Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.56 (insulin-degrading enzyme)
 737 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe resistance to subcutaneous insulin but sensitivity to intravenous insulin persisted for 15 months in a 17-year-old diabetic girl. Heat-labile insulin-degrading activity was present in the patient's ketotic sera and in the 100,000 g fraction (soluble fraction) of adipose tissue. Serum-degrading activity was not inhibited by N-ethylmaleimide. The soluble fraction also degraded glucagon and B chain but not growth hormone or myoglobin. It was inhibited by incubation with the patient's nonketotic sera, normal sera, or Trasylol. Glutathione-insulin-transhydrogenase (GIT) activity was 66% of normal. The biopsy of adipose tissue at remission showed a normal level of insulin- and glucagon-degrading activity. The activity was eluted from Sephadex G200 as a single peak and had properties consistent with those of the insulin-specific protease (ISP). The increased degrading activity present during insulin resistance had properties not shared with ISP, suggesting the presence of an uncharacterized protease.
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PMID:Insulin resistance caused by massive degradation of subcutaneous insulin. 10 40

Insulin was enzymatically moniodinated with 127-I or 125-I, and an improved method of purification by anion exchange chromatography was employed. (127-I)Monoiodoinsulin was identified by spectrophotometric analysis and its molar extinction coefficient determined to be 6.31 times 10-3 M-1 cm minus 1. The observed specific activity of carrier-free (125-I)monoidoinsulin was close to the theoretical value (378mCi/mg). The monoiodotyrosyl residue of monoidoinsulin was shown to be solvent-exposed. The ionic properties of the substituted hormone were altered at pH values close to the pK of monoiodotyrosine (8.85), but the pI was unchanged (5.65). (127-I)Monoiodoinsulin formed rhombohedral crystals and co-crystallized with native insulin. Monoidoinsulin was indistinguishable from insulin with respect to binding to two out of three guinea pig anti-insulin sera, to binding to IM9 cultured human lymphocytes, and to binding to isolated rat hepatocyte plasma membranes. The potency of monoidoinsulin was not statistically different from that of insulin in the rat fat cell bioassay and in the mouse convulsion assay. An insulin-degrading enzyme extracted from rat liver degraded monoiodoinsulin less readily than native insulin; monoiodoinsulin was a competitive inhibitor of insulin degradation, and the Km values were 30 nM AND 78 NM for monoidoinsulin and native insulin, respectively. It is concluded that monoidination does not markedly alter the three-dimensional structure of the molecule and that only a few sensitive biological systems are able to distinguish the monoidinated from the native hormone.
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PMID:[127-I]- or carrier-free [125-I]monoiodoinsulin. 23 16

Exposure of insulin to insulin protease (insulinase, EC 3.4.22.11), a degradative enzyme with considerable specificity toward insulin, results in alterations in the properties of the insulin molecule. Limited degradation by the enzyme results in a decrease in the ability of insulin to bind to membrane receptors with less change in the immunoprecipitability or trichloracetic acid precipitability of the hormone. Limited degradation by insulin protease also alters insulin so that the molecule becomes susceptible to attack by nonspecific endopeptidases which have no effect on unaltered insulin. These data demonstrate the production of an intermediate in the proteolytic degradation of insulin. By labeling with [14C]dansyl chloride, an insulin intermediate with three amino-terminal residues, glycine, phenylalanine, and leucine, was identified. Analysis of this intermediate demonstrated that it was composed of an intact A chain and a B chain cleaved between residues B16 and B17, with the three peptide chains held together by disulfide bonds. Based on these findings, we hypothesize that a stepwise degradation of insulin occurs in vivo and that an early step in the process is the cleavage between B16 and B17 that renders the molecule sucseptible to further degradation by nonspecific proteases.
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PMID:Initial site of insulin cleavage by insulin protease. 28 88

The degradation of insulin by insulin protease and glutathion-insulin transhydrogenase (glutathioneproteindisulphide oxidoreductase--EC 1.8.4.2, GIT) was measured in rat liver either after replacing food and water by 15% glucose solution, or after daily insulin administration 8 U daily for 3 days or after fasting. The breakdown of radioiodinated insulin was followed by measuring the increase of TCA soluble radioactivity during incubation of cell fractions with 125I insulin at 37 degrees C. The highest GIT activity was observed in liver microsomes of rats after glucose feeding and after insulin administration, whereas enzyme activity of fasted animals did not essentially differ from corresponding values of normally fed controls. The insulin protease in cytosol of liver cells remained unchanged after these procedures. The important role of GIT in insulin degradation seems to be conclusively demonstrated.
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PMID:Effect of insulin and glucose on the activity of insulin-degrading enzymes in rat liver. 30 91

