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)

Calcium chloride increased the liver insulinase activity (LIA) in normal rabbits. No significant changes were noted in the plasma insulinlike activity (PILA), serum zinc level (SZ), and pancreatic zinc content (PZ). Insulin elevated PILA, SZ and PZ but did not affect LIA. Calcium chloride enhanced the effect of insulin on PILA, SZ and PZ. However, insulin did not affect the action of calcium chloride on LIA. Tolbutamide raised PILA, inhibited both LIA and SZ but did not affect PZ. Calcium chloride produced no change in the action of tolbutamide on PILA. On the other hand, tolbutamide prevented the rise of PILA obtained by calcium chloride. PZ was unaltered with calcium chloride and tolbutamide combination. Phenformin increased PILA, LIA, SZ and PZ. When it was given with calcium chloride no further changes in PILA and PZ were observed. The elevation of SZ was abolished but the rise of LIA was synergized. In alloxanized rabbits, LIA was decreased by calcium chloride. No changes were found in PILA, SZ and PZ. Insulin elevated PILA, LIA and SZ although it reduced PZ. Calcium chloride stimulated insulin effect on PILA, did not affect its action on SZ or PZ, and antagonized its effect on LIA. Tolbutamide increased LIA and SZ but did not affect PILA or PZ. Calcium chloride could not change the effect of tolbutamide on SZ or PILA although it could abolish the action of this drug on LIA and PZ. Phenformin significantly lowered PILA, LIA and PZ but raised SZ. Calcium chloride combination with phenformin produced a further decrease in LIA but no other changes in PIAL, SZ or PZ were recorded.
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PMID:Effect of calcium chloride on some metabolic actions of certain antidiabetic drugs in normal and alloxanised rabbits. 118 41

The mechanisms of cellular insulin degradation remain uncertain. Considerable evidence now exists that the primary cellular insulin-degrading activity is a metallothiol proteinase. Two similar degrading activities have been purified and characterized. Insulin protease has been purified from rat skeletal muscle and insulin-degrading enzyme from human red blood cells. Whereas the two degrading activities share a number of similar properties, significant differences have also been reported; and it is not at all established that they are the same enzyme. To examine this, we have compared antigenic and catalytic properties of the two enzymatic activities. Monoclonal antibodies against the red blood cell enzyme adsorb the skeletal muscle enzyme; and on Western blots, the antibodies react with an identical 110-kDa protein. Immunoaffinity-purified enzymes from both red blood cells and skeletal muscle degrade [125I]iodo(B26)insulin to the same products as seen with purified insulin protease and with intact liver and kidney. Chelator-treated muscle and red blood cell enzymes can be reactivated with either Mn2+ or Ca2+. Thus, insulin-degrading enzyme and insulin protease have similar properties. These results support the hypothesis that these activities reside in the same enzyme.
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PMID:Human red blood cell insulin-degrading enzyme and rat skeletal muscle insulin protease share antigenic sites and generate identical products from insulin. 168 96

We find, contrary to previous reports, that substantial cleavage of glucagon by insulin proteinase occurs at only one region, namely the double-basic sequence -Arg17-Arg18-. Cleavage takes place almost exclusively between these two residues, liberating fragments glucagon-(1-17) and glucagon-(18-29). Others have shown that the fragment glucagon-(19-29) is 1000-fold more efficient compared with intact glucagon, at inhibiting the Ca2+-activated and Mg2+-dependent ATPase activity and the Ca2+ pump of liver plasma membranes. We show that this fragment is not liberated in detectable quantities by our insulin proteinase preparation. On the other hand, others have shown that glucagon-(18-29), though less active than glucagon-(19-29), was still 100-fold more active than glucagon itself in the above-mentioned system. Our observations represent the first demonstration of the release by insulin proteinase of a hormone fragment having enhanced activity, although it has yet to be shown that the activity of this fragment is important in vivo. Since the formation of glucagon-(19-29) from glucagon-(18-29) would involve merely removal of Arg18, a second enzyme might exist to provide the more active fragment.
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PMID:Insulin proteinase liberates from glucagon a fragment known to have enhanced activity against Ca2+ + Mg2+-dependent ATPase. 297 45

