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)

The activity of glutathione-insulin transhydrogenase (glutathione:protein-disulfide oxidoreductase, EC 1.8.4.2) in the liver and kidneys of rats during the development of streptozotocin-induced diabetes has been studied. Following a single injection of streptozotocin, the transhydrogenase activity fell rapidly for 7-8 days and then gradually with time in both organs. In contrast to the control rats where approximately 25% of the enzyme is in a 'latent' state, nearly all the transhydrogenase activity in the diabetic liver appears to be in the free or functional form. The results are consistent with the hypothesis that both hepatic and renal glutathione-insulin transhydrogenase activity are under feedback control by circulating insulin. The possibility is discussed that the latent state may represent a storage form of the enzyme, which in insulin-insufficiency states is mobilized to the free or functional form for cell function.
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PMID:Insulin degradation. XXV. Glutathione-insulin transhydrogenase activity of rat liver and kidney during the development of streptozotocin-diabetes. 45 31

Isolated liver cells contain insulin-degrading activity. Examination by chromatography on Sephadex G-75 of the products formed from 125I-insulin (1 nM or 1 muM) upon incubation with suspensions of hepatocytes for various time periods showed that there is at first a transient accumulation of the intermediate product, A chain, which is further hydrolyzed by protease(s) to low-molecular-weight components. These results indicate that the sequential degradative pathway is operative, both at low and high concentrations of insulin, in isolated liver cells, i.e., the insulin is first split at the disulfide bonds by glutathione-insulin transhydrogenase (GIT) into A and B chains, followed by proteolysis of the resultant polypeptides, and that this system might be used for well-defined studies of factors controlling insulin metabolism. The chelating agent ethylenediamine tetraacetic acid (EDTA) accelerated the accumulation of A chain (i.e., enhanced the activity of GIT), which is in keeping with its effect with purified GIT. In contrast to previous studies with tissue homogenates in which EDTA caused a marked inhibition of the proteolytic stage, EDTA had little or no effect with intact liver cells. Since EDTA does not appreciably penetrate the cell membrane, these data suggest that GIT activity either occurs on the cell surface or is readily available at the cell surface, whereas the proteolytic activity either occurs inside the cell or is inaccessible at the cell surface.
Diabetes 1976 Mar
PMID:Insulin degradation. XVI. Evidence for the sequential degradative pathway in isolated liver cells. 81 21

Five monoclonal antibodies specific for glutathione-insulin transhydrogenase were characterized. None of the monoclonal antibodies cross-reacted with another insulin-degrading enzyme, neutral thiopeptidase. The isotype of four antibodies was IgG1 and of the fifth IgG2b. Affinity studies, competitive binding studies and immunoblot analysis of CNBr and trypsin cleavage products of glutathione-insulin transhydrogenase demonstrated that the four IgG1 antibodies were directed to an epitope of the enzyme which was distinct from the epitope recognized by the IgG2b antibody. Inhibition studies indicated that each monoclonal antibody, when added singly to glutathione-insulin transhydrogenase, was unable to inhibit the insulin-degrading activity of the enzyme. However, when monoclonal antibodies directed against separate epitopes of glutathione-insulin transhydrogenase were presented together (i.e., the IgG2b with any one of the four IgG1 antibodies), a loss in enzymatic activity was noted. Immunoblot analysis of rat organ extracts with the IgG1 antibodies demonstrated one immunoreactive protein band of Mr 56,000 in all tissues examined (liver, fat, pancreas and kidney) except the spleen, which demonstrated two immunoreactive protein bands of Mr 56,000 and 51,000. The same immunoblots, when probed with the IgG2b antibody, demonstrated the same immunoreactive protein banding pattern as above plus an additional immunoreactive protein band of Mr 67,000 in all tissues. Studies with spleen extracts from steptozotocin-induced diabetic rats demonstrated that there was a loss of the 51,000 immunoreactive band in diabetes. This 51,000 protein was restored upon insulin treatment of the diabetic rats and nullified upon concomitant administration of cycloheximide or actinomycin D with insulin. Immunoblots of human liver, adipose and skeletal muscle extracts indicated that each monoclonal antibody cross-reacted with the human form of the enzyme which had a molecular weight of Mr 63,000; a second minor immunoreactive band of 67,000 was detected with the IgG2b antibody. The physiological significance of additional molecular forms of the enzyme (i.e., 67,000 and 51,000) remains to be determined.
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PMID:Characterization and application of monoclonal antibodies directed to separate epitopes of glutathione-insulin transhydrogenase. 243 25