It was previously proposed (Varandani, P. T., Proc Natl Acad Sci 69:1681, 1972) that insulin is first degraded by rat liver homogenates in an enzyme-catalyzed reductive process by microsomal glutathione-insulin transhydrogenase before being proteolytically cleaved by the cytosolic enzyme activity designated insulin protease. This study was, however, carried out with concentrations of the hormone 10,000 times the maximal concentration seen in peripheral blood. In the present study, physiological levels of insulin (approximately 0.1 nM) and concentrations of reduced and oxidized glutathione approximating the reductive potentials of normal liver were used. Rates of degradation by separable particulate and soluble components of the homogenate were determined by following enzymatic conversion of [125I]-iodoinsulin to the trichloroacetic acid-solube form. Assessment of the mode of degradation was determined by gel filtration on Sephadex G-50 in the presence of 1 M acetic acid-6M urea. From these studies it was seen that 1) insulin is reduced at a very significant rate nonenzymatically; 2) during short periods of incubation (30 sec) where no significant hormone is reduced nonenzymatically, the rate of cleavage by the insulin protease present in the cytosol is extremely high and the microsomal GIT activity is negligible; and 3) insulin destruction noted in isolated liver cells and perfused liver is most probably due to the insulin protease activity of the cytosol.
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PMID:The importance of proteolysis as the initial step of insulin degradation in rat liver homogenates. 44 84

The effect of acetazolamide on the sensitivity to exogenous insulin in the alloxanised diabetic dogs was studied. The administration of acetazolamide caused acidosis and insulin resistance. The liver insulinase activity of diabetic dogs after acetazolamide administration was also studied to evaluate the role of this enzyme for the destruction of exogenous insulin. It was observed that insulinase did not play role for the development of insulin resistance after acetazolamide administration.
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PMID:Effect of acetazolamide on insulin sensitivity in dogs with alloxan diabetes. 72 Dec 53

Nonsuppressible insulin-like activity, provided by three sources, was evaluated for its effect on the proteolytic degradation of insulin utilizing insulin protease obtained from rat liver homogenate as well as liver cell membranes. All three preparations of nonsuppressible insulin-like activity were found to be competitive inhibitors of insulin degradation. In addition human plasma was fractionated yielding an acetone precipitate which was found to have nonsuppressible insulin-like activity and to be a competitive inhibitor of insulin protease.
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PMID:Inhibition of insulin degradation by nonsuppressible insulin-like activity. 94 51

Results obtained with Cerasi & Luft's method and OGTT in subjects with a historical, clinical and laboratory suspicion of dysmetabolism were compared. It was found that: 1) obese subjects showed increased blood sugar and insulinase areas by comparison with normal controls; 2) subjects of normal weight displayed: a) a mean increase in blood sugar areas by comparison with normal controls; b) less evident changes in blood insulin areas; in these subjects, it was also noted that, c) an early-phase secretion irregularity detected with Cerasi & Luft's method did not involve changes in the oral loading pattern displayed by subjects classed as normal by means of such method; d) in subjects classed as "chemical diabetics" by OGTT, the response to glucagon after venous loading was defective. In border-line cases, early-phase changes were observed in the venous curve after oral glucose, whereas the response to glucagone remained efficient. It is felt that OGTT is an effective means in the diagnosis of infantile dysmetabolism. Attention is also drawn to the possibilities offered by the method of Cerasi & Luft in the detailed and specific appraisal of insulin secretion.
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PMID:[Comparative evaluation of the results obtained with the Cerasi and Luft method and the OGGT in children]. 99 83

The disappearance rate of intravenously injected insulin was investigated in the serum of 30 women during the third trimester of pregnancy and 6 to 8 weeks post partum, in order to determine whether pregnancy has an influence on insulin kinetics in human subjects. Both women with unimpaired glucose tolerance and those with latent diabetes were included in this study. The disappearance rate of exogenous serum insulin in pregnancy was characterized by a two-compartment model. Multivariate analyses of variance were used to determine whether the estimated parameters of this model during pregnancy differ from those obtained after the puerperium and whether the insulin kinetics are altered when carbohydrate metabolism is disturbed. The kinetics of insulin during pregnancy did not differ from those after pregnancy. Thus, hyperinsulinemia observed in pregnancy cannot be explained by a change in the insulin kinetics. It appears improbable that the insulin-degrading enzyme activities of the placenta participate in degradation of insulin circulating in the maternal blood. A connection between the decline of glucose tolerance during pregnancy and the kinetics of exogenous insulin could not be found.
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PMID:Influence of pregnancy on the kinetics of insulin. 114 34

This study compares some properties of the immunoreactive insulin-like material extracted from the urine of children with overt diabetes with that from normal children. Insulin-like species were fractionated by gel filtration and by isoelectric focusing and were tested for sensitivity to an insulin-specific degradative enzyme. Insulin concentration was measured by radioimmunoassay. The major insulin-like component from the urine of ten normal children and fifteen untreated juvenile diabetics and from the urine of four and the serum of one latent diabetics behaved (on gel filtration) as normal insulin, was sensitive to insulinase, and (in all cases studied) had an identical isoelectric point (resolution 0.1 pH units). A proportion of the immunoreactivity extracted from urine (0-4 per cent from normal children, 5-30 per cent from twelve of the thirteen nonobese untreated diabetic children) eluted from the gel filtration column before insulin. This material from diabetic urine was of two size classes, "proinsulin-like" and "mid-insulin," both resistant to degradation by insulinase. Insulinase-resistant immunoreactivity from one patient was analyzed by isoelectric focusing. Urine samples from two obese children with overt diabetes and four children with latent diabetes contained normal proportions (less than 4 per cent) of immunoreactive species larger than insulin. The possible nature and significance of the present insulinase-resistant species are briefly considered.
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PMID:Insulin-like insulinase-resistant material, distinguishable from normal insulin, in juvenile diabetes. 117 3


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