The effect of calcium on insulin degradation by intact or homogenized skeletal muscle, by skeletal muscle cytosol, and by partially purified skeletal muscle insulin-degrading protease activity was examined. After a 15-min lag phase, intact soleus muscles degraded [125I]insulin to trichloroacetic acid-soluble products in a time-dependent fashion. Degradation was accelerated by the addition of calcium (greater than or equal to 1 mM), such that maximal stimulation (2-fold) was obtained with 10 or 25 mM calcium. Calcium stimulated insulin degradation by skeletal muscle homogenate and by cytosol in a nearly identical manner. Furthermore, after inactivation of the purified skeletal muscle, insulin-degrading protease by dialysis against EDTA, this enzyme was reactivated fully (greater than 80%) by a 100 microM concentration of free Ca2+. These observations identify a previously unrecognized but important influence of calcium on cellular insulin handling and provide further evidence for a major role of the calcium-activated enzyme, insulin protease, in cellular insulin degradation.
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PMID:The calcium dependence of insulin degradation by rat skeletal muscle. 392 38

Insulin protease activity has resisted high-yield purification to homogeneity, due to its low amount in tissues, its instability, and its erratic recovery from several types of chromatography. This report outlines the preliminary characterization of a naturally-occurring insulin protease inhibitor that accounts for some of these problems in rat skeletal muscle. In these experiments, inhibitory activity was assayed by its effect upon hydrolysis of 125I-(A14)-insulin by the partially purified insulin protease activity of rat skeletal muscle cytosol. During Sephadex G-200 chromatography of cytosol at pH 7.5, inhibitory activity copurifies with insulin protease activity, and the incomplete resolution of the two activities contributes to the impression that insulin protease exists in distinct 180,000-dalton and 80,000-dalton forms. By contrast, during DEAE-Sephacel chromatography of cytosol at pH 7.5, inhibitory activity and insulin protease activity are resolved by eluting the resin with 50 mM NaCl and 200 mM NaCl, respectively. Post-DEAE-Sephacel inhibitor has an Mr(app) of 67,000 daltons or 80,000-120,000 daltons, as determined by high-performance liquid chromatography or Sephadex G-150 chromatography, respectively. Post-DEAE-Sephacel insulin protease activity exhibits a Km for insulin of 15 nM and resides in a 200,000-dalton neutral thiol protease which requires 50 micromolar calcium for its maximum insulin-degrading activity. The inhibitor reduces the enzyme's activity reversibly, nonprogressively, and non-competitively with respect to insulin, but it does not alter the enzyme's sensitivity to calcium ion. These observations suggest that calcium and an endogenous protease inhibitor may influence cellular degradation of insulin via previously unrecognized effects upon cytosolic insulin protease activity.
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PMID:Partial characterization of an endogenous inhibitor of a calcium-dependent form of insulin protease. 635 96

Insulin protease was purified 700-fold from rat liver homogenate by combined ultracentrifugation, ammonium sulfate fractionation, and glucagon-Sepharose-4B affinity chromatography. Optimum degradation of insulin was observed at pH 7.6 with the purified protease whose Km was 24 nM. The enzyme activity was inhibited completely by N-ethylmaleimide, p-hydroxymercuribenzoate, and heavy metals at 1 mM, whereas at the same concentration glutathione and mercaptoethanol stimulated the protease activity. These results indicate that the catabolic activity of the protease is sulfhydryl dependent. Furthermore, the activity of insulin protease was also enhanced by calcium and other divalent metal ions at a concentration of 1 mM. When supernatants, recovered from rat liver homogenates after centrifugation at 100,000g, were subjected to combined Sepharose 4B-insulin protease affinity chromatography and dialysis, a potent inhibitor of insulin protease was obtained which was heat stable. On the basis of kinetic studies, the inhibition of insulin degradation caused by this inhibitor was of the competitive type. Greater than 90% of the inhibitor activity was retained on dialysis with tubing with an inclusion limit of 3500 Da, whereas only 10% of this activity could be retained in dialysis tubing with an exclusion limit of 15,000 Da. These findings suggest that the insulin protease inhibitor is a low-molecular-weight protein. Analysis of homogenates from 13 different tissues of the rat showed that the highest levels of insulin protease inhibitor activity were associated with those tissues which have the highest capacity to degrade insulin. These data suggest that insulin protease and insulin protease inhibitor may be an important natural regulatory mechanism of insulin activity.
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PMID:Partial purification and characterization of insulin protease and its intracellular inhibitor from rat liver. 636 62

