plasmin system is studied. Treatment of plasminogen with methylglyoxal at a 20-fold molar excess results in covalent modification of the molecule as evidenced by the decreased number of NH(2) side chains, arginine side chain residues and the new band in the non-tryptophan dependent fluorescent spectrum. This structural modification is associated with profound functional alterations: the rate of activation by streptokinase, tissue-type plasminogen activator, urokinase-type plasminogen activator and trypsin decreases and the amidolytic activity of the generated plasmin is impaired. Plasmin treatment with methylglyoxal on the other hand does not alter its steady-state kinetic parameters on a peptidyl-anilide synthetic substrate, indicating that modification susceptible side chains are sensitive to methylglyoxal only in the zymogen. Our data suggest that in vivo fibrinolysis could be impaired under pathological conditions, e.g. increased methylglyoxal formation in diabetes mellitus.
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PMID:Modulation of plasminogen activation and plasmin activity by methylglyoxal modification of the zymogen. 1089 32

Missense mutations in the tyrosine kinase domain of the human insulin receptor frequently result in a dominantly inherited form of insulin resistance. We noted a marked disparity in the clinical phenotypes of our study subjects with different missense mutations at the same residue (Arg1174) of the insulin receptor. Subjects with a tryptophan substitution (W) were only moderately hyperinsulinemic, whereas those with a glutamine substitution (Q) had severe clinical and biochemical insulin resistance. Studies were undertaken to explore the molecular mechanisms underlying these differences. Both W and Q mutant receptors bound insulin normally but were kinase inactive. The W mutation resulted in more rapid degradation of newly synthesized mutant receptor, which contrasted with the near-normal biosynthesis of the Q receptor. The propensity of the W receptor to form hybrids with the cotransfected wild-type (WT) receptor was also markedly impaired compared with the Q receptor, to an extent greater than could be explained by lower steady-state expression. Thus, the more clinically benign consequences of the heterozygous W mutant receptor are likely to relate to its impaired biosynthesis and/or reduced capacity to form hybrids with WT receptors. In addition to providing an explanation for the milder phenotype of 1174W versus 1174Q carriers, these studies provide further support for the notion that the dominant-negative effect of insulin receptor tyrosine kinase mutations involves the competition between inactive mutant homodimers and WT/mutant hybrids with active WT homodimers for both ligands and intracellular substrates.
Diabetes 2000 Jul
PMID:Naturally occurring amino acid substitutions at Arg1174 in the human insulin receptor result in differential effects on receptor biosynthesis and hybrid formation, leading to discordant clinical phenotypes. 1090 87

Insulin resistance has been associated with people diagnosed with depression. Conversely, it has also been documented that diabetics have an increased risk of depression. Evidence suggests that insulin activity plays a role in serotonergic activity by increasing the influx of tryptophan into the brain. This increased influx of tryptophan has been shown to result in an increase in serotonin synthesis. In accordance with the serotonin theory of depression, it may be possible to treat depression by increasing insulin activity. The antioxidant alpha lipoic acid has been shown to increase insulin sensitivity and is used to treat people with diabetes. Therefore, the nutrient alpha lipoic acid should be clinically tested as an adjunct treatment for depression.
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PMID:Alpha lipoic acid: a novel treatment for depression. 1109 Mar

Retroviral vectors encoding glucose-responsive promoters driving furin expression may provide an amplified, glucose-regulated secretion of insulin. We constructed LhI*TFSN virus to encode a glucose-regulatable transforming growth factor alpha promoter controlling furin expression with a viral LTR promoter driving constitutive expression of furin-cleavable human proinsulin. Autologous BB rat vascular smooth muscle cells transduced with LhI*TFSN virus and cultured in 1.7 and 16.7 mM glucose secreted 50.7 +/- 3.2 and 136.0 +/- 11.0 microU (mean +/- SD) of insulin per 10(6) cells per day, respectively. After the onset of diabetes spontaneously diabetic congenic DR lyp/lyp BB rats received stomach implants containing 2 x 10(6) LhI*TFSN-transduced primary rat vascular smooth muscle cells. In eight treated rats there was a major reduction in insulin requirement to as low as 25% of pretreatment level for up to 3 months and one rat became insulin free without hypoglycemia. Intraperitoneal glucose tolerance tests (IPGTTs) in diabetic rats receiving control implants did not show the characteristic decline in blood glucose of normal rats after glucose administration. In contrast, diabetic rats receiving LhI*TFSN-transduced cells showed significant clearances of blood glucose. These data suggest clinically significant levels of glucose-regulated insulin delivery from implanted vascular smooth muscle cells transduced with LhI*TFSN vector.
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PMID:Glucose-regulated insulin expression in diabetic rats. 1117 50

Hyperglycemia has been assumed to be responsible for oxidative stress in diabetes. In this respect, glucose autoxidation and advanced glycation end products (AGE) may play a causal role in the etiology of diabetic complications as e.g. atherosclerosis. There is now growing evidence that the oxidative modification of LDL plays a potential role in atherogenesis. Glucose derived oxidants have been shown to peroxidise LDL. In the present study, genistein, a compound derived from soy with a flavonoid chemical structure (4', 5, 7-trihydroxyisoflavone) has been evaluated for its ability to act as an antioxidant against the atherogenic modification of LDL by glucose autoxidation radical products. Daidzein, (4',7-dihydroxyisoflavone) an other phytoestrogen of soy, was tested in parallel. Genistein--in contrast to daidzein--effectively prevented the glucose mediated LDL oxidation as measured by thiobarbituric acid-reactive substance formation (TBARS), alteration in electrophoretic mobility, lipid hydroperoxides and fluorescence quenching of tryptophan residues of the lipoprotein. In addition the potential of glucose-oxidized LDL to increase tissue factor (TF) synthesis human endothelial cells (HUVEC) was completely inhibited when genistein was present during LDL oxidative modification by glucose. Both phytoestrogens did not influence the nonenzymatic protein glycation reaction as measured by the in vitro formation of glycated LDL. As the protective effect of genistein on LDL atherogenic modification was found at glucose/genistein molar ratios which may occur in vivo, our findings support the suggested beneficial action of a soy diet in preventing chronic vascular diseases and early atherogenic events.
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PMID:Genistein prevents the glucose autoxidation mediated atherogenic modification of low density lipoprotein. 1123 92


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