The activity of the insulin-degrading enzyme neutral cysteine proteinase (EC 3.4.22.11, insulinase) was studied in adipose tissue and in liver of nondiabetic, streptozotocin-diabetic, and insulin-treated diabetic rats. Proteinase activity was found to be significantly decreased during diabetes and was restored to near normal levels in both tissues following insulin treatment. The insulin-mediated increase of proteinase activity in both tissues was partially or completely blocked by actinomycin D (an inhibitor of RNA synthesis) and by cyclohexamide (an inhibitor of protein synthesis). Kinetic analysis showed that the changes in proteinase activity of both liver and adipose tissues were accompanied by a change in Vmax (i.e., maximal enzyme activity) without a change in Km (i.e., substrate affinity). These data indicate that insulin functions as an inducer for neutral cysteine proteinase in both tissues. These alterations in the proteinase activity paralleled the alterations in the activity of a second insulin-degrading enzyme, glutathione-insulin transhydrogenase in adipose tissue (this paper) and in liver (previously published papers) under the same physiological conditions.
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PMID:Insulin-degrading neutral cysteine proteinase activity of adipose tissue and liver of nondiabetic, streptozotocin-diabetic, and insulin-treated diabetic rats. 355 42

Insulin-degrading activity in mononuclear (MN) and polymorphonuclear (PMN) fractions of circulating leukocytes obtained from 7 nondiabetic and 13 insulin-dependent diabetic subjects was studied. Insulin-degrading activity in both MN and PMN fractions was activated by reduced glutathione and was inhibited completely by N-ethylmaleimide. Both fractions had Michaelis-Menten constant (Km) (insulin) values within the range of values reported for purified glutathione-insulin transhydrogenase (GIT). In double immunodiffusion tests with antibody to human liver GIT, the MN fraction showed immunoprecipitin bands continuous with those of purified liver enzyme, but the PMN fraction showed little or no reaction with the antibody. These data indicate that both leukocyte fractions contain thiol-dependent insulin-degrading activity; however, only in the MN fraction was the degrading activity immunologically similar to that of liver GIT. Kinetic studies showed that the insulin-degrading activity of MN and PMN cells from diabetic patients had a 3.6- and 14.5-fold, respectively, higher maximal capacity (Vmax) than the insulin-degrading activity of these cells from nondiabetic subjects, without any change in the half-saturation constant for the substrate (Km for insulin). These results demonstrate that diabetes and/or insulin therapy result in increased leukocyte glutathione-dependent insulin-degrading activity.
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PMID:Insulin-degrading activity in mononuclear and polymorphonuclear circulating leukocytes of nondiabetic and diabetic subjects. 642 85

In order to analyze the detoxication functions in rats with diabetes induced by streptozotocin, the authors administered to the diabetic animals two drugs, ethionine and benzo(a)pyrene, which affect mainly the liver and are metabolized through a glutathione conjugation process, and examined the changes in the content of glutathione and activities of related enzymes in the liver. In the liver of the rats with streptozotocin-induced diabetes, the total glutathione content, glutathione S-transferase activity and glutathione-insulin transhydrogenase activity were lower than those of normal rat livers, while the glutathione peroxidase activity showed high values. Although specific changes in the glutathione-related detoxication functions were observed in the rats to which ethionine or benzo(a)pyrene had been administered, these changes were not revealed under diabetic conditions. It is suggested that in diabetic rats responses to toxic stimuli are suppressed.
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PMID:Glutathione-related detoxication functions in streptozotocin-induced diabetic rats. 811 29