Transtemporal approaches to the petrous apex and CP angle are standard procedures in the armamentarium of the neurotologist. In the majority of these cases, it is not possible to achieve a watertight suture closure of the dura following the procedure. Subsequently, cerebrospinal fluid leakage and potential meningitis are among the most troublesome complications for both patient and surgeon. Recent use of calcium phosphate cement (hydroxyapatite [HA]) has proved efficacious in animal studies and is now being used to close cranial defects in several medical centers, as part of an FDA-IDE study in human subjects. The use of this material is described in 11 neurotologic procedures. It is believed that hydroxyapatite cement (HAC) will become a standard tool in the management of cranial base and temporal bone defects following surgery.
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PMID:Hydroxyapatite cement: a new method for achieving watertight closure in transtemporal surgery. 810 30

The signal transduction of the formyl-Met-Leu-Phe (FMLP) receptor in polymorphonuclear leukocytes (PMNLs) from patients with non-insulin-dependent diabetes mellitus (NIDDM) was compared to that of PMNLs obtained from healthy volunteers. According to our previous studies in this group of patients neither the decrease in insulin binding capacity nor the enhanced insulin-degrading enzyme activity was involved. In control PMNLs, 10 nM FMLP induced a pertussis toxin-sensitive increase in phosphatidyl inositol (PI) cleavage and a subsequent Ca2+ signaling from the intracellular pools. On the other hand, the FMLP-induced protein kinase C (PKC) activation and translocation into the membrane could not be detected in these cells via the measurement of 32P incorporation into histone. In contrast, in PMNLs of this special group of patients suffering from NIDDM the FMLP stimulus produced a significantly low increase in PI cleavage and Ca2+ signaling from the intracellular pools. Moreover, in resting PMNLs of these patients with NIDDM, not only the [Ca2+]i but also the membrane-bound PKC activity was found to be significantly increased. In addition, PKC translocation into the cell membrane of diabetic PMNLs could be further triggered with FMLP as judged by the measurement of 32P incorporation into histone. Based on these results, it appears that the signaling of FMLP receptors in PMNLs of some NIDDM patients may have an alternative pathway through Ca2+ influx from extracellular medium, arachidonic acid cascade, and PKC activation.
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PMID:Altered postreceptor signal transduction of formyl-Met-Leu-Phe receptors in polymorphonuclear leukocytes of patients with non-insulin-dependent diabetes mellitus. 943 1

The insulin-degrading enzyme (IDE) plays an important role in the cellular metabolism of insulin. Recent studies have also suggested a regulatory role for this protein in controlling the activity of cytoplasmic protein complexes, including the proteasome [multicatalytic proteinase (MCP)] and the glucocorticoid and androgen receptors. Binding of IDE to these complexes increases their activity, whereas the addition of substrates for IDE inhibits activity. This provides a potential mechanism of action for internalized insulin and other IDE substrates in the control of protein turnover. To examine further the interactions, partially purified IDE-MCP complex was treated with EDTA or EGTA, and activity was measured in the absence and presence of various divalent cations (Ca2+, Mn2+, Co2+, and Zn2+) and insulin. EDTA treatment reduced MCP activity and eliminated the effect of insulin on the complex. Divalent cations partially or completely restored MCP activity, but did not restore the effect of insulin. EGTA treatment had a lesser effect on MCP activity, but abolished insulin inhibition of activity. Divalent cations restored the insulin effect. Inhibitors of IDE also blocked the insulin effect on MCP activity, as did treatment with SDS. These findings suggest that conformational changes in the complex may play a role in the insulin control of MCP activity.
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PMID:Regulation of multicatalytic enzyme activity by insulin and the insulin-degrading enzyme. 975 83